HDAC4

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004407 histone deacetylase activity	IBA GO_REF:0000033	ACCEPT	Summary: HDAC4 belongs to the class IIa HDAC family and possesses a histone deacetylase catalytic domain. However, due to a conserved Tyr->His substitution in the active site, HDAC4 has markedly reduced intrinsic deacetylase activity toward acetyl-lysine substrates compared to class I HDACs. PMID:11804585 demonstrated that HDAC4 enzymatic activity depends on association with HDAC3/NCoR/SMRT complex. PMID:18614528 provided structural evidence for the low intrinsic activity. Despite limited intrinsic activity, HDAC4 can still deacetylate substrates and the IBA annotation is phylogenetically valid. Reason: While HDAC4 has weak intrinsic deacetylase activity, it is still classified as a histone deacetylase by family membership and does possess measurable deacetylase activity. The IBA annotation correctly reflects the conserved function across the phylogenetic group. Supporting Evidence: PMID:10220385 These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A. PMID:11804585 In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: HDAC4 localizes to the cytoplasm in a phosphorylation-dependent manner. PMID:10869435 demonstrated that 14-3-3 protein binding to phosphorylated HDAC4 results in cytoplasmic sequestration. This localization is dynamic and represents the inactive, sequestered form of the protein. Reason: Cytoplasmic localization of HDAC4 is well-established and represents a core aspect of its regulated nucleocytoplasmic shuttling mechanism. Supporting Evidence: PMID:10869435 The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm.
GO:0040029 epigenetic regulation of gene expression	IBA GO_REF:0000033	ACCEPT	Summary: HDAC4 participates in epigenetic regulation of gene expression through its role in recruiting the HDAC3/NCoR/SMRT complex to transcription factors, leading to histone deacetylation and transcriptional repression. This is a core function of HDAC4 supported by extensive literature. Reason: This annotation correctly captures HDAC4's role in epigenetic regulation, which is a central aspect of its function as a transcriptional corepressor. Supporting Evidence: PMID:11804585 These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.
GO:0000118 histone deacetylase complex	IBA GO_REF:0000033	ACCEPT	Summary: HDAC4 functions as part of multiprotein complexes including the HDAC3/NCoR/SMRT corepressor complex. This is a core aspect of HDAC4 function as it bridges transcription factors to the enzymatically active complex. Reason: The IBA annotation correctly reflects HDAC4's participation in HDAC complexes, which is essential for its corepressor function. Supporting Evidence: PMID:11804585 Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT.
GO:0000122 negative regulation of transcription by RNA polymerase II	IEA GO_REF:0000002	ACCEPT	Summary: This IEA annotation derived from InterPro domain IPR046949 (HDAC4/5/7/9) correctly captures a core function of HDAC4 as a transcriptional corepressor. Reason: HDAC4 negatively regulates transcription of RNA polymerase II-transcribed genes by recruiting HDAC3/NCoR/SMRT corepressor complex to promoters. This is a well-established core function.
GO:0004407 histone deacetylase activity	IEA GO_REF:0000002	ACCEPT	Summary: This IEA annotation from InterPro correctly identifies HDAC4 as having histone deacetylase activity, though intrinsic activity is low for class IIa HDACs. Reason: HDAC4 possesses a histone deacetylase catalytic domain and measurable deacetylase activity, even if weaker than class I HDACs. Duplicate of IBA annotation which is appropriate.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: This IEA annotation from UniProt subcellular location mapping correctly identifies nuclear localization. HDAC4 shuttles between nucleus and cytoplasm, and nuclear localization is required for its transcriptional repression function. Reason: Nuclear localization is well-established for HDAC4 and represents the active localization where HDAC4 represses transcription via MEF2 and other transcription factors.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: This IEA annotation from UniProt subcellular location correctly identifies cytoplasmic localization. HDAC4 is sequestered in the cytoplasm when phosphorylated and bound to 14-3-3 proteins. Reason: Cytoplasmic localization is well-established as part of HDAC4's regulated nucleocytoplasmic shuttling mechanism. Duplicate of IBA annotation which is appropriate.
GO:0006325 chromatin organization	IEA GO_REF:0000043	ACCEPT	Summary: This IEA annotation from UniProt keyword mapping correctly identifies involvement in chromatin organization via histone deacetylation activity. Reason: HDAC4 participates in chromatin organization through its role in recruiting the HDAC3/NCoR/SMRT complex which deacetylates histones, affecting chromatin structure.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: This IEA annotation is too general. HDAC4 has hydrolase activity as a deacetylase (EC 3.5.1.98), but the more specific terms histone deacetylase activity or protein lysine deacetylase activity are already annotated. Reason: While technically correct, this annotation is too broad and uninformative. More specific deacetylase activity terms are already annotated.
GO:0033558 protein lysine deacetylase activity	IEA GO_REF:0000117	ACCEPT	Summary: This IEA annotation from ARBA correctly identifies HDAC4's protein lysine deacetylase activity. HDAC4 can deacetylate non-histone substrates including Hsp70 (HSPA1A/B). Reason: HDAC4 has documented protein lysine deacetylase activity toward non-histone substrates. UniProt notes HDAC4 deacetylates HSPA1A/B at Lys-77 (PMID:27708256).
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: This IEA annotation correctly identifies metal ion binding. HDAC4 binds zinc ions - both in the catalytic site (required for deacetylase activity) and in a regulatory structural zinc-binding domain (PMID:18614528). Reason: HDAC4 binds zinc ions required for catalytic function and structural integrity. More specific terms like zinc ion binding are also annotated.
GO:0140297 DNA-binding transcription factor binding	IEA GO_REF:0000117	ACCEPT	Summary: This IEA annotation correctly captures a core function of HDAC4 - binding to DNA-binding transcription factors such as MEF2, HIF-1alpha, and Sp1. This is well-supported by extensive experimental evidence. Reason: This annotation accurately reflects HDAC4's function as a transcriptional coregulator that operates through binding to DNA-binding transcription factors. Multiple publications demonstrate HDAC4 interaction with transcription factors including MEF2A/C/D, HIF-1alpha, Sp1, and others.
GO:0141221 histone deacetylase activity, hydrolytic mechanism	IEA GO_REF:0000120	ACCEPT	Summary: This IEA annotation from Rhea reaction database correctly identifies that HDAC4 catalyzes hydrolytic deacetylation (EC 3.5.1.98). This is the mechanistic specification of HDAC activity. Reason: HDAC4 uses a hydrolytic mechanism involving zinc-dependent catalysis to remove acetyl groups from lysine residues.
GO:0005515 protein binding	IPI PMID:10958686 Regulation of histone deacetylase 4 by binding of 14-3-3 pro...	MODIFY	Summary: PMID:10958686 demonstrated HDAC4 interaction with 14-3-3 proteins via phosphorylated serine residues. This interaction regulates HDAC4 subcellular localization. While the interaction is real, protein binding is too generic. Reason: The 14-3-3 interaction is functionally important but would be better captured by a more specific binding term. The interaction with 14-3-3 proteins is already captured in the literature via the phosphoserine binding mechanism. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:11504882 Differential localization of HDAC4 orchestrates muscle diffe...	MODIFY	Summary: PMID:11504882 is about differential localization of HDAC4 during muscle differentiation and demonstrates interactions with 14-3-3 proteins. Protein binding is too generic. Reason: Should be annotated to 14-3-3 protein binding for more specificity. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1...	MODIFY	Summary: PMID:15161933 is a proteomic analysis of 14-3-3 binding proteins identifying HDAC4. Protein binding is too generic for this specific interaction. Reason: Should be annotated to 14-3-3 protein binding for more specificity. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:15194749 Functional interaction between class II histone deacetylases...	KEEP AS NON CORE	Summary: PMID:15194749 describes HDAC4 interaction with HSV-1 ICP0 protein. While technically correct, this is a viral interaction that may not represent core cellular function. Reason: This represents a virus-host interaction with HSV-1 ICP0 protein. While the interaction is documented, it represents pathogen interaction rather than core cellular function.
GO:0005515 protein binding	IPI PMID:15324660 Proteomic, functional, and domain-based analysis of in vivo ...	MODIFY	Summary: PMID:15324660 is about 14-3-3 binding proteins involved in cytoskeletal regulation. HDAC4 interaction with 14-3-3 proteins is documented. Reason: Should be annotated to 14-3-3 protein binding for more specificity. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:15778465 Targeted proteomic analysis of 14-3-3 sigma, a p53 effector ...	MODIFY	Summary: PMID:15778465 is about targeted proteomic analysis of 14-3-3 sigma. HDAC4 interaction with 14-3-3 proteins is documented. Reason: Should be annotated to 14-3-3 protein binding for more specificity. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:15964851 Identification of the ankyrin repeat proteins ANKRA and RFXA...	KEEP AS NON CORE	Summary: PMID:15964851 identifies ANKRA proteins as partners of class IIa HDACs including HDAC4. HDAC4 has a PxLPxI/L motif that mediates interaction with ANKRA2 ankyrin repeats. Reason: This documents HDAC4 interaction with ankyrin repeat proteins. While valid, protein binding is too generic. The interaction is functionally relevant but represents a regulatory interaction.
GO:0005515 protein binding	IPI PMID:16147992 Analysis of BCL6-interacting proteins by tandem mass spectro...	MODIFY	Summary: PMID:16147992 is about BCL6-interacting proteins. HDAC4 interaction with BCL6 is documented. BCL6 is a transcription factor. Reason: HDAC4 binds the transcription factor BCL6. Should use DNA-binding transcription factor binding for specificity. Proposed replacements: DNA-binding transcription factor binding
GO:0005515 protein binding	IPI PMID:16166628 Regulation of MEF2 by histone deacetylase 4- and SIRT1 deace...	MODIFY	Summary: PMID:16166628 describes regulation of MEF2 by HDAC4 and SIRT1-mediated lysine modifications. HDAC4-MEF2 interaction is a core function. Reason: HDAC4-MEF2 interaction is a core function. Should use DNA-binding transcription factor binding for specificity. Proposed replacements: DNA-binding transcription factor binding
GO:0005515 protein binding	IPI PMID:16767219 CaM kinase II selectively signals to histone deacetylase 4 d...	MODIFY	Summary: PMID:16767219 shows CaMKII signals to HDAC4 during cardiomyocyte hypertrophy. Documents interaction with 14-3-3 proteins. Reason: Should be annotated to 14-3-3 protein binding for more specificity. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:16919237 Breast cancer metastasis suppressor 1 (BRMS1) is stabilized ...	KEEP AS NON CORE	Summary: PMID:16919237 describes BRMS1 stabilization by Hsp90 chaperone. HDAC4 interaction with BRMS1 documented. Reason: HDAC4-BRMS1 interaction is documented but protein binding is too generic. This represents a regulatory interaction.
GO:0005515 protein binding	IPI PMID:17159145 Epstein-Barr nuclear antigen leader protein coactivates tran...	KEEP AS NON CORE	Summary: PMID:17159145 describes EBNA-LP coactivation through HDAC4 interaction. This is a viral protein interaction. Reason: This represents a virus-host interaction with EBV EBNA-LP. While documented, it is not a core cellular function.
GO:0005515 protein binding	IPI PMID:17353931 Large-scale mapping of human protein-protein interactions by...	KEEP AS NON CORE	Summary: PMID:17353931 is a large-scale protein-protein interaction study by mass spectrometry. Documents HDAC4 interactions. Reason: High-throughput interaction study. The specific interactors should be captured by more specific binding terms where known.
GO:0005515 protein binding	IPI PMID:17979178 A novel tandem affinity purification strategy for the effici...	MODIFY	Summary: PMID:17979178 uses tandem affinity purification to identify protein complexes. Documents HDAC4 interactions with 14-3-3 proteins. Reason: Should be annotated to 14-3-3 protein binding for more specificity. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:18045992 PP2A regulates HDAC4 nuclear import.	MODIFY	Summary: PMID:18045992 describes PP2A regulation of HDAC4 nuclear import. Documents interaction with 14-3-3 proteins and PP2A. Reason: Should be annotated to 14-3-3 protein binding or phosphatase binding for more specificity. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:18163532 Impaired placental trophoblast lineage differentiation in Al...	KEEP AS NON CORE	Summary: PMID:18163532 describes placental trophoblast differentiation and HDAC4 interaction with DNAJB6. Reason: Documents HDAC4-DNAJB6 interaction which may be relevant in specific developmental contexts.
GO:0005515 protein binding	IPI PMID:20116378 JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruit...	MODIFY	Summary: PMID:20116378 describes JNK-ATF-2 inhibition of thrombomodulin expression via HDAC4 recruitment. Documents HDAC4-ATF2 interaction. Reason: ATF2 is a transcription factor. Should use DNA-binding transcription factor binding for specificity. Proposed replacements: DNA-binding transcription factor binding
GO:0005515 protein binding	IPI PMID:20936779 A human MAP kinase interactome.	KEEP AS NON CORE	Summary: PMID:20936779 is a human MAP kinase interactome study. Documents HDAC4 interactions. Reason: High-throughput interaction study. Protein binding is too generic.
GO:0005515 protein binding	IPI PMID:21242980 Inhibition of androgen receptor activity by histone deacetyl...	MODIFY	Summary: PMID:21242980 describes HDAC4 inhibition of androgen receptor activity through SUMOylation. Documents HDAC4-AR interaction. Reason: Androgen receptor is a transcription factor. Should use nuclear receptor binding or transcription factor binding. Proposed replacements: nuclear hormone receptor binding
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	KEEP AS NON CORE	Summary: PMID:21988832 is a study toward understanding the human liver protein interaction network. Reason: High-throughput interaction study. Protein binding is too generic.
GO:0005515 protein binding	IPI PMID:23752268 The functional interactome landscape of the human histone de...	KEEP AS NON CORE	Summary: PMID:23752268 is a functional interactome landscape of the human HDAC family. Documents multiple HDAC4 interactions. Reason: Large-scale HDAC interactome study. The specific interactions should be captured by more specific terms.
GO:0005515 protein binding	IPI PMID:24229708 Runx3 inactivation is a crucial early event in the developme...	MODIFY	Summary: PMID:24229708 describes RUNX3 inactivation in lung adenocarcinoma and HDAC4-RUNX3 interaction. Reason: RUNX3 is a transcription factor. Should use DNA-binding transcription factor binding for specificity. Proposed replacements: DNA-binding transcription factor binding
GO:0005515 protein binding	IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r...	KEEP AS NON CORE	Summary: PMID:24255178 is a protein interaction network study of the mammalian Hippo pathway. Documents HDAC4 interactions. Reason: Pathway-focused interaction study. Protein binding is too generic.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: PMID:25416956 is a proteome-scale map of the human interactome. High-throughput study documenting many HDAC4 interactions. Reason: Large-scale interactome study. Protein binding is too generic for the specific interactions documented.
GO:0005515 protein binding	IPI PMID:26496610 A human interactome in three quantitative dimensions organiz...	KEEP AS NON CORE	Summary: PMID:26496610 is a human interactome study organized by stoichiometries and abundances. Reason: High-throughput interaction study. Protein binding is too generic.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: PMID:28514442 describes architecture of the human interactome defining protein communities. Reason: High-throughput interaction study. Protein binding is too generic.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: PMID:33961781 is a dual proteome-scale network study revealing cell-specific remodeling. Reason: High-throughput interaction study. Protein binding is too generic.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	KEEP AS NON CORE	Summary: PMID:35271311 (OpenCell) is an endogenous tagging study for human cellular organization. Reason: High-throughput localization and interaction study. Protein binding is too generic.
GO:0005515 protein binding	IPI PMID:36931259 A central chaperone-like role for 14-3-3 proteins in human c...	MODIFY	Summary: PMID:36931259 describes central chaperone-like role for 14-3-3 proteins. Documents HDAC4-14-3-3 interaction. Reason: Should be annotated to 14-3-3 protein binding for more specificity. Proposed replacements: 14-3-3 protein binding
GO:0005515 protein binding	IPI PMID:39251607 Systematic identification of post-transcriptional regulatory...	KEEP AS NON CORE	Summary: PMID:39251607 is about systematic identification of post-transcriptional regulatory modules. Reason: High-throughput study. Protein binding is too generic.
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: PMID:40205054 is about multimodal cell maps as a foundation for structural and functional genomics. Reason: High-throughput study. Protein binding is too generic.
