HAND2 (dHAND) is a Twist-family class B basic helix-loop-helix transcription factor that heterodimerizes with E-proteins (TCF3/E12-E47, TCF4, TCF12) and other bHLH factors (HAND1, TWIST1) to bind E-box elements, and activates target genes through an N-terminal activation domain. It also acts without direct DNA binding by forming complexes with partner transcription factors, notably GATA4 (via its bHLH domain, recruiting p300), MEF2C, NKX2-5 and PHOX2A, to synergistically activate cardiac genes such as NPPA/ANF and noradrenergic genes such as DBH. Dimer partner choice is regulated by PKA/PP2A phosphorylation of helix I. In development it is expressed in lateral mesoderm, the right-ventricle-fated heart tube, cardiac and cranial neural crest, posterior limb bud and sympathetic/enteric neuron precursors, and is required for right ventricle formation, outflow tract and aortic arch alignment, branchial arch development, posterior limb identity upstream of Sonic hedgehog, and sympathetic and enteric neuron differentiation. In the adult it is induced by progesterone in endometrial stroma, where it suppresses FGF production to permit implantation, and is re-expressed in failing myocardium downstream of calcineurin/NFAT, where it promotes pathological hypertrophy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | IDA PMID:16280598 Phox2 and dHAND transcription factors select shared and uniq... | ACCEPT | Summary: ChIP in SH-SY5Y neuroblastoma cells shows HAND2 bound at the DBH, PHOX2B, GATA2 and HAND1 promoter regions. Reason: Direct chromatin occupancy by ChIP is appropriate evidence for chromatin location of a DNA-binding TF. Supporting Evidence: PMID:16280598 All three proteins are bound to the DBH and PHOX2B promoter regions in SH-SY5Y neuroblastoma cells PMID:16280598 dHAND binds to genes independently of Phox2a |
| GO:0000785 chromatin | IDA PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | ACCEPT | Summary: Chromatin localization from the heart-failure study of Hand2 reactivation (abstract only cached); consistent with HAND2 as a nuclear chromatin-bound TF. Reason: Curator read the full text; chromatin occupancy is fully consistent with HAND2 function as a sequence-specific TF, and is independently supported by ChIP in PMID:16280598. Supporting Evidence: PMID:24161931 increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium PMID:16280598 All three proteins are bound to the DBH and PHOX2B promoter regions in SH-SY5Y neuroblastoma cells |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA transfer from mouse Hand2, which binds E-box cis-regulatory elements as a heterodimer with E12 (contributes_to). Reason: The contributes_to qualifier correctly reflects that HAND2 binds DNA as an obligate heterodimer with E-proteins; supported by mouse IDA and consistent with the bHLH domain. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0000976 transcription cis-regulatory region binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer from mouse Hand2, which binds E-box cis-regulatory elements as a heterodimer with E12 (contributes_to). Reason: The contributes_to qualifier correctly reflects that HAND2 binds DNA as an obligate heterodimer with E-proteins; supported by mouse IDA and consistent with the bHLH domain. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for Pol II cis-regulatory sequence-specific DNA binding across the Twist/Hand bHLH clade; HAND2 is itself among the experimental sources. Reason: Phylogenetically sound; HAND2 binds E-box elements as a heterodimer and occupies promoters (ChIP). Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:16280598 All three proteins are bound to the DBH and PHOX2B promoter regions in SH-SY5Y neuroblastoma cells |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:16280598 Phox2 and dHAND transcription factors select shared and uniq... | ACCEPT | Summary: ChIP shows HAND2 bound to the DBH and PHOX2B promoters and, independently of Phox2a, to GATA2 and HAND1 genes in noradrenergic neuroblastoma cells. Reason: ChIP occupancy of Pol II promoters; a sequence-specific bHLH factor. Accepted. Supporting Evidence: PMID:16280598 All three proteins are bound to the DBH and PHOX2B promoter regions in SH-SY5Y neuroblastoma cells PMID:16280598 dHAND binds to genes independently of Phox2a |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for Pol II DNA-binding TF activity, placed at the Twist-family bHLH node. Reason: Core MF of HAND2: activates targets (ANP, Shh, noradrenergic genes) as E-protein heterodimer. Matches the module annoton function. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:11812799 HAND2 contains a strong transcriptional activation domain in the amino-terminal third of the protein PMID:12392994 HAND2 is an upstream transcriptional regulator of ANP expression |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: IEA (Ensembl Compara) from rat Hand2 for Pol II DNA-binding TF activity. Reason: Consistent with the experimentally established activator function of HAND2. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from rat Hand2 for Pol II DNA-binding TF activity. Reason: Consistent with the experimentally established activator function of HAND2. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:12392994 HAND2 is an upstream transcriptional regulator of ANP expression |
