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.
| 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 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 Ξ± 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 Ξ± 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 Ξ± 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 receptor binding (GO:0016922) for specificity. Proposed replacements: nuclear 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. |
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