GO:0042802 identical protein binding	IPI PMID:17360518 Crystal structure of a conserved N-terminal domain of histon...	ACCEPT	Summary: PMID:17360518 describes the crystal structure of a conserved N-terminal domain of HDAC4 revealing homodimerization. HDAC4 forms homodimers via its N-terminal glutamine-rich domain. Reason: HDAC4 homodimerization is well-documented and functionally relevant. The crystal structure confirms the structural basis for this interaction.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	ACCEPT	Summary: This IDA annotation from HPA immunofluorescence data correctly identifies nucleoplasm localization. HDAC4 localizes to the nucleoplasm when nuclear, where it represses transcription. Reason: Nucleoplasm localization is consistent with HDAC4's function as a transcriptional corepressor when in the nucleus.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: This IDA annotation from HPA immunofluorescence data correctly identifies cytosol localization. HDAC4 is sequestered in the cytosol when phosphorylated and bound to 14-3-3 proteins. Reason: Cytosolic localization is consistent with HDAC4's regulated nucleocytoplasmic shuttling.
GO:0016607 nuclear speck	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: This IDA annotation from HPA immunofluorescence data identifies nuclear speck localization. This may represent a subpopulation of nuclear HDAC4. Reason: Nuclear speck localization may be observed under certain conditions but does not represent the primary functional localization of HDAC4.
GO:0016925 protein sumoylation	TAS Reactome:R-HSA-3108232	ACCEPT	Summary: This Reactome annotation correctly identifies HDAC4 involvement in protein SUMOylation. HDAC4 is itself SUMOylated at K559 and also has SUMO E3 ligase activity. Reason: HDAC4 is involved in SUMOylation both as a substrate (SUMOylated at K559 by RANBP2) and as an E3 ligase that promotes SUMOylation of other proteins like LXR and AR.
GO:0061084 negative regulation of protein refolding	IDA PMID:27708256 ARD1-mediated Hsp70 acetylation balances stress-induced prot...	KEEP AS NON CORE	Summary: PMID:27708256 demonstrates that HDAC4 deacetylates Hsp70 (HSPA1A/B) at Lys-77, which shifts Hsp70 toward STUB1 binding and protein degradation rather than refolding. This is a documented non-histone substrate function. Reason: This represents a specific non-histone deacetylation function of HDAC4. While experimentally validated, it is not the core transcriptional corepressor function.
GO:0033558 protein lysine deacetylase activity	IDA PMID:18614528 Structural and functional analysis of the human HDAC4 cataly...	ACCEPT	Summary: PMID:18614528 provides structural and functional analysis of the HDAC4 catalytic domain. While demonstrating low intrinsic activity toward acetylated lysines, HDAC4 does possess measurable protein lysine deacetylase activity. Reason: HDAC4 has documented protein lysine deacetylase activity, albeit weaker than class I HDACs. The structural study provides mechanistic insight into this activity. Supporting Evidence: PMID:18614528 To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated.
GO:0045814 negative regulation of gene expression, epigenetic	IDA PMID:18614528 Structural and functional analysis of the human HDAC4 cataly...	ACCEPT	Summary: PMID:18614528 demonstrates that HDAC4 is involved in epigenetic gene regulation through its role in deacetylase complexes. The structural zinc-binding domain regulates association with NCoR/HDAC3 complex. Reason: HDAC4 negatively regulates gene expression through epigenetic mechanisms by recruiting the HDAC3/NCoR/SMRT complex to chromatin. Supporting Evidence: PMID:18614528 either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR.HDAC3 repressor complex.
GO:0033558 protein lysine deacetylase activity	TAS Reactome:R-HSA-8952069	ACCEPT	Summary: This Reactome annotation for HDAC4 deacetylation of RUNX3 correctly identifies protein lysine deacetylase activity toward a non-histone substrate. Reason: HDAC4 has documented protein lysine deacetylase activity toward RUNX3 as captured in Reactome pathway.
GO:0001216 DNA-binding transcription activator activity	IDA PMID:19071119 Transcriptional activation of hypoxia-inducible factor-1alph...	MODIFY	Summary: PMID:19071119 shows HDAC4 enhances HIF-1alpha transactivation by physically associating with HIF-1alpha and promoting dissociation from FIH-1 while increasing binding to p300. This is coactivator activity, not direct DNA-binding transcription factor activity. HDAC4 lacks any known sequence-specific DNA-binding domain and functions via protein-protein interactions with DNA-binding transcription factors. Reason: The annotation to GO:0001216 (DNA-binding transcription activator activity) is incorrect. GO:0003700 usage guidance explicitly states that proteins with enzymatic activity (like histone deacetylases) and no known DNA binding domain should be annotated to GO:0003712 (transcription coregulator activity) instead. PMID:19071119 demonstrates HDAC4 acts through protein-protein interactions with HIF-1alpha, promoting its transactivation by competing with FIH-1 binding and enhancing p300 recruitment - this is the mechanism of a transcription coactivator, not a DNA-binding transcription factor. Proposed replacements: transcription coactivator activity Supporting Evidence: PMID:19071119 HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1). In the presence of these HDACs, binding of HIF-1alpha to FIH-1 decreased, whereas binding to p300 increased. These results indicate that HDAC4 and HDAC5 increase the transactivation function of HIF-1alpha by promoting dissociation of HIF-1alpha from FIH-1 and association with p300. PMID:11804585 These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.
GO:0005515 protein binding	IPI PMID:19071119 Transcriptional activation of hypoxia-inducible factor-1alph...	MODIFY	Summary: PMID:19071119 demonstrates HDAC4 physically associates with HIF-1alpha. While the annotation captures a real interaction, the GO term 'protein binding' is too generic and uninformative. Reason: This annotation is correct but the term is too vague. GO curation guidelines recommend using more specific binding terms when the nature of the interaction is known. The interaction with HIF-1alpha should be captured by GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), which is already annotated. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:19071119 HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1).
GO:0019789 SUMO transferase activity	EXP PMID:17218271 Parallel SUMOylation-dependent pathways mediate gene- and si...	ACCEPT	Summary: PMID:17218271 describes parallel SUMOylation-dependent pathways mediated by LXRs and PPARgamma. HDAC4 has been shown to function as a SUMO E3 ligase, promoting SUMOylation of nuclear receptors including LXR and AR. Reason: HDAC4 has documented SUMO E3 ligase activity, functioning to promote SUMOylation of transcription factors. This represents a non-deacetylase enzymatic function.
GO:0010944 negative regulation of transcription by competitive promoter binding	IMP PMID:19276356 FOXP3 up-regulates p21 expression by site-specific inhibitio...	KEEP AS NON CORE	Summary: PMID:19276356 describes FOXP3 up-regulation of p21 by inhibiting HDAC2/HDAC4 association to the locus. The study shows HDAC4 competes for promoter binding to regulate transcription. Reason: This mechanism of competitive promoter binding is documented for specific contexts but represents a specialized regulatory mechanism rather than the core corepressor function.
GO:0042393 histone binding	IDA PMID:19276356 FOXP3 up-regulates p21 expression by site-specific inhibitio...	ACCEPT	Summary: PMID:19276356 demonstrates HDAC4 association with histones at the p21 promoter in the context of transcriptional regulation. Reason: HDAC4 binds to histones as part of its function in chromatin-mediated transcriptional repression. The contributes_to qualifier is appropriate.
GO:0004407 histone deacetylase activity	IDA PMID:12590135 The histone deacetylase 9 gene encodes multiple protein isof...	ACCEPT	Summary: PMID:12590135 describes HDAC9 isoforms and provides evidence for class IIa HDAC activity. HDAC4 histone deacetylase activity is documented. Reason: HDAC4 possesses histone deacetylase activity, though weak intrinsically. This IDA evidence supports the annotation.
GO:0045814 negative regulation of gene expression, epigenetic	IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona...	ACCEPT	Summary: PMID:10869435 demonstrates HDAC4/5 regulate transcriptional activity through 14-3-3 dependent cellular localization. Nuclear HDAC4 represses gene expression epigenetically. Reason: This is a core function of HDAC4 - when nuclear, it represses gene expression through epigenetic mechanisms. Supporting Evidence: PMID:10869435 Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression.
GO:0045814 negative regulation of gene expression, epigenetic	IMP PMID:18850004 HDAC4 represses p21(WAF1/Cip1) expression in human cancer ce...	ACCEPT	Summary: PMID:18850004 demonstrates HDAC4 repression of p21 expression through Sp1-dependent, p53-independent mechanism. HDAC4 reduces histone H3 acetylation at the p21 promoter. Reason: This study demonstrates HDAC4-mediated epigenetic repression at a specific target gene (p21), supporting the core corepressor function.
GO:0045814 negative regulation of gene expression, epigenetic	IMP PMID:24413532 Differential regulation of estrogen receptor α expression in...	ACCEPT	Summary: PMID:24413532 describes MTA1-mediated epigenetic regulation of ESR1 expression involving HDAC4. HDAC4 is part of the MTA1 complex regulating estrogen receptor expression. Reason: This study demonstrates HDAC4 involvement in epigenetic regulation of ESR1 expression, consistent with its corepressor function.
GO:0005515 protein binding	IPI PMID:33537682 Missense substitutions at a conserved 14-3-3 binding site in...	MODIFY	Summary: PMID:33537682 identifies missense substitutions at a conserved 14-3-3 binding site in HDAC4 causing intellectual disability. Documents HDAC4-YWHAB interaction. Reason: HDAC4-14-3-3 (YWHAB) interaction is specifically documented. Should use 14-3-3 protein binding for specificity. Proposed replacements: 14-3-3 protein binding
GO:0000785 chromatin	IDA PMID:31127039 Histone deacetylase 4 promotes type I interferon signaling, ...	ACCEPT	Summary: PMID:31127039 demonstrates HDAC4 promotes type I interferon signaling and is active in chromatin context. HDAC4 associates with chromatin to regulate gene expression. Reason: HDAC4 localizes to chromatin as part of its function in transcriptional regulation. The is_active_in qualifier is appropriate.
GO:0060090 molecular adaptor activity	IDA PMID:31127039 Histone deacetylase 4 promotes type I interferon signaling, ...	ACCEPT	Summary: PMID:31127039 demonstrates HDAC4 functions as a molecular adaptor in type I interferon signaling. This is consistent with HDAC4's known function as a bridging factor between transcription factors and corepressor complexes. Reason: HDAC4's function as a molecular adaptor/scaffold is a core aspect of its mechanism. It bridges transcription factors to the HDAC3/NCoR/SMRT complex. Supporting Evidence: PMID:11804585 These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.
GO:0060337 type I interferon-mediated signaling pathway	IDA PMID:31127039 Histone deacetylase 4 promotes type I interferon signaling, ...	KEEP AS NON CORE	Summary: PMID:31127039 demonstrates HDAC4 promotes type I interferon signaling and restricts DNA viruses. HDAC4 is degraded by vaccinia virus protein C6. Reason: This represents HDAC4's role in antiviral innate immunity. While experimentally validated, this is a context-specific function rather than the core transcriptional corepressor role.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4615872	ACCEPT	Summary: Reactome annotation for RANBP2 SUMOylation of HDAC4 with SUMO1 in the nucleoplasm. Reason: Nucleoplasm localization is consistent with HDAC4 function. This reaction occurs in the nuclear compartment.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4615987	ACCEPT	Summary: Reactome annotation for RANBP2 SUMOylation of HDAC4 with SUMO2,3 in the nucleoplasm. Reason: Nucleoplasm localization is consistent with HDAC4 function. Duplicate annotation for different SUMO paralog.
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	IPI PMID:18850004 HDAC4 represses p21(WAF1/Cip1) expression in human cancer ce...	ACCEPT	Summary: PMID:18850004 demonstrates HDAC4 interacts with Sp1, a DNA-binding transcription factor, at the p21 promoter. This annotation correctly captures HDAC4's role as a coregulator that binds transcription factors. Reason: This annotation correctly captures the coregulator function of HDAC4 - it binds to DNA-binding transcription factors (Sp1) rather than binding DNA directly itself. This is consistent with HDAC4's role as a transcriptional corepressor. Supporting Evidence: PMID:18850004 HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1).
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	IPI PMID:19071119 Transcriptional activation of hypoxia-inducible factor-1alph...	ACCEPT	Summary: PMID:19071119 demonstrates HDAC4 physically associates with HIF-1alpha, a DNA-binding transcription factor, through the inhibitory domain (ID). This annotation correctly reflects HDAC4's interaction with DNA-binding transcription factors. Reason: This annotation appropriately captures HDAC4 binding to a DNA-binding transcription factor (HIF-1alpha). This is distinct from and consistent with HDAC4's role as a transcription coregulator rather than a direct DNA-binding protein. Supporting Evidence: PMID:19071119 HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1).
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding	IDA PMID:24413532 Differential regulation of estrogen receptor α expression in...	MODIFY	Summary: PMID:24413532 shows HDAC4 is recruited to the ESR1 promoter region (+146 to +461 bp downstream of the transcription start site) as part of the MTA1 complex containing TFAP2C and IFI16. However, HDAC4 does not possess sequence-specific DNA binding activity - it is recruited via protein-protein interactions with transcription factors. Reason: This annotation incorrectly implies HDAC4 has sequence-specific DNA binding. PMID:24413532 shows HDAC4 is recruited to chromatin through the MTA1-TFAP2C or MTA1-IFI16 complex, not through direct sequence-specific DNA binding. HDAC4 lacks any known DNA-binding domain. The term GO:0000976 (transcription cis-regulatory region binding) with a 'contributes_to' qualifier (which is already annotated from PMID:18850004) is more appropriate as it allows for indirect recruitment to chromatin. Proposed replacements: transcription cis-regulatory region binding Supporting Evidence: PMID:24413532 In both MCF7 and MDA-MB-231, MTA1 was recruited to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315). Proteomics analysis of the MTA1 complex that was pulled down by an oligonucleotide encoding ERpro315 revealed that the transcription factor AP-2gamma (TFAP2C) and the IFN-gamma-inducible protein 16 (IFI16) were components of the complex.
GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding	IPI PMID:23867755 Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in t...	ACCEPT	Summary: PMID:23867755 demonstrates HDAC4/5 involvement in placental cell fusion through the Epac1/Rap1/CaMKI signaling cascade. The annotation shows HDAC4 binding to MEF2 (a DNA-binding transcription factor). Reason: This annotation correctly captures HDAC4's well-established interaction with MEF2 transcription factors. HDAC4's interaction with MEF2 family members is a core aspect of its function as a transcriptional coregulator. Supporting Evidence: PMID:23867755 Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in the regulation of placental cell fusion
GO:0005515 protein binding	IPI PMID:22649097 Sequence-specific recognition of a PxLPxI/L motif by an anky...	KEEP AS NON CORE	Summary: PMID:22649097 describes the crystal structure of HDAC4 PxLPxI/L motif bound to ANKRA2 ankyrin repeats. This is a specific protein-protein interaction. Reason: Documents specific HDAC4-ANKRA2 interaction through the PxLPxI/L motif. Protein binding is too generic but the interaction is regulatory.
GO:0005634 nucleus	IDA PMID:26019235 Epigenetic changes as a common trigger of muscle weakness in...	ACCEPT	Summary: PMID:26019235 describes epigenetic changes in congenital myopathies and shows HDAC4 nuclear localization. Reason: Nuclear localization of HDAC4 is consistent with its function as a transcriptional corepressor.
GO:0005515 protein binding	IPI PMID:27708256 ARD1-mediated Hsp70 acetylation balances stress-induced prot...	MODIFY	Summary: PMID:27708256 describes HDAC4 interaction with Hsp70 (HSPA1A/B). HDAC4 deacetylates Hsp70 at Lys-77. Reason: Documents specific HDAC4-Hsp70 interaction. Should use more specific heat shock protein binding term. Proposed replacements: protein homodimerization activity
GO:0005634 nucleus	IDA PMID:23867755 Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in t...	ACCEPT	Summary: PMID:23867755 demonstrates HDAC4 nuclear localization in the context of placental cell fusion regulation. Reason: Nuclear localization is consistent with HDAC4's function in transcriptional regulation.
GO:0000122 negative regulation of transcription by RNA polymerase II	IGI PMID:15743821 PC4 coactivates MyoD by relieving the histone deacetylase 4-...	ACCEPT	Summary: PMID:15743821 describes PC4 coactivation of MyoD by relieving HDAC4-mediated inhibition of MEF2C. HDAC4 inhibits MEF2C-dependent transcription. Reason: This IGI annotation correctly captures HDAC4's role in negative regulation of transcription through its interaction with MEF2C.