| GO:0001223 transcription coactivator binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from rat Hand2 for transcription coactivator binding; HAND2 bHLH domain binds the CH3 domain of p300. Reason: Direct p300 binding by the dHAND bHLH domain, and p300/CBP-dependence of HAND2 neurogenic activity, support coactivator binding. Supporting Evidence: PMID:11994297 the bHLH domain of dHAND directly interacted with the CH3 domain of p300 PMID:16145670 this function is dependent on its interaction with the histone acetyltransferase p300/CBP |
| GO:0001223 transcription coactivator binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from rat Hand2 for transcription coactivator binding; HAND2 bHLH domain binds the CH3 domain of p300. Reason: Direct p300 binding by the dHAND bHLH domain, and p300/CBP-dependence of HAND2 neurogenic activity, support coactivator binding. Supporting Evidence: PMID:11994297 the bHLH domain of dHAND directly interacted with the CH3 domain of p300 PMID:16145670 this function is dependent on its interaction with the histone acetyltransferase p300/CBP |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | ACCEPT | Summary: dHAND and MEF2C synergistically activate the ANP promoter in reporter assays and co-occupy the ANP promoter in H9c2 cells. Reason: Transactivation with promoter occupancy supports Pol II-specific activator activity; corroborated by the N-terminal activation domain and ANP activation (PMID:11812799, PMID:12392994). Supporting Evidence: PMID:15486975 dHAND and MEF2C synergistically activated expression of the atrial naturetic peptide gene (ANP) in transfected HeLa cells PMID:15486975 dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP PMID:11812799 HAND2 contains a strong transcriptional activation domain in the amino-terminal third of the protein |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse Hand2 (IDA, PMID:11812799) for Pol II activator activity. Reason: Mouse HAND2 shown to be a transcriptional activator binding E-boxes as heterodimer. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:11812799 HAND2 contains a strong transcriptional activation domain in the amino-terminal third of the protein |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse Hand2 (IDA, PMID:11812799) for Pol II activator activity. Reason: Mouse HAND2 shown to be a transcriptional activator binding E-boxes as heterodimer. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:11812799 HAND2 contains a strong transcriptional activation domain in the amino-terminal third of the protein |
| GO:0003151 outflow tract morphogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse: neural-crest deletion of Hand2 causes outflow tract and aortic arch artery misalignment. Reason: Hand2 in cardiac neural crest is required for outflow tract alignment; a core developmental role of HAND2. Supporting Evidence: PMID:19008477 loss of Hand2 in the NC lineage leads to the misalignment of the outflow tract and aortic arch arteries PMID:9171826 the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches |
| GO:0003151 outflow tract morphogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: neural-crest deletion of Hand2 causes outflow tract and aortic arch artery misalignment. Reason: Hand2 in cardiac neural crest is required for outflow tract alignment; a core developmental role of HAND2. Supporting Evidence: PMID:19008477 loss of Hand2 in the NC lineage leads to the misalignment of the outflow tract and aortic arch arteries PMID:9171826 the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches |
| GO:0003219 cardiac right ventricle formation | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse: Hand2-null mice fail to form the right ventricle. Reason: Classical core phenotype of dHAND loss; dHAND is expressed in the right ventricle-fated segment and acts there as a TF. Supporting Evidence: PMID:9171826 the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches PMID:9171826 restricted to segments of the heart tube fated to form the right and left ventricles PMID:11784028 Complete ventricular dysgenesis was observed in Nkx2.5(-/-)dHAND(-/-) mutants |
| GO:0003266 regulation of secondary heart field cardioblast proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from mouse: neural crest Hand2 loss affects proliferation of second heart field-derived myocardium. Reason: The effect is non-cell-autonomous (cNC signalling to SHF); valid but secondary to HAND2 TF function in the neural crest. Supporting Evidence: PMID:19008477 Loss of Hand2 in NC also uncovered a novel role for the cNC in regulating proliferation and differentiation of the second heart field-derived myocardium PMID:19008477 Hand2 functions in part by regulating signaling from the cNC to other cardiac lineages but not by regulating migration or survival of the cNC |