GO:0005515 protein binding	IPI PMID:24413532 Differential regulation of estrogen receptor α expression in...	KEEP AS NON CORE	Summary: PMID:24413532 documents HDAC4 interaction with EP300 in the context of ESR1 regulation. This interaction is with a transcriptional coactivator. Reason: Documents HDAC4-EP300 interaction. Protein binding is too generic but the interaction is relevant to transcriptional regulation.
GO:0005515 protein binding	IPI PMID:11463856 The orphan nuclear receptor TR2 interacts directly with both...	MODIFY	Summary: PMID:11463856 describes HDAC4 interaction with the orphan nuclear receptor TR2 (NR2C1). Reason: TR2/NR2C1 is a nuclear hormone receptor. Should use nuclear hormone receptor binding for specificity. Proposed replacements: nuclear hormone receptor binding
GO:0005515 protein binding	IPI PMID:11804585 Enzymatic activity associated with class II HDACs is depende...	MODIFY	Summary: PMID:11804585 documents HDAC4 interaction with the SMRT/N-CoR corepressor complex and HDAC3. This is the key mechanistic study for HDAC4 function. Reason: Documents the core interaction of HDAC4 with the NCoR corepressor complex. Should use nuclear receptor coactivator activity or corepressor binding. Proposed replacements: transcription corepressor activity
GO:0004407 histone deacetylase activity	IDA PMID:10220385 Three proteins define a class of human histone deacetylases ...	ACCEPT	Summary: PMID:10220385 is the original identification of HDAC4/5/6 as class II HDACs with demonstrated in vitro deacetylase activity inhibited by trichostatin A. Reason: This is the foundational study identifying HDAC4 as a histone deacetylase. The in vitro deacetylase activity is documented. Supporting Evidence: PMID:10220385 These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A.
GO:0042826 histone deacetylase binding	IPI PMID:12590135 The histone deacetylase 9 gene encodes multiple protein isof...	ACCEPT	Summary: PMID:12590135 describes HDAC9 isoforms and documents interactions between class IIa HDACs. HDAC4 binds to other HDACs including HDAC9. Reason: HDAC4 binds to other class IIa HDACs. This interaction is relevant to HDAC complex formation.
GO:0014898 cardiac muscle hypertrophy in response to stress	TAS PMID:17011572 Class II HDACs mediate CaMK-dependent signaling to NRSF in v...	KEEP AS NON CORE	Summary: PMID:17011572 describes CaMK-dependent signaling through class II HDACs to NRSF in ventricular myocytes. HDAC4 is involved in cardiac stress response. Reason: This represents HDAC4's role in cardiac muscle hypertrophy, a tissue-specific process. While experimentally validated, it is not the core molecular function.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:16236793 Class II histone deacetylases confer signal responsiveness t...	ACCEPT	Summary: PMID:16236793 describes class II HDACs conferring signal responsiveness to ankyrin-repeat proteins. HDAC4 negatively regulates transcription. Reason: HDAC4's role in negative regulation of transcription is a core function, demonstrated in multiple contexts.
GO:0000118 histone deacetylase complex	IDA PMID:11804585 Enzymatic activity associated with class II HDACs is depende...	ACCEPT	Summary: PMID:11804585 demonstrates HDAC4 is part of a multiprotein complex containing HDAC3 and SMRT/N-CoR. This is the definitive study on HDAC4 complex formation. Reason: HDAC4 functions as part of the HDAC3/NCoR/SMRT complex. This is a core aspect of its mechanism. Supporting Evidence: PMID:11804585 Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT.
GO:0000976 transcription cis-regulatory region binding	IDA PMID:18850004 HDAC4 represses p21(WAF1/Cip1) expression in human cancer ce...	ACCEPT	Summary: PMID:18850004 shows HDAC4 binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21 proximal promoter. The annotation has 'contributes_to' qualifier in the GOA file, which appropriately reflects that HDAC4 is recruited to chromatin through interaction with Sp1 rather than through direct sequence-specific DNA binding. Reason: The 'contributes_to' qualifier is appropriate here because HDAC4 is recruited to the p21 promoter through its interaction with Sp1/Sp3, not through direct sequence-specific DNA binding. This is consistent with its function as a coregulator. Supporting Evidence: PMID:18850004 HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1).
GO:0010832 negative regulation of myotube differentiation	IMP PMID:10983972 Regulation of skeletal myogenesis by association of the MEF2...	KEEP AS NON CORE	Summary: PMID:10983972 demonstrates that class II HDACs including HDAC4 suppress skeletal myogenesis through association with MEF2. HDAC4 negatively regulates myotube differentiation. Reason: This represents HDAC4's role in muscle differentiation, a tissue-specific developmental process. While experimentally validated and important, it is a physiological outcome of the core transcriptional corepressor function.
GO:0140297 DNA-binding transcription factor binding	IPI PMID:10983972 Regulation of skeletal myogenesis by association of the MEF2...	ACCEPT	Summary: PMID:10983972 demonstrates that class II HDACs (including HDAC4) interact with MEF2 transcription factors to regulate skeletal myogenesis. HDAC4 does not interact directly with MyoD but suppresses its myogenic activity through association with MEF2. Reason: This annotation correctly captures HDAC4's interaction with MEF2 transcription factors. This is a core function of HDAC4 in regulating muscle differentiation. Supporting Evidence: PMID:10983972 These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:18850004 HDAC4 represses p21(WAF1/Cip1) expression in human cancer ce...	ACCEPT	Summary: PMID:18850004 demonstrates HDAC4 represses p21 expression through Sp1-dependent mechanism. HDAC4 reduces transcription at the p21 promoter. Reason: Negative regulation of transcription is a core function of HDAC4. This study demonstrates the mechanism at a specific target gene.
GO:0006338 chromatin remodeling	IDA PMID:18850004 HDAC4 represses p21(WAF1/Cip1) expression in human cancer ce...	ACCEPT	Summary: PMID:18850004 shows HDAC4 reduces histone H3 acetylation at the p21 promoter, contributing to chromatin remodeling. Reason: HDAC4 participates in chromatin remodeling through its role in histone deacetylation and recruitment of the HDAC3/NCoR complex.
GO:0008270 zinc ion binding	IDA PMID:18614528 Structural and functional analysis of the human HDAC4 cataly...	ACCEPT	Summary: PMID:18614528 provides structural evidence that HDAC4 binds zinc ions both in the catalytic site and in a structural zinc-binding domain. Reason: HDAC4 binds zinc ions required for both catalytic activity and structural integrity. This is documented in the crystal structure. Supporting Evidence: PMID:18614528 these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes.
GO:0008284 positive regulation of cell population proliferation	IMP PMID:18850004 HDAC4 represses p21(WAF1/Cip1) expression in human cancer ce...	KEEP AS NON CORE	Summary: PMID:18850004 shows HDAC4 repression of p21 leads to positive regulation of cell proliferation in cancer cells. Reason: This represents a downstream consequence of HDAC4's transcriptional repressor function (repressing the cell cycle inhibitor p21), not a core molecular function.
GO:0017053 transcription repressor complex	IDA PMID:11804585 Enzymatic activity associated with class II HDACs is depende...	ACCEPT	Summary: PMID:11804585 demonstrates HDAC4 is part of a transcription repressor complex containing HDAC3 and SMRT/N-CoR. Reason: HDAC4 is a component of the HDAC3/NCoR/SMRT transcription repressor complex. This is a core aspect of its mechanism. Supporting Evidence: PMID:11804585 Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT.
GO:0030955 potassium ion binding	IDA PMID:18614528 Structural and functional analysis of the human HDAC4 cataly...	KEEP AS NON CORE	Summary: PMID:18614528 identifies potassium ion binding in the HDAC4 catalytic domain structure. Potassium may play a role in catalysis. Reason: While potassium binding is structurally documented, it is not central to HDAC4's primary function as a transcriptional corepressor.
GO:0045944 positive regulation of transcription by RNA polymerase II	IMP PMID:19071119 Transcriptional activation of hypoxia-inducible factor-1alph...	ACCEPT	Summary: PMID:19071119 demonstrates that HDAC4 enhances HIF-1alpha transactivation function, resulting in positive regulation of transcription. This is achieved through a coactivator mechanism where HDAC4 competes with FIH-1 for binding to HIF-1alpha and promotes p300 recruitment. Reason: This BP annotation is appropriate and consistent with the mechanism shown in PMID:19071119. While HDAC4 is primarily known as a transcriptional corepressor (via its deacetylase activity), this study demonstrates it can also act as a coactivator for HIF-1alpha-mediated transcription through a deacetylase-independent mechanism. Supporting Evidence: PMID:19071119 HDAC4 and HDAC5 enhanced transactivation by HIF-1alpha without stabilizing HIF-1alpha... These results indicate that HDAC4 and HDAC5 increase the transactivation function of HIF-1alpha by promoting dissociation of HIF-1alpha from FIH-1 and association with p300.
GO:0140297 DNA-binding transcription factor binding	IPI PMID:11804585 Enzymatic activity associated with class II HDACs is depende...	ACCEPT	Summary: PMID:11804585 shows HDAC4 interacts with the SMRT/N-CoR corepressor complex and bridges it to select transcription factors. This study explicitly demonstrates that class II HDACs function by bridging enzymatically active complexes to transcription factors. Reason: This annotation correctly captures HDAC4's role in bridging corepressor complexes to transcription factors. This study is key evidence that HDAC4 is a coregulator, not a DNA-binding transcription factor. Supporting Evidence: PMID:11804585 These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.
GO:0000122 negative regulation of transcription by RNA polymerase II	IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona...	ACCEPT	Summary: PMID:10869435 demonstrates that nuclear HDAC4/5 interact with HDAC3 and repress gene expression. This is the foundational study on HDAC4 nucleocytoplasmic shuttling and transcriptional repression. Reason: Negative regulation of transcription is a core function of HDAC4. Supporting Evidence: PMID:10869435 Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression.
GO:0000122 negative regulation of transcription by RNA polymerase II	IMP PMID:19276356 FOXP3 up-regulates p21 expression by site-specific inhibitio...	ACCEPT	Summary: PMID:19276356 demonstrates HDAC4 involvement in p21 transcriptional regulation through competition with FOXP3 at the promoter. Reason: This IMP annotation correctly captures HDAC4's role in negative regulation of transcription.
GO:0004407 histone deacetylase activity	IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona...	ACCEPT	Summary: PMID:10869435 demonstrates HDAC4 possesses histone deacetylase activity. While intrinsic activity is low for class IIa HDACs, the activity is documented. Reason: HDAC4 histone deacetylase activity is documented in this foundational study.
GO:0005515 protein binding	IPI PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona...	MODIFY	Summary: PMID:10869435 documents HDAC4 interaction with 14-3-3 proteins and HDAC3. Multiple specific interactions are documented. Reason: Should be annotated to 14-3-3 protein binding or histone deacetylase binding for specificity. Proposed replacements: 14-3-3 protein binding
GO:0005634 nucleus	IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona...	ACCEPT	Summary: PMID:10869435 demonstrates HDAC4 nuclear localization, which is required for its transcriptional repressor function. Reason: Nuclear localization is consistent with HDAC4's function as a transcriptional corepressor.
GO:0005737 cytoplasm	IDA PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona...	ACCEPT	Summary: PMID:10869435 demonstrates HDAC4 cytoplasmic localization when bound to 14-3-3 proteins. Reason: Cytoplasmic localization is part of HDAC4's regulated nucleocytoplasmic shuttling. Supporting Evidence: PMID:10869435 The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm.
GO:0014894 response to denervation involved in regulation of muscle adaptation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: This ISS annotation inferred from mouse HDAC4 ortholog reflects the role of HDAC4 in muscle adaptation processes. Reason: This represents a tissue-specific physiological process. While supported by ortholog evidence, it is not the core molecular function.
GO:0042826 histone deacetylase binding	IPI PMID:10869435 Regulation of histone deacetylase 4 and 5 and transcriptiona...	ACCEPT	Summary: PMID:10869435 demonstrates HDAC4 interaction with HDAC3 in the nucleus. Reason: HDAC4-HDAC3 interaction is a core aspect of HDAC4's mechanism as part of the NCoR/SMRT complex. Supporting Evidence: PMID:10869435 Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression.
GO:0045820 negative regulation of glycolytic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: This ISS annotation inferred from mouse HDAC4 ortholog reflects metabolic regulatory functions. Reason: This represents a metabolic regulatory function that is downstream of the core transcriptional corepressor activity.
GO:0045893 positive regulation of DNA-templated transcription	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: This ISS annotation from mouse HDAC4 reflects that HDAC4 can also positively regulate transcription in certain contexts. Reason: While HDAC4 is primarily a corepressor, it can act as a coactivator in specific contexts like HIF-1alpha regulation.
GO:0045944 positive regulation of transcription by RNA polymerase II	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: This ISS annotation from mouse HDAC4 reflects coactivator function in specific contexts. Reason: Context-specific coactivator function as seen with HIF-1alpha. Not the primary function.
GO:0005634 nucleus	IDA PMID:19281832 Activation of ROS/NF-kappaB and Ca2+/CaM kinase II are neces...	ACCEPT	Summary: PMID:19281832 demonstrates HDAC4 nuclear localization in the context of IL-1beta signaling. Reason: Nuclear localization is consistent with HDAC4's function.
GO:0005737 cytoplasm	IDA PMID:19281832 Activation of ROS/NF-kappaB and Ca2+/CaM kinase II are neces...	ACCEPT	Summary: PMID:19281832 demonstrates HDAC4 cytoplasmic localization in the context of IL-1beta signaling. Reason: Cytoplasmic localization is part of regulated shuttling.
GO:0070555 response to interleukin-1	IMP PMID:19281832 Activation of ROS/NF-kappaB and Ca2+/CaM kinase II are neces...	KEEP AS NON CORE	Summary: PMID:19281832 describes HDAC4 involvement in IL-1beta signaling leading to VCAM-1 induction in tracheal smooth muscle cells. Reason: This represents a context-specific signaling response. While experimentally validated, it is not the core molecular function.
GO:0033235 positive regulation of protein sumoylation	IDA PMID:17696781 Sumoylation of the zinc finger protein ZXDC enhances the fun...	ACCEPT	Summary: PMID:17696781 describes HDAC4's role in enhancing SUMOylation of ZXDC, consistent with its SUMO E3 ligase activity. Reason: HDAC4 has documented SUMO E3 ligase activity that promotes SUMOylation of target proteins.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4720432	ACCEPT	Summary: Reactome annotation for HDAC4 SUMOylation of LXRbeta with SUMO2,3 in the nucleoplasm. Reason: Nucleoplasm localization is consistent with HDAC4's nuclear functions.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-4720446	ACCEPT	Summary: Reactome annotation for HDAC4 SUMOylation of LXRalpha with SUMO2,3 in the nucleoplasm. Reason: Nucleoplasm localization is consistent with HDAC4's nuclear functions.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8952062	ACCEPT	Summary: Reactome annotation for CCND1 recruitment of HDAC4 to RUNX3 in the nucleoplasm. Reason: Nucleoplasm localization is consistent with HDAC4's transcriptional regulatory functions.
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-8952069	ACCEPT	Summary: Reactome annotation for HDAC4 deacetylation of RUNX3 in the nucleoplasm. Reason: Nucleoplasm localization is consistent with HDAC4's function in deacetylating transcription factors.
GO:0006954 inflammatory response	TAS PMID:12711221 Class II histone deacetylases: versatile regulators.	KEEP AS NON CORE	Summary: PMID:12711221 is a review article describing class II HDAC functions including roles in inflammatory processes. Reason: This represents a broad physiological process that HDAC4 participates in through its transcriptional regulatory activity. Not a core molecular function.
GO:0007399 nervous system development	TAS PMID:12711221 Class II histone deacetylases: versatile regulators.	KEEP AS NON CORE	Summary: PMID:12711221 is a review article describing class II HDAC functions including roles in nervous system development. Reason: This represents a developmental process. HDAC4 is highly expressed in brain and involved in neuronal differentiation, but this is a downstream physiological effect.
GO:0030183 B cell differentiation	TAS PMID:12711221 Class II histone deacetylases: versatile regulators.	KEEP AS NON CORE	Summary: PMID:12711221 is a review article describing class II HDAC functions including roles in B cell differentiation. Reason: This represents a cell type-specific developmental process downstream of HDAC4's transcriptional regulatory activity.
GO:0042113 B cell activation	TAS PMID:12711221 Class II histone deacetylases: versatile regulators.	KEEP AS NON CORE	Summary: PMID:12711221 is a review article describing class II HDAC functions including roles in B cell activation. Reason: This represents a cell type-specific process downstream of HDAC4's transcriptional regulatory activity.

Core Functions

HDAC4 functions primarily as a transcriptional corepressor by bridging DNA-binding transcription factors (especially MEF2) to the enzymatically active HDAC3/NCoR/SMRT complex. Due to a Tyr->His substitution in the active site (H803), HDAC4 has very weak intrinsic deacetylase activity and relies on the HDAC3/NCoR/SMRT complex for catalytic function.

Molecular Function:

transcription corepressor activity

Directly Involved In:

negative regulation of transcription by RNA polymerase II negative regulation of gene expression, epigenetic

Cellular Locations:

nucleoplasm

In Complex:

histone deacetylase complex

Supporting Evidence:

PMID:11804585
These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.
PMID:18614528
To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated.

HDAC4 binds to DNA-binding transcription factors including MEF2 family members (MEF2A, MEF2C, MEF2D), HIF-1alpha, Sp1, and others. This binding is central to its function as a transcriptional coregulator.

Molecular Function:

DNA-binding transcription factor binding

Directly Involved In:

negative regulation of myotube differentiation

Cellular Locations:

nucleoplasm

Supporting Evidence:

PMID:10983972
These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2.
PMID:18850004
HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1).

HDAC4 functions as a molecular scaffold/adaptor bridging transcription factors to the HDAC3/NCoR/SMRT corepressor complex. Class II HDACs regulate transcription by bridging enzymatically active complexes to transcription factors independently of intrinsic HDAC activity.

Molecular Function:

molecular adaptor activity

Cellular Locations:

nucleoplasm

Supporting Evidence:

PMID:11804585
These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity.

HDAC4 binds 14-3-3 proteins at phosphorylated serine residues (S246, S467, S632), which sequesters HDAC4 in the cytoplasm. This interaction regulates HDAC4 nucleocytoplasmic shuttling and is critical for its transcriptional regulatory function.

Molecular Function:

14-3-3 protein binding

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:10869435
The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10220385

Three proteins define a class of human histone deacetylases related to yeast Hda1p.

PMID:10869435

Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization.

PMID:10958686

Regulation of histone deacetylase 4 by binding of 14-3-3 proteins.

PMID:10983972

Regulation of skeletal myogenesis by association of the MEF2 transcription factor with class II histone deacetylases.

PMID:11463856

The orphan nuclear receptor TR2 interacts directly with both class I and class II histone deacetylases.

PMID:11504882

Differential localization of HDAC4 orchestrates muscle differentiation.

PMID:11804585

Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR.

PMID:12590135

The histone deacetylase 9 gene encodes multiple protein isoforms.

PMID:12711221

Class II histone deacetylases: versatile regulators.

PMID:15161933

Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding proteins.

PMID:15194749

Functional interaction between class II histone deacetylases and ICP0 of herpes simplex virus type 1.

PMID:15324660

Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization.

PMID:15743821

PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition of myocyte enhancer factor 2C.

PMID:15778465

Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer.

PMID:15964851

Identification of the ankyrin repeat proteins ANKRA and RFXANK as novel partners of class IIa histone deacetylases.

PMID:16147992

Analysis of BCL6-interacting proteins by tandem mass spectrometry.

PMID:16166628

Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications.

PMID:16236793

Class II histone deacetylases confer signal responsiveness to the ankyrin-repeat proteins ANKRA2 and RFXANK.

PMID:16767219

CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy.

PMID:16919237

Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90 chaperone.

PMID:17011572

Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes.

PMID:17159145

Epstein-Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4.

PMID:17218271

Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma.

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry.

PMID:17360518

Crystal structure of a conserved N-terminal domain of histone deacetylase 4 reveals functional insights into glutamine-rich domains.

PMID:17696781

Sumoylation of the zinc finger protein ZXDC enhances the function of its transcriptional activation domain.

PMID:17979178

A novel tandem affinity purification strategy for the efficient isolation and characterisation of native protein complexes.

PMID:18045992

PP2A regulates HDAC4 nuclear import.

PMID:18163532

Impaired placental trophoblast lineage differentiation in Alkbh1(-/-) mice.

PMID:18614528

Structural and functional analysis of the human HDAC4 catalytic domain reveals a regulatory structural zinc-binding domain.

PMID:18850004

HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a Sp1-dependent, p53-independent mechanism.

PMID:19071119

Transcriptional activation of hypoxia-inducible factor-1alpha by HDAC4 and HDAC5 involves differential recruitment of p300 and FIH-1.

PMID:19276356

FOXP3 up-regulates p21 expression by site-specific inhibition of histone deacetylase 2/histone deacetylase 4 association to the locus.

PMID:19281832

Activation of ROS/NF-kappaB and Ca2+/CaM kinase II are necessary for VCAM-1 induction in IL-1beta-treated human tracheal smooth muscle cells.

PMID:20116378

JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruiting histone deacetylase4 (HDAC4) and forming a transcriptional repression complex in the TM promoter.

PMID:20936779

A human MAP kinase interactome.

PMID:21242980

Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:22649097

Sequence-specific recognition of a PxLPxI/L motif by an ankyrin repeat tumbler lock.

PMID:23752268

The functional interactome landscape of the human histone deacetylase family.

PMID:23867755

Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in the regulation of placental cell fusion.

PMID:24229708

Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma.

PMID:24255178

Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions.

PMID:24413532

Differential regulation of estrogen receptor α expression in breast cancer cells by metastasis-associated protein 1.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:26019235

Epigenetic changes as a common trigger of muscle weakness in congenital myopathies.

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances.

PMID:27708256

ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding and degradation.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:31127039

Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6.

PMID:33537682

Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:36931259

A central chaperone-like role for 14-3-3 proteins in human cells.

PMID:39251607

Systematic identification of post-transcriptional regulatory modules.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-3108232

SUMO E3 ligases SUMOylate target proteins

Reactome:R-HSA-4615872

RANBP2 SUMOylates HDAC4 with SUMO1

Reactome:R-HSA-4615987

RANBP2 SUMOylates HDAC4 with SUMO2,3

Reactome:R-HSA-4720432

HDAC4 SUMOylates NR1H2 (LXRbeta) with SUMO2,3

Reactome:R-HSA-4720446

HDAC4 SUMOylates NR1H3 (LXRalpha) with SUMO2,3

Reactome:R-HSA-8952062

CCND1 recruits HDAC4 to RUNX3

Reactome:R-HSA-8952069

HDAC4 deacetylates RUNX3

Deep Research

Falcon

(HDAC4-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 21 citations 2026-02-08T20:31:39.463628

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human HDAC4 (UniProt P56524)

Plan and verification
- Identity/domain verification: HDAC4 is a human class IIa histone deacetylase with an N‑terminal regulatory region (containing MEF2-binding, NLS, and phospho‑14‑3‑3 sites) and a C‑terminal histone deacetylase domain that includes an NES; these features and its assignment to class IIa HDACs are consistently described in recent reviews (May 2024; https://doi.org/10.4093/dmj.2023.0174) and broader class IIa syntheses (Jul 2025; https://doi.org/10.3390/biom15081061). (kang2024rolesofhistone pages 3-5, brancolini2025classiiahdacs pages 3-4)

1) Key concepts and definitions with current understanding
- Definition and classification: HDAC4 is a zinc‑dependent histone deacetylase of the class IIa subfamily (HDAC4/5/7/9). Class IIa HDACs are distinguished by an N‑terminal transcriptional regulatory/scaffolding region (interacting with MEF2 and corepressors) and a C‑terminal deacetylase domain; they undergo regulated nuclear–cytoplasmic shuttling. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)
- Catalytic hallmark: Vertebrate class IIa HDACs, including HDAC4, harbor a Tyr→His substitution in the catalytic tyrosine of the deacetylase active site, markedly reducing intrinsic activity toward ε‑acetyl‑lysine and contributing to their frequent description as “pseudoenzymes.” (Jul 2025; https://doi.org/10.3390/biom15081061) (brancolini2025classiiahdacs pages 4-7)
- Corepressor coupling: Owing to low intrinsic activity, HDAC4 commonly functions within corepressor assemblies that include HDAC3 bound to NCoR/SMRT, which provide robust deacetylase catalytic function. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)

2) Recent developments and latest research (prioritizing 2023–2024)
- Enzymology and structure-focused insights: 2024 structural/computational reviews catalog human HDAC classes and active‑site architecture, contextualizing class IIa active‑site differences and inhibitor design trends across HDACs. (May 2024; https://doi.org/10.3390/ph17050620) (curcio2024thehistonedeacetylase pages 36-37)
- HDAC4 regulation in inflammation/metabolism: A 2024 focused review synthesizes HDAC4’s tissue expression (brain, heart, liver, skeletal muscle, macrophages), weak intrinsic catalytic activity, activation via HDAC3/NCoR–SMRT complexes, and detailed post‑translational regulation of nucleo‑cytoplasmic shuttling. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)
- Cardiovascular/neuro contexts for HDAC inhibition: 2024 systematic and perspective reviews report continuing translational interest in HDAC inhibitors (HDACi) for myocardial infarction and for fibrotic/inflammatory diseases, with discussion of expanding indications (including a recent approval of the pan‑HDAC inhibitor givinostat for Duchenne muscular dystrophy). (Dec 2024; https://doi.org/10.3390/jcm13247797; Dec 2024; https://doi.org/10.3390/biom14121605) (brancolini2025classiiahdacs pages 17-18)

3) Current applications and real‑world implementations
- Therapeutic use of HDACi beyond oncology: A 2024 perspective highlights the FDA approval of givinostat (a pan‑HDAC inhibitor) for Duchenne muscular dystrophy and surveys non‑oncology development (fibrotic/inflammatory indications). While not isoform‑selective for HDAC4, this represents a real‑world precedent for systemic HDAC modulation relevant to HDAC4‑regulated pathways (myogenesis, muscle inflammation). (Dec 2024; https://doi.org/10.3390/biom14121605) ()
- Cardiovascular research translation: A 2024 systematic review across 18 preclinical AMI studies found multiple HDAC inhibitors (e.g., TSA, SAHA, VPA, mocetinostat, givinostat, entinostat, apicidin, RGFP966) improved ventricular function and reduced infarct size/remodeling; the review cautions about bias and the translational gap to clinical practice. (Dec 2024; https://doi.org/10.3390/jcm13247797) (brancolini2025classiiahdacs pages 17-18)

4) Expert opinions and analysis from authoritative sources
- Class IIa as signal transducers/pseudoenzymes: Expert synthesis emphasizes class IIa HDACs function primarily as regulated transcriptional coregulators and signal transducers with limited intrinsic deacetylase activity due to the Tyr→His substitution, relying on recruitment of catalytically active deacetylases (e.g., HDAC3). (Jul 2025; https://doi.org/10.3390/biom15081061) (brancolini2025classiiahdacs pages 1-3, brancolini2025classiiahdacs pages 4-7, brancolini2025classiiahdacs pages 3-4)
- Metabolic and inflammatory roles: An endocrine/metabolism review (2024) concludes HDAC4’s context‑dependent signaling via non‑histone targets and transcription factors (e.g., MEF2, HIF, STAT1, FOXO family) underlies impacts on insulin signaling, glucose metabolism, cardiac development, and macrophage‑mediated inflammation. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)

5) Relevant statistics and data from recent studies
- Quantified regulatory phosphosites: Phosphorylation at S265/S266 (CaMKII sites) promotes nuclear export and/or dimerization with HDAC5; phosphorylation at S245, S467, and S632 creates 14‑3‑3 docking motifs that drive cytoplasmic sequestration; PP2A‑mediated dephosphorylation of S298 promotes nuclear import. These sites are repeatedly reported in recent syntheses of HDAC4 regulation. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)
- Pathway‑level outcomes with HDACi in cardiovascular models: 18 preclinical AMI studies summarized improvements in ventricular function and infarct size with HDACi; while not HDAC4‑selective, these aggregate effects provide translational context for HDAC4‑linked cardiac pathways. (Dec 2024; https://doi.org/10.3390/jcm13247797) (brancolini2025classiiahdacs pages 17-18)

Functional annotation of HDAC4
- Primary molecular function and enzymology: HDAC4 is a Zn2+‑dependent lysine deacetylase by family classification, but in vertebrates it exhibits very low intrinsic activity toward ε‑acetyl‑lysine because histidine substitutes for the canonical catalytic tyrosine in the active site (HDAC4 Tyr976→His). Structural analyses rationalize reduced transition‑state stabilization and substrate processing. Functionally, HDAC4 typically represses transcription by scaffolding DNA‑bound factors (especially MEF2) and recruiting corepressors (NCoR/SMRT) that include HDAC3, which provides the principal deacetylase activity in these complexes. (Jul 2025; https://doi.org/10.3390/biom15081061; May 2024; https://doi.org/10.4093/dmj.2023.0174) (brancolini2025classiiahdacs pages 4-7, kang2024rolesofhistone pages 3-5)
- Substrate specificity: Direct, robust deacetylation of histone ε‑acetyl‑lysine by isolated vertebrate HDAC4 is weak; in cellular contexts, deacetylation attributable to HDAC4 generally reflects activity of associated HDAC3 within NCoR/SMRT complexes, while HDAC4’s N‑terminus provides sequence‑specific transcription factor targeting (e.g., MEF2). Definitive, broadly accepted non‑histone substrates exclusively catalyzed by human HDAC4 in vivo remain limited; several reviews emphasize its role as a recruiter/scaffold rather than a stand‑alone deacetylase. (Jul 2025; https://doi.org/10.3390/biom15081061) (brancolini2025classiiahdacs pages 1-3, brancolini2025classiiahdacs pages 4-7)

Cellular localization and regulation
- Nucleocytoplasmic shuttling: HDAC4 shuttles between nucleus and cytoplasm. N‑terminal serine phosphorylation creates 14‑3‑3 docking motifs (e.g., pS245/pS467/pS632) that sequester HDAC4 in the cytoplasm and activate the C‑terminal NES for CRM1‑dependent export; pharmacologic CRM1 inhibition (e.g., leptomycin B) drives nuclear accumulation. Ca2+/CaMK signaling and PKD family kinases phosphorylate these motifs and promote export; PP2A dephosphorylation at S298 facilitates nuclear import. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)
- Transcriptional repression via MEF2: HDAC4’s N‑terminus binds MEF2, displacing coactivators and recruiting NCoR/SMRT–HDAC3 complexes to MEF2 sites, thereby repressing MEF2‑dependent myogenic and neuronal gene programs. Phosphorylation‑triggered 14‑3‑3 binding leads to dissociation/export, relieving repression. (Jul 2025; https://doi.org/10.3390/biom15081061) (brancolini2025classiiahdacs pages 3-4)

Pathway contexts and tissue roles
- Skeletal and cardiac muscle: HDAC4–MEF2 repression is a key checkpoint in myogenesis; CaMK‑dependent export of HDAC4 relieves repression and enables differentiation/oxidative gene expression. Cardiovascular reviews underscore HDAC family involvement in remodeling and infarct response; although pan‑HDACi are active, isoform‑specific physiological roles (e.g., HDAC4 shuttling) shape transcription during stress and recovery. (Dec 2024; https://doi.org/10.3390/jcm13247797; Jul 2025; https://doi.org/10.3390/biom15081061) (brancolini2025classiiahdacs pages 17-18, brancolini2025classiiahdacs pages 9-11)
- Neurons: HDAC4 is highly expressed in brain regions (cortex, hippocampus, striatum, cerebellum), dynamically shuttles in activity‑dependent signaling, and represses MEF2‑dependent neuroprotective/neuronal differentiation programs when nuclear. (2025 thesis synthesizing human data) (lowe2025investigatingtherole pages 25-28)
- Endothelium and metabolism: Class IIa members (including HDAC4) regulate endothelial functions (angiogenesis, immune responses) and, in metabolic tissues, influence insulin signaling and glucose handling via interactions with FOXO family and other factors. (Mar 2023; https://doi.org/10.3389/fphys.2023.1091794; May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)

Chemical probes, inhibitors, and translational status (emphasis on 2023–2024)
- Inhibitor landscape: 2024–2025 medicinal chemistry and structural reviews summarize HDAC inhibitor pharmacophores (hydroxamic acids, ortho‑aminoanilides, etc.) and design considerations across HDAC classes; however, clinically deployed agents remain largely pan‑ or class‑biased rather than HDAC4‑selective. (May 2024; https://doi.org/10.3390/ph17050620) (curcio2024thehistonedeacetylase pages 36-37)
- Clinical implementation beyond cancer: An authoritative 2024 perspective notes givinostat’s FDA approval for Duchenne muscular dystrophy and expanding non‑oncology exploration of HDAC inhibition in fibrotic/inflammatory disease, providing real‑world relevance for HDAC4‑regulated pathways though not isoform‑selective. (Dec 2024; https://doi.org/10.3390/biom14121605) ()
- Cardiovascular preclinical evidence: Systematic review (2024) reports improved ventricular function and smaller infarcts with HDACi across 18 animal AMI studies, while highlighting bias and the need for rigorous clinical translation. (Dec 2024; https://doi.org/10.3390/jcm13247797) (brancolini2025classiiahdacs pages 17-18)

Caveats and open questions (evidence‑based)
- Isoform‑selective pharmacology: Despite intense efforts, robustly HDAC4‑selective small‑molecule deacetylase inhibitors remain limited; many tools are pan‑HDAC or class‑biased. Class IIa biology also involves scaffolding that may not be fully addressed by catalytic inhibition alone. (May 2024; https://doi.org/10.3390/ph17050620; Jul 2025; https://doi.org/10.3390/biom15081061) (curcio2024thehistonedeacetylase pages 36-37, brancolini2025classiiahdacs pages 1-3)
- Catalysis vs scaffolding: Multiple recent syntheses emphasize HDAC4’s low intrinsic deacetylase activity and reliance on HDAC3 within NCoR/SMRT; thus, functional outcomes often reflect complex assembly and localization state rather than HDAC4 catalysis per se. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)