| GO:0003266 regulation of secondary heart field cardioblast proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: neural crest Hand2 loss affects proliferation of second heart field-derived myocardium. Reason: The effect is non-cell-autonomous (cNC signalling to SHF); valid but secondary to HAND2 TF function in the neural crest. Supporting Evidence: PMID:19008477 Loss of Hand2 in NC also uncovered a novel role for the cNC in regulating proliferation and differentiation of the second heart field-derived myocardium PMID:19008477 Hand2 functions in part by regulating signaling from the cNC to other cardiac lineages but not by regulating migration or survival of the cNC |
| GO:0003357 noradrenergic neuron differentiation | NAS PMID:16280598 Phox2 and dHAND transcription factors select shared and uniq... | ACCEPT | Summary: NAS: HAND2 is part of the Phox2/GATA/MASH1 transcription factor network of noradrenergic neurons and potentiates Phox2a on the DBH promoter. Reason: Well supported by mouse conditional knockouts showing loss of sympathetic neurons and TH expression, and by loss of norepinephrine synthesis in neural crest Hand2 mutants. Supporting Evidence: PMID:16280598 dHAND causes an eightfold increase in the affinity of Phox2a for its recognition sites on the DBH promoter region PMID:18501887 conditional disruption of Hand2 results in a significant and progressive loss of neurons as well as a significant loss of TH expression PMID:18501887 Hand2 is a multifunctional DNA binding protein affecting differentiation and cell type-specific gene expression in neural crest-derived noradrenergic sympathetic ganglion neurons PMID:19008477 the lethality is attributable to loss of norepinephrine synthesis that can be overcome by activating adrenergic receptors |
| GO:0003680 minor groove of adenine-thymine-rich DNA binding | IDA PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | MARK AS OVER ANNOTATED | Summary: GO:0003680 minor groove AT-rich DNA binding based on ChIP of a dHAND-MEF2C complex at an A/T sequence of the ANP promoter. Reason: The A/T element is the MEF2 site; HAND2 is a bHLH E-box (major-groove) binder, EMSA showed MEF2C and dHAND do not alter each other's DNA binding, and the ChIP signal most plausibly reflects HAND2 recruited by MEF2C. Abstract-only; not removed, but this does not represent a HAND2 activity. Supporting Evidence: PMID:15486975 dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP PMID:15486975 MEF2C and dHAND do not influence each other's DNA binding activity |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning annotation to the generic DNA-binding TF activity term. Reason: Correct but less specific than the Pol II-specific term supported by experiments and IBA. Proposed replacements: DNA-binding transcription factor activity, RNA polymerase II-specific Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0005515 protein binding | IPI PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | MODIFY | Summary: IPI: HAND2 interacts with MEF2C (GST-pulldown, co-IP). Reason: Generic protein binding is uninformative; the partner is a Pol II DNA-binding TF, so GO:0061629 captures the function. Proposed replacements: RNA polymerase II-specific DNA-binding transcription factor binding Supporting Evidence: PMID:15486975 full-length MEF2C protein is able to interact with dHAND in vitro and in vivo PMID:15486975 dHAND and MEF2C synergistically activated expression of the atrial naturetic peptide gene (ANP) in transfected HeLa cells |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MODIFY | Summary: IPI: binary Y2H interactome detects HAND2 with the E-protein TCF4. Reason: Generic protein binding; TCF4 is a class I bHLH E-protein, the obligate heterodimerization partner class of HAND2, so bHLH transcription factor binding is informative. Proposed replacements: bHLH transcription factor binding Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: IPI: BioPlex AP-MS detects HAND2 with TCF4. Reason: As above: bHLH E-protein heterodimerization partner; replace generic protein binding. Proposed replacements: bHLH transcription factor binding Supporting Evidence: PMID:33961781 Through affinity-purification mass spectrometry, we have created two proteome-scale, cell-line-specific interaction networks PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA nucleus. Reason: HAND2 is a nuclear TF. Supporting Evidence: PMID:16280598 All three proteins are bound to the DBH and PHOX2B promoter regions in SH-SY5Y neuroblastoma cells |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: IEA nucleus (UniProt subcellular location / orthology). Reason: Nuclear TF. Supporting Evidence: PMID:16280598 All three proteins are bound to the DBH and PHOX2B promoter regions in SH-SY5Y neuroblastoma cells |