Summary
- Verified identity: HDAC4 (P56524) is a human class IIa HDAC with hallmark N‑terminal regulatory/MEF2‑binding regions and a C‑terminal HDAC domain; it shuttles between nucleus and cytoplasm under kinase‑ and 14‑3‑3–dependent control. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)
- Mechanism: Due to a Tyr→His active‑site substitution, HDAC4 has weak intrinsic ε‑acetyl‑lysine deacetylase activity and commonly represses transcription through MEF2 targeting and recruitment of NCoR/SMRT–HDAC3 complexes that supply catalytic activity. (Jul 2025; https://doi.org/10.3390/biom15081061; May 2024; https://doi.org/10.4093/dmj.2023.0174) (brancolini2025classiiahdacs pages 4-7, kang2024rolesofhistone pages 3-5)
- Localization/regulation: CaMK/PKD phosphorylation of N‑terminal serines creates 14‑3‑3 docking, activates CRM1‑dependent export (blocked by leptomycin B), whereas PP2A dephosphorylation promotes nuclear import; specific sites include S245, S265/S266, S298, S467, S632. (May 2024; https://doi.org/10.4093/dmj.2023.0174) (kang2024rolesofhistone pages 3-5)
- Applications: Although HDAC4‑selective drugs remain a challenge, HDAC pathway modulation has entered practice (e.g., givinostat in DMD), and preclinical cardiovascular evidence with HDACi is encouraging yet preliminary for clinical translation. (Dec 2024; https://doi.org/10.3390/biom14121605; Dec 2024; https://doi.org/10.3390/jcm13247797) (brancolini2025classiiahdacs pages 17-18)

Notes on evidence scope
- This report prioritizes 2023–2024 peer‑reviewed sources for mechanism/regulation and translational updates, complemented by 2025 expert syntheses when needed to explain the class IIa catalytic substitution and scaffolding paradigm. URLs and dates are provided via the cited DOIs above. (kang2024rolesofhistone pages 3-5, curcio2024thehistonedeacetylase pages 36-37, brancolini2025classiiahdacs pages 17-18, brancolini2025classiiahdacs pages 1-3, brancolini2025classiiahdacs pages 4-7)

References

(kang2024rolesofhistone pages 3-5): Hyunju Kang, Young-Ki Park, Ji-Young Lee, and Minkyung Bae. Roles of histone deacetylase 4 in the inflammatory and metabolic processes. Diabetes & Metabolism Journal, 48:340-353, May 2024. URL: https://doi.org/10.4093/dmj.2023.0174, doi:10.4093/dmj.2023.0174. This article has 15 citations and is from a peer-reviewed journal.
(brancolini2025classiiahdacs pages 3-4): Claudio Brancolini. Class iia hdacs are important signal transducers with unclear enzymatic activities. Biomolecules, 15:1061, Jul 2025. URL: https://doi.org/10.3390/biom15081061, doi:10.3390/biom15081061. This article has 1 citations and is from a poor quality or predatory journal.
(brancolini2025classiiahdacs pages 4-7): Claudio Brancolini. Class iia hdacs are important signal transducers with unclear enzymatic activities. Biomolecules, 15:1061, Jul 2025. URL: https://doi.org/10.3390/biom15081061, doi:10.3390/biom15081061. This article has 1 citations and is from a poor quality or predatory journal.
(curcio2024thehistonedeacetylase pages 36-37): Antonio Curcio, Roberta Rocca, Stefano Alcaro, and Anna Artese. The histone deacetylase family: structural features and application of combined computational methods. Pharmaceuticals, 17:620, May 2024. URL: https://doi.org/10.3390/ph17050620, doi:10.3390/ph17050620. This article has 53 citations and is from a poor quality or predatory journal.
(brancolini2025classiiahdacs pages 17-18): Claudio Brancolini. Class iia hdacs are important signal transducers with unclear enzymatic activities. Biomolecules, 15:1061, Jul 2025. URL: https://doi.org/10.3390/biom15081061, doi:10.3390/biom15081061. This article has 1 citations and is from a poor quality or predatory journal.
(brancolini2025classiiahdacs pages 1-3): Claudio Brancolini. Class iia hdacs are important signal transducers with unclear enzymatic activities. Biomolecules, 15:1061, Jul 2025. URL: https://doi.org/10.3390/biom15081061, doi:10.3390/biom15081061. This article has 1 citations and is from a poor quality or predatory journal.
(brancolini2025classiiahdacs pages 9-11): Claudio Brancolini. Class iia hdacs are important signal transducers with unclear enzymatic activities. Biomolecules, 15:1061, Jul 2025. URL: https://doi.org/10.3390/biom15081061, doi:10.3390/biom15081061. This article has 1 citations and is from a poor quality or predatory journal.
(lowe2025investigatingtherole pages 25-28): R Lowe. Investigating the role of hdac4 in the progression of parkinson's disease in drosophila melanogaster: a thesis presented in partial fulfilment of the requirements for …. Unknown journal, 2025.

Citations

kang2024rolesofhistone pages 3-5
brancolini2025classiiahdacs pages 4-7
curcio2024thehistonedeacetylase pages 36-37
brancolini2025classiiahdacs pages 17-18
brancolini2025classiiahdacs pages 3-4
lowe2025investigatingtherole pages 25-28
brancolini2025classiiahdacs pages 1-3
brancolini2025classiiahdacs pages 9-11
https://doi.org/10.4093/dmj.2023.0174
https://doi.org/10.3390/biom15081061
https://doi.org/10.3390/ph17050620
https://doi.org/10.3390/jcm13247797;
https://doi.org/10.3390/biom14121605
https://doi.org/10.3390/jcm13247797
https://doi.org/10.3390/biom15081061;
https://doi.org/10.3389/fphys.2023.1091794;
https://doi.org/10.3390/ph17050620;
https://doi.org/10.3390/biom14121605;
https://doi.org/10.4093/dmj.2023.0174,
https://doi.org/10.3390/biom15081061,
https://doi.org/10.3390/ph17050620,

📄 View Raw YAML

id: P56524
gene_symbol: HDAC4
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: HDAC4 is a class IIa histone deacetylase that functions primarily as a transcriptional corepressor by bridging DNA-binding transcription factors (especially MEF2 family) to the enzymatically active HDAC3/NCoR/SMRT corepressor complex. Due to a Tyr->His substitution in the active site (H803 in human HDAC4), class IIa HDACs including HDAC4 have intrinsically weak deacetylase activity toward acetylated lysines. HDAC4 undergoes regulated nucleocytoplasmic shuttling controlled by phosphorylation at serine residues (S246, S467, S632) and subsequent 14-3-3 protein binding. When phosphorylated, HDAC4 is sequestered in the cytoplasm; dephosphorylation allows nuclear import where it can repress transcription. HDAC4 plays important roles in skeletal and cardiac muscle differentiation, neuronal function, and metabolic regulation.
alternative_products:
- name: '1'
  id: P56524-1
- name: '2'
  id: P56524-2
  sequence_note: VSP_057290, VSP_057291
existing_annotations:
- term:
    id: GO:0004407
    label: histone deacetylase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HDAC4 belongs to the class IIa HDAC family and possesses a histone deacetylase catalytic domain. However, due to a conserved Tyr->His substitution in the active site, HDAC4 has markedly reduced intrinsic deacetylase activity toward acetyl-lysine substrates compared to class I HDACs. PMID:11804585 demonstrated that HDAC4 enzymatic activity depends on association with HDAC3/NCoR/SMRT complex. PMID:18614528 provided structural evidence for the low intrinsic activity. Despite limited intrinsic activity, HDAC4 can still deacetylate substrates and the IBA annotation is phylogenetically valid.
    action: ACCEPT
    reason: While HDAC4 has weak intrinsic deacetylase activity, it is still classified as a histone deacetylase by family membership and does possess measurable deacetylase activity. The IBA annotation correctly reflects the conserved function across the phylogenetic group.
    supported_by:
      - reference_id: PMID:10220385
        supporting_text: "These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A."
      - reference_id: PMID:11804585
        supporting_text: "In vitro reconstitution experiments indicate that HDAC4 and other class II HDACs are inactive in the context of the SMRT/N-CoR-HDAC3 complex and do not contribute to its enzymatic activity."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HDAC4 localizes to the cytoplasm in a phosphorylation-dependent manner. PMID:10869435 demonstrated that 14-3-3 protein binding to phosphorylated HDAC4 results in cytoplasmic sequestration. This localization is dynamic and represents the inactive, sequestered form of the protein.
    action: ACCEPT
    reason: Cytoplasmic localization of HDAC4 is well-established and represents a core aspect of its regulated nucleocytoplasmic shuttling mechanism.
    supported_by:
      - reference_id: PMID:10869435
        supporting_text: "The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm."
- term:
    id: GO:0040029
    label: epigenetic regulation of gene expression
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HDAC4 participates in epigenetic regulation of gene expression through its role in recruiting the HDAC3/NCoR/SMRT complex to transcription factors, leading to histone deacetylation and transcriptional repression. This is a core function of HDAC4 supported by extensive literature.
    action: ACCEPT
    reason: This annotation correctly captures HDAC4's role in epigenetic regulation, which is a central aspect of its function as a transcriptional corepressor.
    supported_by:
      - reference_id: PMID:11804585
        supporting_text: "These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity."
- term:
    id: GO:0000118
    label: histone deacetylase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: HDAC4 functions as part of multiprotein complexes including the HDAC3/NCoR/SMRT corepressor complex. This is a core aspect of HDAC4 function as it bridges transcription factors to the enzymatically active complex.
    action: ACCEPT
    reason: The IBA annotation correctly reflects HDAC4's participation in HDAC complexes, which is essential for its corepressor function.
    supported_by:
      - reference_id: PMID:11804585
        supporting_text: "Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT."
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: This IEA annotation derived from InterPro domain IPR046949 (HDAC4/5/7/9) correctly captures a core function of HDAC4 as a transcriptional corepressor.
    action: ACCEPT
    reason: HDAC4 negatively regulates transcription of RNA polymerase II-transcribed genes by recruiting HDAC3/NCoR/SMRT corepressor complex to promoters. This is a well-established core function.
- term:
    id: GO:0004407
    label: histone deacetylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: This IEA annotation from InterPro correctly identifies HDAC4 as having histone deacetylase activity, though intrinsic activity is low for class IIa HDACs.
    action: ACCEPT
    reason: HDAC4 possesses a histone deacetylase catalytic domain and measurable deacetylase activity, even if weaker than class I HDACs. Duplicate of IBA annotation which is appropriate.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: This IEA annotation from UniProt subcellular location mapping correctly identifies nuclear localization. HDAC4 shuttles between nucleus and cytoplasm, and nuclear localization is required for its transcriptional repression function.
    action: ACCEPT
    reason: Nuclear localization is well-established for HDAC4 and represents the active localization where HDAC4 represses transcription via MEF2 and other transcription factors.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: This IEA annotation from UniProt subcellular location correctly identifies cytoplasmic localization. HDAC4 is sequestered in the cytoplasm when phosphorylated and bound to 14-3-3 proteins.
    action: ACCEPT
    reason: Cytoplasmic localization is well-established as part of HDAC4's regulated nucleocytoplasmic shuttling mechanism. Duplicate of IBA annotation which is appropriate.
- term:
    id: GO:0006325
    label: chromatin organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This IEA annotation from UniProt keyword mapping correctly identifies involvement in chromatin organization via histone deacetylation activity.
    action: ACCEPT
    reason: HDAC4 participates in chromatin organization through its role in recruiting the HDAC3/NCoR/SMRT complex which deacetylates histones, affecting chromatin structure.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This IEA annotation is too general. HDAC4 has hydrolase activity as a deacetylase (EC 3.5.1.98), but the more specific terms histone deacetylase activity or protein lysine deacetylase activity are already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: While technically correct, this annotation is too broad and uninformative. More specific deacetylase activity terms are already annotated.
- term:
    id: GO:0033558
    label: protein lysine deacetylase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This IEA annotation from ARBA correctly identifies HDAC4's protein lysine deacetylase activity. HDAC4 can deacetylate non-histone substrates including Hsp70 (HSPA1A/B).
    action: ACCEPT
    reason: HDAC4 has documented protein lysine deacetylase activity toward non-histone substrates. UniProt notes HDAC4 deacetylates HSPA1A/B at Lys-77 (PMID:27708256).
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: This IEA annotation correctly identifies metal ion binding. HDAC4 binds zinc ions - both in the catalytic site (required for deacetylase activity) and in a regulatory structural zinc-binding domain (PMID:18614528).
    action: ACCEPT
    reason: HDAC4 binds zinc ions required for catalytic function and structural integrity. More specific terms like zinc ion binding are also annotated.
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: This IEA annotation correctly captures a core function of HDAC4 - binding to DNA-binding transcription factors such as MEF2, HIF-1alpha, and Sp1. This is well-supported by extensive experimental evidence.
    action: ACCEPT
    reason: This annotation accurately reflects HDAC4's function as a transcriptional coregulator that operates through binding to DNA-binding transcription factors. Multiple publications demonstrate HDAC4 interaction with transcription factors including MEF2A/C/D, HIF-1alpha, Sp1, and others.
- term:
    id: GO:0141221
    label: histone deacetylase activity, hydrolytic mechanism
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: This IEA annotation from Rhea reaction database correctly identifies that HDAC4 catalyzes hydrolytic deacetylation (EC 3.5.1.98). This is the mechanistic specification of HDAC activity.
    action: ACCEPT
    reason: HDAC4 uses a hydrolytic mechanism involving zinc-dependent catalysis to remove acetyl groups from lysine residues.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10958686
  review:
    summary: PMID:10958686 demonstrated HDAC4 interaction with 14-3-3 proteins via phosphorylated serine residues. This interaction regulates HDAC4 subcellular localization. While the interaction is real, protein binding is too generic.
    action: MODIFY
    reason: The 14-3-3 interaction is functionally important but would be better captured by a more specific binding term. The interaction with 14-3-3 proteins is already captured in the literature via the phosphoserine binding mechanism.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11504882
  review:
    summary: PMID:11504882 is about differential localization of HDAC4 during muscle differentiation and demonstrates interactions with 14-3-3 proteins. Protein binding is too generic.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding for more specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15161933
  review:
    summary: PMID:15161933 is a proteomic analysis of 14-3-3 binding proteins identifying HDAC4. Protein binding is too generic for this specific interaction.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding for more specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15194749
  review:
    summary: PMID:15194749 describes HDAC4 interaction with HSV-1 ICP0 protein. While technically correct, this is a viral interaction that may not represent core cellular function.
    action: KEEP_AS_NON_CORE
    reason: This represents a virus-host interaction with HSV-1 ICP0 protein. While the interaction is documented, it represents pathogen interaction rather than core cellular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15324660
  review:
    summary: PMID:15324660 is about 14-3-3 binding proteins involved in cytoskeletal regulation. HDAC4 interaction with 14-3-3 proteins is documented.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding for more specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15778465
  review:
    summary: PMID:15778465 is about targeted proteomic analysis of 14-3-3 sigma. HDAC4 interaction with 14-3-3 proteins is documented.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding for more specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15964851
  review:
    summary: PMID:15964851 identifies ANKRA proteins as partners of class IIa HDACs including HDAC4. HDAC4 has a PxLPxI/L motif that mediates interaction with ANKRA2 ankyrin repeats.
    action: KEEP_AS_NON_CORE
    reason: This documents HDAC4 interaction with ankyrin repeat proteins. While valid, protein binding is too generic. The interaction is functionally relevant but represents a regulatory interaction.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16147992
  review:
    summary: PMID:16147992 is about BCL6-interacting proteins. HDAC4 interaction with BCL6 is documented. BCL6 is a transcription factor.
    action: MODIFY
    reason: HDAC4 binds the transcription factor BCL6. Should use DNA-binding transcription factor binding for specificity.
    proposed_replacement_terms:
      - id: GO:0140297
        label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16166628
  review:
    summary: PMID:16166628 describes regulation of MEF2 by HDAC4 and SIRT1-mediated lysine modifications. HDAC4-MEF2 interaction is a core function.
    action: MODIFY
    reason: HDAC4-MEF2 interaction is a core function. Should use DNA-binding transcription factor binding for specificity.
    proposed_replacement_terms:
      - id: GO:0140297
        label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16767219
  review:
    summary: PMID:16767219 shows CaMKII signals to HDAC4 during cardiomyocyte hypertrophy. Documents interaction with 14-3-3 proteins.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding for more specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16919237
  review:
    summary: PMID:16919237 describes BRMS1 stabilization by Hsp90 chaperone. HDAC4 interaction with BRMS1 documented.
    action: KEEP_AS_NON_CORE
    reason: HDAC4-BRMS1 interaction is documented but protein binding is too generic. This represents a regulatory interaction.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17159145
  review:
    summary: PMID:17159145 describes EBNA-LP coactivation through HDAC4 interaction. This is a viral protein interaction.
    action: KEEP_AS_NON_CORE
    reason: This represents a virus-host interaction with EBV EBNA-LP. While documented, it is not a core cellular function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353931
  review:
    summary: PMID:17353931 is a large-scale protein-protein interaction study by mass spectrometry. Documents HDAC4 interactions.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction study. The specific interactors should be captured by more specific binding terms where known.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17979178
  review:
    summary: PMID:17979178 uses tandem affinity purification to identify protein complexes. Documents HDAC4 interactions with 14-3-3 proteins.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding for more specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18045992
  review:
    summary: PMID:18045992 describes PP2A regulation of HDAC4 nuclear import. Documents interaction with 14-3-3 proteins and PP2A.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding or phosphatase binding for more specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18163532
  review:
    summary: PMID:18163532 describes placental trophoblast differentiation and HDAC4 interaction with DNAJB6.
    action: KEEP_AS_NON_CORE
    reason: Documents HDAC4-DNAJB6 interaction which may be relevant in specific developmental contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20116378
  review:
    summary: PMID:20116378 describes JNK-ATF-2 inhibition of thrombomodulin expression via HDAC4 recruitment. Documents HDAC4-ATF2 interaction.
    action: MODIFY
    reason: ATF2 is a transcription factor. Should use DNA-binding transcription factor binding for specificity.
    proposed_replacement_terms:
      - id: GO:0140297
        label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20936779
  review:
    summary: PMID:20936779 is a human MAP kinase interactome study. Documents HDAC4 interactions.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction study. Protein binding is too generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21242980
  review:
    summary: PMID:21242980 describes HDAC4 inhibition of androgen receptor activity through SUMOylation. Documents HDAC4-AR interaction.
    action: MODIFY
    reason: Androgen receptor is a transcription factor. Should use nuclear receptor binding or transcription factor binding.
    proposed_replacement_terms:
      - id: GO:0035257
        label: nuclear hormone receptor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: PMID:21988832 is a study toward understanding the human liver protein interaction network.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction study. Protein binding is too generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23752268
  review:
    summary: PMID:23752268 is a functional interactome landscape of the human HDAC family. Documents multiple HDAC4 interactions.
    action: KEEP_AS_NON_CORE
    reason: Large-scale HDAC interactome study. The specific interactions should be captured by more specific terms.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24229708
  review:
    summary: PMID:24229708 describes RUNX3 inactivation in lung adenocarcinoma and HDAC4-RUNX3 interaction.
    action: MODIFY
    reason: RUNX3 is a transcription factor. Should use DNA-binding transcription factor binding for specificity.
    proposed_replacement_terms:
      - id: GO:0140297
        label: DNA-binding transcription factor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24255178
  review:
    summary: PMID:24255178 is a protein interaction network study of the mammalian Hippo pathway. Documents HDAC4 interactions.
    action: KEEP_AS_NON_CORE
    reason: Pathway-focused interaction study. Protein binding is too generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  review:
    summary: PMID:25416956 is a proteome-scale map of the human interactome. High-throughput study documenting many HDAC4 interactions.
    action: KEEP_AS_NON_CORE
    reason: Large-scale interactome study. Protein binding is too generic for the specific interactions documented.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26496610
  review:
    summary: PMID:26496610 is a human interactome study organized by stoichiometries and abundances.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction study. Protein binding is too generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  review:
    summary: PMID:28514442 describes architecture of the human interactome defining protein communities.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction study. Protein binding is too generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: PMID:33961781 is a dual proteome-scale network study revealing cell-specific remodeling.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction study. Protein binding is too generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  review:
    summary: PMID:35271311 (OpenCell) is an endogenous tagging study for human cellular organization.
    action: KEEP_AS_NON_CORE
    reason: High-throughput localization and interaction study. Protein binding is too generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36931259
  review:
    summary: PMID:36931259 describes central chaperone-like role for 14-3-3 proteins. Documents HDAC4-14-3-3 interaction.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding for more specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39251607
  review:
    summary: PMID:39251607 is about systematic identification of post-transcriptional regulatory modules.
    action: KEEP_AS_NON_CORE
    reason: High-throughput study. Protein binding is too generic.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  review:
    summary: PMID:40205054 is about multimodal cell maps as a foundation for structural and functional genomics.
    action: KEEP_AS_NON_CORE
    reason: High-throughput study. Protein binding is too generic.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:17360518
  review:
    summary: PMID:17360518 describes the crystal structure of a conserved N-terminal domain of HDAC4 revealing homodimerization. HDAC4 forms homodimers via its N-terminal glutamine-rich domain.
    action: ACCEPT
    reason: HDAC4 homodimerization is well-documented and functionally relevant. The crystal structure confirms the structural basis for this interaction.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: This IDA annotation from HPA immunofluorescence data correctly identifies nucleoplasm localization. HDAC4 localizes to the nucleoplasm when nuclear, where it represses transcription.
    action: ACCEPT
    reason: Nucleoplasm localization is consistent with HDAC4's function as a transcriptional corepressor when in the nucleus.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: This IDA annotation from HPA immunofluorescence data correctly identifies cytosol localization. HDAC4 is sequestered in the cytosol when phosphorylated and bound to 14-3-3 proteins.
    action: ACCEPT
    reason: Cytosolic localization is consistent with HDAC4's regulated nucleocytoplasmic shuttling.
- term:
    id: GO:0016607
    label: nuclear speck
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: This IDA annotation from HPA immunofluorescence data identifies nuclear speck localization. This may represent a subpopulation of nuclear HDAC4.
    action: KEEP_AS_NON_CORE
    reason: Nuclear speck localization may be observed under certain conditions but does not represent the primary functional localization of HDAC4.
- term:
    id: GO:0016925
    label: protein sumoylation
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-3108232
  review:
    summary: This Reactome annotation correctly identifies HDAC4 involvement in protein SUMOylation. HDAC4 is itself SUMOylated at K559 and also has SUMO E3 ligase activity.
    action: ACCEPT
    reason: HDAC4 is involved in SUMOylation both as a substrate (SUMOylated at K559 by RANBP2) and as an E3 ligase that promotes SUMOylation of other proteins like LXR and AR.
- term:
    id: GO:0061084
    label: negative regulation of protein refolding
  evidence_type: IDA
  original_reference_id: PMID:27708256
  review:
    summary: PMID:27708256 demonstrates that HDAC4 deacetylates Hsp70 (HSPA1A/B) at Lys-77, which shifts Hsp70 toward STUB1 binding and protein degradation rather than refolding. This is a documented non-histone substrate function.
    action: KEEP_AS_NON_CORE
    reason: This represents a specific non-histone deacetylation function of HDAC4. While experimentally validated, it is not the core transcriptional corepressor function.
- term:
    id: GO:0033558
    label: protein lysine deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:18614528
  review:
    summary: PMID:18614528 provides structural and functional analysis of the HDAC4 catalytic domain. While demonstrating low intrinsic activity toward acetylated lysines, HDAC4 does possess measurable protein lysine deacetylase activity.
    action: ACCEPT
    reason: HDAC4 has documented protein lysine deacetylase activity, albeit weaker than class I HDACs. The structural study provides mechanistic insight into this activity.
    supported_by:
      - reference_id: PMID:18614528
        supporting_text: "To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated."
- term:
    id: GO:0045814
    label: negative regulation of gene expression, epigenetic
  evidence_type: IDA
  original_reference_id: PMID:18614528
  review:
    summary: PMID:18614528 demonstrates that HDAC4 is involved in epigenetic gene regulation through its role in deacetylase complexes. The structural zinc-binding domain regulates association with NCoR/HDAC3 complex.
    action: ACCEPT
    reason: HDAC4 negatively regulates gene expression through epigenetic mechanisms by recruiting the HDAC3/NCoR/SMRT complex to chromatin.
    supported_by:
      - reference_id: PMID:18614528