| GO:0005667 transcription regulator complex | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse: HAND2 forms heterodimeric DNA-binding complexes with E-proteins and higher order complexes with GATA4/p300. Reason: Well supported by heterodimer and enhanceosome-like complex data. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:11994297 the bHLH domain of dHAND physically interacted with the C-terminal zinc finger domain of GATA4 forming a higher order complex |
| GO:0005667 transcription regulator complex | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: HAND2 forms heterodimeric DNA-binding complexes with E-proteins and higher order complexes with GATA4/p300. Reason: Well supported by heterodimer and enhanceosome-like complex data. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:11994297 the bHLH domain of dHAND physically interacted with the C-terminal zinc finger domain of GATA4 forming a higher order complex |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA regulation of transcription by RNA polymerase II. Reason: Core process for a Pol II TF. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:12392994 HAND2 is an upstream transcriptional regulator of ANP expression |
| GO:0007507 heart development | IBA GO_REF:0000033 | ACCEPT | Summary: IBA heart development at the Hand clade node. Reason: Hand factors are conserved cardiac regulators (fly Hand to vertebrate HAND1/2); matches module process. Supporting Evidence: PMID:9171826 the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches PMID:11784028 Complete ventricular dysgenesis was observed in Nkx2.5(-/-)dHAND(-/-) mutants |
| GO:0007507 heart development | IEA GO_REF:0000107 | ACCEPT | Summary: IEA heart development from rat. Reason: Core developmental role. Supporting Evidence: PMID:9171826 the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches |
| GO:0007507 heart development | NAS PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | ACCEPT | Summary: NAS statement that dHAND is essential for heart development. Reason: Supported by knockout data (PMID:9171826). Supporting Evidence: PMID:9171826 the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches |
| GO:0007512 adult heart development | IEP PMID:9878849 Molecular cloning of the human HAND2 gene. | MARK AS OVER ANNOTATED | Summary: IEP: HAND2 mRNA strongly expressed in human heart (Northern blot). Reason: Expression in heart does not show involvement in adult heart development; HAND2 roles are embryonic, with pathological re-expression in failing adult myocardium covered by the hypertrophy annotations. Supporting Evidence: PMID:9878849 Northern analysis indicates that the HAND2 transcript is 2.3 kb in length and strongly expressed in the human heart PMID:24161931 increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium |
| GO:0010613 positive regulation of cardiac muscle hypertrophy | IDA PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | KEEP AS NON CORE | Summary: Hand2 re-expression drives pathological cardiac hypertrophy; Hand2 deletion confers resistance to pressure-overload hypertrophy. Reason: Supported by gain- and loss-of-function data; a disease-context role downstream of calcineurin/NFAT, not the developmental core. Supporting Evidence: PMID:24161931 mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy PMID:24161931 conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program |
| GO:0010613 positive regulation of cardiac muscle hypertrophy | IGI PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | KEEP AS NON CORE | Summary: IGI with calcineurin (PPP3CA): calcineurin/NFAT signalling re-induces Hand2 in hypertrophy. Reason: Genetic interaction in hypertrophy pathway; pathological context. Supporting Evidence: PMID:24161931 increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium PMID:24161931 mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy |
| GO:0010613 positive regulation of cardiac muscle hypertrophy | IGI PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | KEEP AS NON CORE | Summary: IGI with MEF2A in pathological hypertrophy. Reason: Abstract-only; deferred to curator; pathological context. Supporting Evidence: PMID:24161931 mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy PMID:24161931 conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program |
| GO:0010628 positive regulation of gene expression | IMP PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | KEEP AS NON CORE | Summary: IMP positive regulation of gene expression: Hand2 required for induction of fetal gene program in pressure overload. Reason: Broad term; HAND2 regulates gene expression via its TF activity (better captured by GO:0045944); retained as non-core. Supporting Evidence: PMID:24161931 conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program |