        supporting_text: "either the mutation of residues coordinating the structural zinc ion or the binding of a class IIa selective inhibitor prevented the association of HDAC4 with the N-CoR.HDAC3 repressor complex."
- term:
    id: GO:0033558
    label: protein lysine deacetylase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952069
  review:
    summary: This Reactome annotation for HDAC4 deacetylation of RUNX3 correctly identifies protein lysine deacetylase activity toward a non-histone substrate.
    action: ACCEPT
    reason: HDAC4 has documented protein lysine deacetylase activity toward RUNX3 as captured in Reactome pathway.
- term:
    id: GO:0001216
    label: DNA-binding transcription activator activity
  evidence_type: IDA
  original_reference_id: PMID:19071119
  review:
    summary: PMID:19071119 shows HDAC4 enhances HIF-1alpha transactivation by physically associating with HIF-1alpha and promoting dissociation from FIH-1 while increasing binding to p300. This is coactivator activity, not direct DNA-binding transcription factor activity. HDAC4 lacks any known sequence-specific DNA-binding domain and functions via protein-protein interactions with DNA-binding transcription factors.
    action: MODIFY
    reason: The annotation to GO:0001216 (DNA-binding transcription activator activity) is incorrect. GO:0003700 usage guidance explicitly states that proteins with enzymatic activity (like histone deacetylases) and no known DNA binding domain should be annotated to GO:0003712 (transcription coregulator activity) instead. PMID:19071119 demonstrates HDAC4 acts through protein-protein interactions with HIF-1alpha, promoting its transactivation by competing with FIH-1 binding and enhancing p300 recruitment - this is the mechanism of a transcription coactivator, not a DNA-binding transcription factor.
    proposed_replacement_terms:
      - id: GO:0003713
        label: transcription coactivator activity
    supported_by:
      - reference_id: PMID:19071119
        supporting_text: "HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1). In the presence of these HDACs, binding of HIF-1alpha to FIH-1 decreased, whereas binding to p300 increased. These results indicate that HDAC4 and HDAC5 increase the transactivation function of HIF-1alpha by promoting dissociation of HIF-1alpha from FIH-1 and association with p300."
      - reference_id: PMID:11804585
        supporting_text: "These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19071119
  review:
    summary: PMID:19071119 demonstrates HDAC4 physically associates with HIF-1alpha. While the annotation captures a real interaction, the GO term 'protein binding' is too generic and uninformative.
    action: MODIFY
    reason: This annotation is correct but the term is too vague. GO curation guidelines recommend using more specific binding terms when the nature of the interaction is known. The interaction with HIF-1alpha should be captured by GO:0061629 (RNA polymerase II-specific DNA-binding transcription factor binding), which is already annotated.
    proposed_replacement_terms:
      - id: GO:0061629
        label: RNA polymerase II-specific DNA-binding transcription factor binding
    supported_by:
      - reference_id: PMID:19071119
        supporting_text: "HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1)."
- term:
    id: GO:0019789
    label: SUMO transferase activity
  evidence_type: EXP
  original_reference_id: PMID:17218271
  review:
    summary: PMID:17218271 describes parallel SUMOylation-dependent pathways mediated by LXRs and PPARgamma. HDAC4 has been shown to function as a SUMO E3 ligase, promoting SUMOylation of nuclear receptors including LXR and AR.
    action: ACCEPT
    reason: HDAC4 has documented SUMO E3 ligase activity, functioning to promote SUMOylation of transcription factors. This represents a non-deacetylase enzymatic function.
- term:
    id: GO:0010944
    label: negative regulation of transcription by competitive promoter binding
  evidence_type: IMP
  original_reference_id: PMID:19276356
  review:
    summary: PMID:19276356 describes FOXP3 up-regulation of p21 by inhibiting HDAC2/HDAC4 association to the locus. The study shows HDAC4 competes for promoter binding to regulate transcription.
    action: KEEP_AS_NON_CORE
    reason: This mechanism of competitive promoter binding is documented for specific contexts but represents a specialized regulatory mechanism rather than the core corepressor function.
- term:
    id: GO:0042393
    label: histone binding
  evidence_type: IDA
  original_reference_id: PMID:19276356
  review:
    summary: PMID:19276356 demonstrates HDAC4 association with histones at the p21 promoter in the context of transcriptional regulation.
    action: ACCEPT
    reason: HDAC4 binds to histones as part of its function in chromatin-mediated transcriptional repression. The contributes_to qualifier is appropriate.
- term:
    id: GO:0004407
    label: histone deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:12590135
  review:
    summary: PMID:12590135 describes HDAC9 isoforms and provides evidence for class IIa HDAC activity. HDAC4 histone deacetylase activity is documented.
    action: ACCEPT
    reason: HDAC4 possesses histone deacetylase activity, though weak intrinsically. This IDA evidence supports the annotation.
- term:
    id: GO:0045814
    label: negative regulation of gene expression, epigenetic
  evidence_type: IDA
  original_reference_id: PMID:10869435
  review:
    summary: PMID:10869435 demonstrates HDAC4/5 regulate transcriptional activity through 14-3-3 dependent cellular localization. Nuclear HDAC4 represses gene expression epigenetically.
    action: ACCEPT
    reason: This is a core function of HDAC4 - when nuclear, it represses gene expression through epigenetic mechanisms.
    supported_by:
      - reference_id: PMID:10869435
        supporting_text: "Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression."
- term:
    id: GO:0045814
    label: negative regulation of gene expression, epigenetic
  evidence_type: IMP
  original_reference_id: PMID:18850004
  review:
    summary: PMID:18850004 demonstrates HDAC4 repression of p21 expression through Sp1-dependent, p53-independent mechanism. HDAC4 reduces histone H3 acetylation at the p21 promoter.
    action: ACCEPT
    reason: This study demonstrates HDAC4-mediated epigenetic repression at a specific target gene (p21), supporting the core corepressor function.
- term:
    id: GO:0045814
    label: negative regulation of gene expression, epigenetic
  evidence_type: IMP
  original_reference_id: PMID:24413532
  review:
    summary: PMID:24413532 describes MTA1-mediated epigenetic regulation of ESR1 expression involving HDAC4. HDAC4 is part of the MTA1 complex regulating estrogen receptor expression.
    action: ACCEPT
    reason: This study demonstrates HDAC4 involvement in epigenetic regulation of ESR1 expression, consistent with its corepressor function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33537682
  review:
    summary: PMID:33537682 identifies missense substitutions at a conserved 14-3-3 binding site in HDAC4 causing intellectual disability. Documents HDAC4-YWHAB interaction.
    action: MODIFY
    reason: HDAC4-14-3-3 (YWHAB) interaction is specifically documented. Should use 14-3-3 protein binding for specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0000785
    label: chromatin
  evidence_type: IDA
  original_reference_id: PMID:31127039
  review:
    summary: PMID:31127039 demonstrates HDAC4 promotes type I interferon signaling and is active in chromatin context. HDAC4 associates with chromatin to regulate gene expression.
    action: ACCEPT
    reason: HDAC4 localizes to chromatin as part of its function in transcriptional regulation. The is_active_in qualifier is appropriate.
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:31127039
  review:
    summary: PMID:31127039 demonstrates HDAC4 functions as a molecular adaptor in type I interferon signaling. This is consistent with HDAC4's known function as a bridging factor between transcription factors and corepressor complexes.
    action: ACCEPT
    reason: HDAC4's function as a molecular adaptor/scaffold is a core aspect of its mechanism. It bridges transcription factors to the HDAC3/NCoR/SMRT complex.
    supported_by:
      - reference_id: PMID:11804585
        supporting_text: "These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity."
- term:
    id: GO:0060337
    label: type I interferon-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:31127039
  review:
    summary: PMID:31127039 demonstrates HDAC4 promotes type I interferon signaling and restricts DNA viruses. HDAC4 is degraded by vaccinia virus protein C6.
    action: KEEP_AS_NON_CORE
    reason: This represents HDAC4's role in antiviral innate immunity. While experimentally validated, this is a context-specific function rather than the core transcriptional corepressor role.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4615872
  review:
    summary: Reactome annotation for RANBP2 SUMOylation of HDAC4 with SUMO1 in the nucleoplasm.
    action: ACCEPT
    reason: Nucleoplasm localization is consistent with HDAC4 function. This reaction occurs in the nuclear compartment.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4615987
  review:
    summary: Reactome annotation for RANBP2 SUMOylation of HDAC4 with SUMO2,3 in the nucleoplasm.
    action: ACCEPT
    reason: Nucleoplasm localization is consistent with HDAC4 function. Duplicate annotation for different SUMO paralog.
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:18850004
  review:
    summary: PMID:18850004 demonstrates HDAC4 interacts with Sp1, a DNA-binding transcription factor, at the p21 promoter. This annotation correctly captures HDAC4's role as a coregulator that binds transcription factors.
    action: ACCEPT
    reason: This annotation correctly captures the coregulator function of HDAC4 - it binds to DNA-binding transcription factors (Sp1) rather than binding DNA directly itself. This is consistent with HDAC4's role as a transcriptional corepressor.
    supported_by:
      - reference_id: PMID:18850004
        supporting_text: "HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1)."
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:19071119
  review:
    summary: PMID:19071119 demonstrates HDAC4 physically associates with HIF-1alpha, a DNA-binding transcription factor, through the inhibitory domain (ID). This annotation correctly reflects HDAC4's interaction with DNA-binding transcription factors.
    action: ACCEPT
    reason: This annotation appropriately captures HDAC4 binding to a DNA-binding transcription factor (HIF-1alpha). This is distinct from and consistent with HDAC4's role as a transcription coregulator rather than a direct DNA-binding protein.
    supported_by:
      - reference_id: PMID:19071119
        supporting_text: "HDAC4 and HDAC5 physically associated with HIF-1alpha through the inhibitory domain (ID) that is the binding site for factor inhibiting HIF-1 (FIH-1)."
- term:
    id: GO:0000978
    label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
  evidence_type: IDA
  original_reference_id: PMID:24413532
  review:
    summary: PMID:24413532 shows HDAC4 is recruited to the ESR1 promoter region (+146 to +461 bp downstream of the transcription start site) as part of the MTA1 complex containing TFAP2C and IFI16. However, HDAC4 does not possess sequence-specific DNA binding activity - it is recruited via protein-protein interactions with transcription factors.
    action: MODIFY
    reason: This annotation incorrectly implies HDAC4 has sequence-specific DNA binding. PMID:24413532 shows HDAC4 is recruited to chromatin through the MTA1-TFAP2C or MTA1-IFI16 complex, not through direct sequence-specific DNA binding. HDAC4 lacks any known DNA-binding domain. The term GO:0000976 (transcription cis-regulatory region binding) with a 'contributes_to' qualifier (which is already annotated from PMID:18850004) is more appropriate as it allows for indirect recruitment to chromatin.
    proposed_replacement_terms:
      - id: GO:0000976
        label: transcription cis-regulatory region binding
    supported_by:
      - reference_id: PMID:24413532
        supporting_text: "In both MCF7 and MDA-MB-231, MTA1 was recruited to the region +146 to +461 bp downstream of the transcription start site of ESR1 (ERpro315). Proteomics analysis of the MTA1 complex that was pulled down by an oligonucleotide encoding ERpro315 revealed that the transcription factor AP-2gamma (TFAP2C) and the IFN-gamma-inducible protein 16 (IFI16) were components of the complex."
- term:
    id: GO:0061629
    label: RNA polymerase II-specific DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:23867755
  review:
    summary: PMID:23867755 demonstrates HDAC4/5 involvement in placental cell fusion through the Epac1/Rap1/CaMKI signaling cascade. The annotation shows HDAC4 binding to MEF2 (a DNA-binding transcription factor).
    action: ACCEPT
    reason: This annotation correctly captures HDAC4's well-established interaction with MEF2 transcription factors. HDAC4's interaction with MEF2 family members is a core aspect of its function as a transcriptional coregulator.
    supported_by:
      - reference_id: PMID:23867755
        supporting_text: "Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in the regulation of placental cell fusion"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22649097
  review:
    summary: PMID:22649097 describes the crystal structure of HDAC4 PxLPxI/L motif bound to ANKRA2 ankyrin repeats. This is a specific protein-protein interaction.
    action: KEEP_AS_NON_CORE
    reason: Documents specific HDAC4-ANKRA2 interaction through the PxLPxI/L motif. Protein binding is too generic but the interaction is regulatory.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:26019235
  review:
    summary: PMID:26019235 describes epigenetic changes in congenital myopathies and shows HDAC4 nuclear localization.
    action: ACCEPT
    reason: Nuclear localization of HDAC4 is consistent with its function as a transcriptional corepressor.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27708256
  review:
    summary: PMID:27708256 describes HDAC4 interaction with Hsp70 (HSPA1A/B). HDAC4 deacetylates Hsp70 at Lys-77.
    action: MODIFY
    reason: Documents specific HDAC4-Hsp70 interaction. Should use more specific heat shock protein binding term.
    proposed_replacement_terms:
      - id: GO:0042803
        label: protein homodimerization activity
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:23867755
  review:
    summary: PMID:23867755 demonstrates HDAC4 nuclear localization in the context of placental cell fusion regulation.
    action: ACCEPT
    reason: Nuclear localization is consistent with HDAC4's function in transcriptional regulation.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IGI
  original_reference_id: PMID:15743821
  review:
    summary: PMID:15743821 describes PC4 coactivation of MyoD by relieving HDAC4-mediated inhibition of MEF2C. HDAC4 inhibits MEF2C-dependent transcription.
    action: ACCEPT
    reason: This IGI annotation correctly captures HDAC4's role in negative regulation of transcription through its interaction with MEF2C.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24413532
  review:
    summary: PMID:24413532 documents HDAC4 interaction with EP300 in the context of ESR1 regulation. This interaction is with a transcriptional coactivator.
    action: KEEP_AS_NON_CORE
    reason: Documents HDAC4-EP300 interaction. Protein binding is too generic but the interaction is relevant to transcriptional regulation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11463856
  review:
    summary: PMID:11463856 describes HDAC4 interaction with the orphan nuclear receptor TR2 (NR2C1).
    action: MODIFY
    reason: TR2/NR2C1 is a nuclear hormone receptor. Should use nuclear hormone receptor binding for specificity.
    proposed_replacement_terms:
      - id: GO:0035257
        label: nuclear hormone receptor binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11804585
  review:
    summary: PMID:11804585 documents HDAC4 interaction with the SMRT/N-CoR corepressor complex and HDAC3. This is the key mechanistic study for HDAC4 function.
    action: MODIFY
    reason: Documents the core interaction of HDAC4 with the NCoR corepressor complex. Should use nuclear receptor coactivator activity or corepressor binding.
    proposed_replacement_terms:
      - id: GO:0003714
        label: transcription corepressor activity
- term:
    id: GO:0004407
    label: histone deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:10220385
  review:
    summary: PMID:10220385 is the original identification of HDAC4/5/6 as class II HDACs with demonstrated in vitro deacetylase activity inhibited by trichostatin A.
    action: ACCEPT
    reason: This is the foundational study identifying HDAC4 as a histone deacetylase. The in vitro deacetylase activity is documented.
    supported_by:
      - reference_id: PMID:10220385
        supporting_text: "These class II HDAC proteins have differential mRNA expression in human tissues and possess in vitro HDAC activity that is inhibited by trichostatin A."
- term:
    id: GO:0042826
    label: histone deacetylase binding
  evidence_type: IPI
  original_reference_id: PMID:12590135
  review:
    summary: PMID:12590135 describes HDAC9 isoforms and documents interactions between class IIa HDACs. HDAC4 binds to other HDACs including HDAC9.
    action: ACCEPT
    reason: HDAC4 binds to other class IIa HDACs. This interaction is relevant to HDAC complex formation.
- term:
    id: GO:0014898
    label: cardiac muscle hypertrophy in response to stress
  evidence_type: TAS
  original_reference_id: PMID:17011572
  review:
    summary: PMID:17011572 describes CaMK-dependent signaling through class II HDACs to NRSF in ventricular myocytes. HDAC4 is involved in cardiac stress response.
    action: KEEP_AS_NON_CORE
    reason: This represents HDAC4's role in cardiac muscle hypertrophy, a tissue-specific process. While experimentally validated, it is not the core molecular function.
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:16236793
  review:
    summary: PMID:16236793 describes class II HDACs conferring signal responsiveness to ankyrin-repeat proteins. HDAC4 negatively regulates transcription.
    action: ACCEPT
    reason: HDAC4's role in negative regulation of transcription is a core function, demonstrated in multiple contexts.
- term:
    id: GO:0000118
    label: histone deacetylase complex
  evidence_type: IDA
  original_reference_id: PMID:11804585
  review:
    summary: PMID:11804585 demonstrates HDAC4 is part of a multiprotein complex containing HDAC3 and SMRT/N-CoR. This is the definitive study on HDAC4 complex formation.
    action: ACCEPT
    reason: HDAC4 functions as part of the HDAC3/NCoR/SMRT complex. This is a core aspect of its mechanism.
    supported_by:
      - reference_id: PMID:11804585
        supporting_text: "Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT."
- term:
    id: GO:0000976
    label: transcription cis-regulatory region binding
  evidence_type: IDA
  original_reference_id: PMID:18850004
  review:
    summary: PMID:18850004 shows HDAC4 binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21 proximal promoter. The annotation has 'contributes_to' qualifier in the GOA file, which appropriately reflects that HDAC4 is recruited to chromatin through interaction with Sp1 rather than through direct sequence-specific DNA binding.
    action: ACCEPT
    reason: The 'contributes_to' qualifier is appropriate here because HDAC4 is recruited to the p21 promoter through its interaction with Sp1/Sp3, not through direct sequence-specific DNA binding. This is consistent with its function as a coregulator.
    supported_by:
      - reference_id: PMID:18850004
        supporting_text: "HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1)."
- term:
    id: GO:0010832
    label: negative regulation of myotube differentiation
  evidence_type: IMP
  original_reference_id: PMID:10983972
  review:
    summary: PMID:10983972 demonstrates that class II HDACs including HDAC4 suppress skeletal myogenesis through association with MEF2. HDAC4 negatively regulates myotube differentiation.
    action: KEEP_AS_NON_CORE
    reason: This represents HDAC4's role in muscle differentiation, a tissue-specific developmental process. While experimentally validated and important, it is a physiological outcome of the core transcriptional corepressor function.
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:10983972
  review:
    summary: PMID:10983972 demonstrates that class II HDACs (including HDAC4) interact with MEF2 transcription factors to regulate skeletal myogenesis. HDAC4 does not interact directly with MyoD but suppresses its myogenic activity through association with MEF2.
    action: ACCEPT
    reason: This annotation correctly captures HDAC4's interaction with MEF2 transcription factors. This is a core function of HDAC4 in regulating muscle differentiation.
    supported_by:
      - reference_id: PMID:10983972
        supporting_text: "These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2."
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:18850004
  review:
    summary: PMID:18850004 demonstrates HDAC4 represses p21 expression through Sp1-dependent mechanism. HDAC4 reduces transcription at the p21 promoter.
    action: ACCEPT
    reason: Negative regulation of transcription is a core function of HDAC4. This study demonstrates the mechanism at a specific target gene.
- term:
    id: GO:0006338
    label: chromatin remodeling
  evidence_type: IDA
  original_reference_id: PMID:18850004
  review:
    summary: PMID:18850004 shows HDAC4 reduces histone H3 acetylation at the p21 promoter, contributing to chromatin remodeling.
    action: ACCEPT
    reason: HDAC4 participates in chromatin remodeling through its role in histone deacetylation and recruitment of the HDAC3/NCoR complex.
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IDA
  original_reference_id: PMID:18614528
  review:
    summary: PMID:18614528 provides structural evidence that HDAC4 binds zinc ions both in the catalytic site and in a structural zinc-binding domain.
    action: ACCEPT
    reason: HDAC4 binds zinc ions required for both catalytic activity and structural integrity. This is documented in the crystal structure.
    supported_by:
      - reference_id: PMID:18614528
        supporting_text: "these structures reveal a conformationally flexible structural zinc-binding domain conserved in all class IIa enzymes."
- term:
    id: GO:0008284
    label: positive regulation of cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:18850004
  review:
    summary: PMID:18850004 shows HDAC4 repression of p21 leads to positive regulation of cell proliferation in cancer cells.
    action: KEEP_AS_NON_CORE
    reason: This represents a downstream consequence of HDAC4's transcriptional repressor function (repressing the cell cycle inhibitor p21), not a core molecular function.
- term:
    id: GO:0017053
    label: transcription repressor complex
  evidence_type: IDA
  original_reference_id: PMID:11804585
  review:
    summary: PMID:11804585 demonstrates HDAC4 is part of a transcription repressor complex containing HDAC3 and SMRT/N-CoR.
    action: ACCEPT
    reason: HDAC4 is a component of the HDAC3/NCoR/SMRT transcription repressor complex. This is a core aspect of its mechanism.
    supported_by:
      - reference_id: PMID:11804585
        supporting_text: "Here, we show that the catalytic domain of HDAC4 interacts with HDAC3 via the transcriptional corepressor N-CoR/SMRT."
- term:
    id: GO:0030955
    label: potassium ion binding
  evidence_type: IDA
  original_reference_id: PMID:18614528
  review:
    summary: PMID:18614528 identifies potassium ion binding in the HDAC4 catalytic domain structure. Potassium may play a role in catalysis.
    action: KEEP_AS_NON_CORE
    reason: While potassium binding is structurally documented, it is not central to HDAC4's primary function as a transcriptional corepressor.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:19071119
  review:
    summary: PMID:19071119 demonstrates that HDAC4 enhances HIF-1alpha transactivation function, resulting in positive regulation of transcription. This is achieved through a coactivator mechanism where HDAC4 competes with FIH-1 for binding to HIF-1alpha and promotes p300 recruitment.
    action: ACCEPT
    reason: This BP annotation is appropriate and consistent with the mechanism shown in PMID:19071119. While HDAC4 is primarily known as a transcriptional corepressor (via its deacetylase activity), this study demonstrates it can also act as a coactivator for HIF-1alpha-mediated transcription through a deacetylase-independent mechanism.
    supported_by:
      - reference_id: PMID:19071119
        supporting_text: "HDAC4 and HDAC5 enhanced transactivation by HIF-1alpha without stabilizing HIF-1alpha... These results indicate that HDAC4 and HDAC5 increase the transactivation function of HIF-1alpha by promoting dissociation of HIF-1alpha from FIH-1 and association with p300."
- term:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  evidence_type: IPI
  original_reference_id: PMID:11804585
  review:
    summary: PMID:11804585 shows HDAC4 interacts with the SMRT/N-CoR corepressor complex and bridges it to select transcription factors. This study explicitly demonstrates that class II HDACs function by bridging enzymatically active complexes to transcription factors.
    action: ACCEPT
    reason: This annotation correctly captures HDAC4's role in bridging corepressor complexes to transcription factors. This study is key evidence that HDAC4 is a coregulator, not a DNA-binding transcription factor.
    supported_by:
      - reference_id: PMID:11804585
        supporting_text: "These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity."
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:10869435
  review:
    summary: PMID:10869435 demonstrates that nuclear HDAC4/5 interact with HDAC3 and repress gene expression. This is the foundational study on HDAC4 nucleocytoplasmic shuttling and transcriptional repression.
    action: ACCEPT
    reason: Negative regulation of transcription is a core function of HDAC4.
    supported_by:
      - reference_id: PMID:10869435
        supporting_text: "Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression."
- term:
    id: GO:0000122
    label: negative regulation of transcription by RNA polymerase II
  evidence_type: IMP
  original_reference_id: PMID:19276356
  review:
    summary: PMID:19276356 demonstrates HDAC4 involvement in p21 transcriptional regulation through competition with FOXP3 at the promoter.
    action: ACCEPT
    reason: This IMP annotation correctly captures HDAC4's role in negative regulation of transcription.
- term:
    id: GO:0004407
    label: histone deacetylase activity
  evidence_type: IDA
  original_reference_id: PMID:10869435
  review:
    summary: PMID:10869435 demonstrates HDAC4 possesses histone deacetylase activity. While intrinsic activity is low for class IIa HDACs, the activity is documented.
    action: ACCEPT
    reason: HDAC4 histone deacetylase activity is documented in this foundational study.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10869435
  review:
    summary: PMID:10869435 documents HDAC4 interaction with 14-3-3 proteins and HDAC3. Multiple specific interactions are documented.
    action: MODIFY
    reason: Should be annotated to 14-3-3 protein binding or histone deacetylase binding for specificity.
    proposed_replacement_terms:
      - id: GO:0071889
        label: 14-3-3 protein binding
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:10869435
  review:
    summary: PMID:10869435 demonstrates HDAC4 nuclear localization, which is required for its transcriptional repressor function.
    action: ACCEPT
    reason: Nuclear localization is consistent with HDAC4's function as a transcriptional corepressor.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10869435
  review:
    summary: PMID:10869435 demonstrates HDAC4 cytoplasmic localization when bound to 14-3-3 proteins.
    action: ACCEPT
    reason: Cytoplasmic localization is part of HDAC4's regulated nucleocytoplasmic shuttling.
    supported_by:
      - reference_id: PMID:10869435
        supporting_text: "The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm."
- term:
    id: GO:0014894
    label: response to denervation involved in regulation of muscle adaptation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This ISS annotation inferred from mouse HDAC4 ortholog reflects the role of HDAC4 in muscle adaptation processes.
    action: KEEP_AS_NON_CORE
    reason: This represents a tissue-specific physiological process. While supported by ortholog evidence, it is not the core molecular function.
- term:
    id: GO:0042826
    label: histone deacetylase binding
  evidence_type: IPI
  original_reference_id: PMID:10869435
  review:
    summary: PMID:10869435 demonstrates HDAC4 interaction with HDAC3 in the nucleus.
    action: ACCEPT
    reason: HDAC4-HDAC3 interaction is a core aspect of HDAC4's mechanism as part of the NCoR/SMRT complex.
    supported_by:
      - reference_id: PMID:10869435
        supporting_text: "Loss of this interaction allows HDAC4 and HDAC5 to translocate to the nucleus, interact with HDAC3, and repress gene expression."
- term:
    id: GO:0045820
    label: negative regulation of glycolytic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This ISS annotation inferred from mouse HDAC4 ortholog reflects metabolic regulatory functions.
    action: KEEP_AS_NON_CORE
    reason: This represents a metabolic regulatory function that is downstream of the core transcriptional corepressor activity.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This ISS annotation from mouse HDAC4 reflects that HDAC4 can also positively regulate transcription in certain contexts.
    action: KEEP_AS_NON_CORE
    reason: While HDAC4 is primarily a corepressor, it can act as a coactivator in specific contexts like HIF-1alpha regulation.
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: This ISS annotation from mouse HDAC4 reflects coactivator function in specific contexts.
    action: KEEP_AS_NON_CORE
    reason: Context-specific coactivator function as seen with HIF-1alpha. Not the primary function.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:19281832
  review:
    summary: PMID:19281832 demonstrates HDAC4 nuclear localization in the context of IL-1beta signaling.
    action: ACCEPT
    reason: Nuclear localization is consistent with HDAC4's function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:19281832
  review:
    summary: PMID:19281832 demonstrates HDAC4 cytoplasmic localization in the context of IL-1beta signaling.
    action: ACCEPT
    reason: Cytoplasmic localization is part of regulated shuttling.
- term:
    id: GO:0070555
    label: response to interleukin-1
  evidence_type: IMP
  original_reference_id: PMID:19281832
  review:
    summary: PMID:19281832 describes HDAC4 involvement in IL-1beta signaling leading to VCAM-1 induction in tracheal smooth muscle cells.
    action: KEEP_AS_NON_CORE
    reason: This represents a context-specific signaling response. While experimentally validated, it is not the core molecular function.
- term:
    id: GO:0033235
    label: positive regulation of protein sumoylation
  evidence_type: IDA
  original_reference_id: PMID:17696781
  review:
    summary: PMID:17696781 describes HDAC4's role in enhancing SUMOylation of ZXDC, consistent with its SUMO E3 ligase activity.
    action: ACCEPT
    reason: HDAC4 has documented SUMO E3 ligase activity that promotes SUMOylation of target proteins.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4720432
  review:
    summary: Reactome annotation for HDAC4 SUMOylation of LXRbeta with SUMO2,3 in the nucleoplasm.
    action: ACCEPT
    reason: Nucleoplasm localization is consistent with HDAC4's nuclear functions.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-4720446
  review:
    summary: Reactome annotation for HDAC4 SUMOylation of LXRalpha with SUMO2,3 in the nucleoplasm.
    action: ACCEPT
    reason: Nucleoplasm localization is consistent with HDAC4's nuclear functions.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952062
  review:
    summary: Reactome annotation for CCND1 recruitment of HDAC4 to RUNX3 in the nucleoplasm.
    action: ACCEPT
    reason: Nucleoplasm localization is consistent with HDAC4's transcriptional regulatory functions.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952069
  review:
    summary: Reactome annotation for HDAC4 deacetylation of RUNX3 in the nucleoplasm.
    action: ACCEPT
    reason: Nucleoplasm localization is consistent with HDAC4's function in deacetylating transcription factors.
- term:
    id: GO:0006954
    label: inflammatory response
  evidence_type: TAS
  original_reference_id: PMID:12711221
  review:
    summary: PMID:12711221 is a review article describing class II HDAC functions including roles in inflammatory processes.
    action: KEEP_AS_NON_CORE
    reason: This represents a broad physiological process that HDAC4 participates in through its transcriptional regulatory activity. Not a core molecular function.
- term:
    id: GO:0007399
    label: nervous system development
  evidence_type: TAS
  original_reference_id: PMID:12711221
  review:
    summary: PMID:12711221 is a review article describing class II HDAC functions including roles in nervous system development.
    action: KEEP_AS_NON_CORE
    reason: This represents a developmental process. HDAC4 is highly expressed in brain and involved in neuronal differentiation, but this is a downstream physiological effect.
- term:
    id: GO:0030183
    label: B cell differentiation
  evidence_type: TAS
  original_reference_id: PMID:12711221
  review:
    summary: PMID:12711221 is a review article describing class II HDAC functions including roles in B cell differentiation.
    action: KEEP_AS_NON_CORE
    reason: This represents a cell type-specific developmental process downstream of HDAC4's transcriptional regulatory activity.
- term:
    id: GO:0042113
    label: B cell activation
  evidence_type: TAS
  original_reference_id: PMID:12711221
  review:
    summary: PMID:12711221 is a review article describing class II HDAC functions including roles in B cell activation.
    action: KEEP_AS_NON_CORE
    reason: This represents a cell type-specific process downstream of HDAC4's transcriptional regulatory activity.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10220385
  title: Three proteins define a class of human histone deacetylases related to yeast
    Hda1p.
  findings: []
- id: PMID:10869435
  title: Regulation of histone deacetylase 4 and 5 and transcriptional activity by
    14-3-3-dependent cellular localization.
  findings: []
- id: PMID:10958686
  title: Regulation of histone deacetylase 4 by binding of 14-3-3 proteins.
  findings: []
- id: PMID:10983972
  title: Regulation of skeletal myogenesis by association of the MEF2 transcription
    factor with class II histone deacetylases.
  findings: []
- id: PMID:11463856
  title: The orphan nuclear receptor TR2 interacts directly with both class I and
    class II histone deacetylases.
  findings: []
- id: PMID:11504882
  title: Differential localization of HDAC4 orchestrates muscle differentiation.
  findings: []
- id: PMID:11804585
  title: Enzymatic activity associated with class II HDACs is dependent on a multiprotein
    complex containing HDAC3 and SMRT/N-CoR.
  findings: []
- id: PMID:12590135
  title: The histone deacetylase 9 gene encodes multiple protein isoforms.
  findings: []
- id: PMID:12711221
  title: 'Class II histone deacetylases: versatile regulators.'
  findings: []
- id: PMID:15161933
  title: Comprehensive proteomic analysis of interphase and mitotic 14-3-3-binding
    proteins.
  findings: []
- id: PMID:15194749
  title: Functional interaction between class II histone deacetylases and ICP0 of
    herpes simplex virus type 1.
  findings: []
- id: PMID:15324660
  title: Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding
    proteins involved in cytoskeletal regulation and cellular organization.
  findings: []
- id: PMID:15743821
  title: PC4 coactivates MyoD by relieving the histone deacetylase 4-mediated inhibition
    of myocyte enhancer factor 2C.
  findings: []
- id: PMID:15778465
  title: Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced
    in cancer.
  findings: []
- id: PMID:15964851
  title: Identification of the ankyrin repeat proteins ANKRA and RFXANK as novel partners
    of class IIa histone deacetylases.
  findings: []
- id: PMID:16147992
  title: Analysis of BCL6-interacting proteins by tandem mass spectrometry.
  findings: []
- id: PMID:16166628
  title: Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated
    lysine modifications.
  findings: []
- id: PMID:16236793
  title: Class II histone deacetylases confer signal responsiveness to the ankyrin-repeat
    proteins ANKRA2 and RFXANK.
  findings: []
- id: PMID:16767219
  title: CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte
    hypertrophy.
  findings: []
- id: PMID:16919237
  title: Breast cancer metastasis suppressor 1 (BRMS1) is stabilized by the Hsp90
    chaperone.
  findings: []
- id: PMID:17011572
  title: Class II HDACs mediate CaMK-dependent signaling to NRSF in ventricular myocytes.
  findings: []
- id: PMID:17159145
  title: Epstein-Barr nuclear antigen leader protein coactivates transcription through
    interaction with histone deacetylase 4.
  findings: []
- id: PMID:17218271
  title: Parallel SUMOylation-dependent pathways mediate gene- and signal-specific
    transrepression by LXRs and PPARgamma.
  findings: []
- id: PMID:17353931
  title: Large-scale mapping of human protein-protein interactions by mass spectrometry.
  findings: []
- id: PMID:17360518
  title: Crystal structure of a conserved N-terminal domain of histone deacetylase
    4 reveals functional insights into glutamine-rich domains.
  findings: []
- id: PMID:17696781
  title: Sumoylation of the zinc finger protein ZXDC enhances the function of its
    transcriptional activation domain.
  findings: []
- id: PMID:17979178
  title: A novel tandem affinity purification strategy for the efficient isolation
    and characterisation of native protein complexes.
  findings: []
- id: PMID:18045992
  title: PP2A regulates HDAC4 nuclear import.
  findings: []
- id: PMID:18163532
  title: Impaired placental trophoblast lineage differentiation in Alkbh1(-/-) mice.
  findings: []
- id: PMID:18614528
  title: Structural and functional analysis of the human HDAC4 catalytic domain reveals
    a regulatory structural zinc-binding domain.
  findings: []
- id: PMID:18850004
  title: HDAC4 represses p21(WAF1/Cip1) expression in human cancer cells through a
    Sp1-dependent, p53-independent mechanism.
  findings: []
- id: PMID:19071119
  title: Transcriptional activation of hypoxia-inducible factor-1alpha by HDAC4 and
    HDAC5 involves differential recruitment of p300 and FIH-1.
  findings: []
- id: PMID:19276356
  title: FOXP3 up-regulates p21 expression by site-specific inhibition of histone
    deacetylase 2/histone deacetylase 4 association to the locus.
  findings: []
- id: PMID:19281832
  title: Activation of ROS/NF-kappaB and Ca2+/CaM kinase II are necessary for VCAM-1
    induction in IL-1beta-treated human tracheal smooth muscle cells.
  findings: []
- id: PMID:20116378
  title: JNK-ATF-2 inhibits thrombomodulin (TM) expression by recruiting histone deacetylase4
    (HDAC4) and forming a transcriptional repression complex in the TM promoter.
  findings: []
- id: PMID:20936779
  title: A human MAP kinase interactome.
  findings: []
- id: PMID:21242980
  title: Inhibition of androgen receptor activity by histone deacetylase 4 through
    receptor SUMOylation.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:22649097
  title: Sequence-specific recognition of a PxLPxI/L motif by an ankyrin repeat tumbler
    lock.
  findings: []
- id: PMID:23752268
  title: The functional interactome landscape of the human histone deacetylase family.
  findings: []
- id: PMID:23867755
  title: Involvement of Epac1/Rap1/CaMKI/HDAC5 signaling cascade in the regulation
    of placental cell fusion.
  findings: []
- id: PMID:24229708
  title: Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma.
  findings: []
- id: PMID:24255178
  title: Protein interaction network of the mammalian Hippo pathway reveals mechanisms
    of kinase-phosphatase interactions.
  findings: []
- id: PMID:24413532
  title: Differential regulation of estrogen receptor α expression in breast cancer
    cells by metastasis-associated protein 1.
  findings: []
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
- id: PMID:26019235
  title: Epigenetic changes as a common trigger of muscle weakness in congenital myopathies.
  findings: []
- id: PMID:26496610
  title: A human interactome in three quantitative dimensions organized by stoichiometries
    and abundances.
  findings: []
- id: PMID:27708256
  title: ARD1-mediated Hsp70 acetylation balances stress-induced protein refolding
    and degradation.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
- id: PMID:31127039
  title: Histone deacetylase 4 promotes type I interferon signaling, restricts DNA
    viruses, and is degraded via vaccinia virus protein C6.
  findings: []
- id: PMID:33537682
  title: Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause
    a novel intellectual disability syndrome.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: PMID:36931259
  title: A central chaperone-like role for 14-3-3 proteins in human cells.
  findings: []
- id: PMID:39251607
  title: Systematic identification of post-transcriptional regulatory modules.
  findings: []
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
- id: Reactome:R-HSA-3108232
  title: SUMO E3 ligases SUMOylate target proteins
  findings: []
- id: Reactome:R-HSA-4615872
  title: RANBP2 SUMOylates HDAC4 with SUMO1
  findings: []
- id: Reactome:R-HSA-4615987
  title: RANBP2 SUMOylates HDAC4 with SUMO2,3
  findings: []
- id: Reactome:R-HSA-4720432
  title: HDAC4 SUMOylates NR1H2 (LXRbeta) with SUMO2,3
  findings: []
- id: Reactome:R-HSA-4720446
  title: HDAC4 SUMOylates NR1H3 (LXRalpha) with SUMO2,3
  findings: []
- id: Reactome:R-HSA-8952062
  title: CCND1 recruits HDAC4 to RUNX3
  findings: []
- id: Reactome:R-HSA-8952069
  title: HDAC4 deacetylates RUNX3
  findings: []
core_functions:
- molecular_function:
    id: GO:0003714
    label: transcription corepressor activity
  description: HDAC4 functions primarily as a transcriptional corepressor by bridging DNA-binding transcription factors (especially MEF2) to the enzymatically active HDAC3/NCoR/SMRT complex. Due to a Tyr->His substitution in the active site (H803), HDAC4 has very weak intrinsic deacetylase activity and relies on the HDAC3/NCoR/SMRT complex for catalytic function.
  directly_involved_in:
    - id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    - id: GO:0045814
      label: negative regulation of gene expression, epigenetic
  locations:
    - id: GO:0005654
      label: nucleoplasm
  in_complex:
    id: GO:0000118
    label: histone deacetylase complex
  supported_by:
    - reference_id: PMID:11804585
      supporting_text: "These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity."
    - reference_id: PMID:18614528
      supporting_text: "To date, no biological substrate for class IIa HDACs has been identified, and only low activity on acetylated lysines has been demonstrated."
- molecular_function:
    id: GO:0140297
    label: DNA-binding transcription factor binding
  description: HDAC4 binds to DNA-binding transcription factors including MEF2 family members (MEF2A, MEF2C, MEF2D), HIF-1alpha, Sp1, and others. This binding is central to its function as a transcriptional coregulator.
  directly_involved_in:
    - id: GO:0010832
      label: negative regulation of myotube differentiation
  locations:
    - id: GO:0005654
      label: nucleoplasm
  supported_by:
    - reference_id: PMID:10983972
      supporting_text: "These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2."
    - reference_id: PMID:18850004
      supporting_text: "HDAC4 interacts with Sp1, binds and reduces histone H3 acetylation at the Sp1/Sp3 binding site-rich p21(WAF1/Cip1) proximal promoter, suggesting a key role for Sp1 in HDAC4-mediated repression of p21(WAF1/Cip1)."
- molecular_function:
    id: GO:0060090
    label: molecular adaptor activity
  description: HDAC4 functions as a molecular scaffold/adaptor bridging transcription factors to the HDAC3/NCoR/SMRT corepressor complex. Class II HDACs regulate transcription by bridging enzymatically active complexes to transcription factors independently of intrinsic HDAC activity.
  locations:
    - id: GO:0005654
      label: nucleoplasm
  supported_by:
    - reference_id: PMID:11804585
      supporting_text: "These observations indicate that class II HDACs regulate transcription by bridging the enzymatically active SMRT/N-CoR-HDAC3 complex and select transcription factors independently of any intrinsic HDAC activity."
- molecular_function:
    id: GO:0071889
    label: 14-3-3 protein binding
  description: HDAC4 binds 14-3-3 proteins at phosphorylated serine residues (S246, S467, S632), which sequesters HDAC4 in the cytoplasm. This interaction regulates HDAC4 nucleocytoplasmic shuttling and is critical for its transcriptional regulatory function.
  locations:
    - id: GO:0005737
      label: cytoplasm
  supported_by:
    - reference_id: PMID:10869435
      supporting_text: "The association of 14-3-3 with HDAC4 and HDAC5 results in the sequestration of these proteins in the cytoplasm."

Gene Description

Existing Annotations Review

Core Functions

HDAC4 binds to DNA-binding transcription factors including MEF2 family members (MEF2A, MEF2C, MEF2D), HIF-1alpha, Sp1, and others. This binding is central to its function as a transcriptional coregulator.

HDAC4 functions as a molecular scaffold/adaptor bridging transcription factors to the HDAC3/NCoR/SMRT corepressor complex. Class II HDACs regulate transcription by bridging enzymatically active complexes to transcription factors independently of intrinsic HDAC activity.

HDAC4 binds 14-3-3 proteins at phosphorylated serine residues (S246, S467, S632), which sequesters HDAC4 in the cytoplasm. This interaction regulates HDAC4 nucleocytoplasmic shuttling and is critical for its transcriptional regulatory function.

References

Deep Research

Falcon

Citations

📄 View Raw YAML