| GO:0010629 negative regulation of gene expression | IMP PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | UNDECIDED | Summary: IMP negative regulation of gene expression from the Hand2/miR-25 heart failure study. Reason: Only the abstract is available; the repressed target(s) cannot be identified, and HAND2 is not otherwise known as a repressor in this context. Supporting Evidence: PMID:24161931 conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from mouse: Hand loss impairs survival/expansion of ventricular myocardium. Reason: Survival effect is a downstream consequence of HAND transcriptional programs; valid but non-core. Supporting Evidence: PMID:11784028 a role of HAND genes in survival and expansion of the ventricular segment, but not in specification of ventricular cardiomyocytes |
| GO:0010667 negative regulation of cardiac muscle cell apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: Hand loss impairs survival/expansion of ventricular myocardium. Reason: Survival effect is a downstream consequence of HAND transcriptional programs; valid but non-core. Supporting Evidence: PMID:11784028 a role of HAND genes in survival and expansion of the ventricular segment, but not in specification of ventricular cardiomyocytes |
| GO:0032991 protein-containing complex | IDA PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | MODIFY | Summary: IDA: dHAND and MEF2C form a protein complex on the ANP promoter. Reason: Protein-containing complex is uninformative; the complex is a transcription regulator complex. Proposed replacements: transcription regulator complex Supporting Evidence: PMID:15486975 dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP PMID:11994297 the bHLH domain of dHAND physically interacted with the C-terminal zinc finger domain of GATA4 forming a higher order complex |
| GO:0034103 regulation of tissue remodeling | IDA PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | KEEP AS NON CORE | Summary: IDA regulation of tissue remodeling: Hand2 deletion reduces pressure-overload fibrosis and remodeling. Reason: Pathological remodeling secondary to HAND2-driven hypertrophic gene programs. Supporting Evidence: PMID:24161931 conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA homodimerization from mouse. Reason: Homodimers form in vitro but HAND2 fails to homodimerize robustly in cells; the physiological partners are E-proteins and other bHLH factors (TWIST1, HAND1). Supporting Evidence: PMID:11812799 HAND2 fails to homodimerize in a mammalian two-hybrid assay but demonstrates robust HAND2/E12 interaction PMID:15735646 Dimerization partner choice by Twist1 and Hand2 can be modulated by protein kinase A- and protein phosphatase 2A-regulated phosphorylation of conserved helix I residues |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | MODIFY | Summary: IEA sequence-specific DNA binding from mouse. Reason: Correct but generic; E-box binding is the specific activity. Proposed replacements: E-box binding Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | ACCEPT | Summary: IDA: dHAND and MEF2C synergistically activate the ANP promoter. Reason: Direct transcriptional activation of a Pol II target. Supporting Evidence: PMID:15486975 dHAND and MEF2C synergistically activated expression of the atrial naturetic peptide gene (ANP) in transfected HeLa cells |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:16280598 Phox2 and dHAND transcription factors select shared and uniq... | ACCEPT | Summary: IDA: dHAND potentiates Phox2a transactivation and binds DBH/PHOX2B promoters. Reason: Potentiation of DBH promoter activity with promoter occupancy. Supporting Evidence: PMID:16280598 dHAND causes an eightfold increase in the affinity of Phox2a for its recognition sites on the DBH promoter region PMID:16280598 All three proteins are bound to the DBH and PHOX2B promoter regions in SH-SY5Y neuroblastoma cells |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | ACCEPT | Summary: IDA positive regulation of transcription in heart failure context. Reason: Consistent with HAND2 activator function; curator read full text. Supporting Evidence: PMID:24161931 conditional gene-targeted Hand2 mice demonstrated a marked resistance to pressure-overload-induced hypertrophy, fibrosis, ventricular dysfunction and induction of a fetal gene program PMID:11812799 HAND2 contains a strong transcriptional activation domain in the amino-terminal third of the protein |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse for positive regulation of Pol II transcription. Reason: Core. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:11812799 HAND2 contains a strong transcriptional activation domain in the amino-terminal third of the protein |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse for positive regulation of Pol II transcription. Reason: Core. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins PMID:11812799 HAND2 contains a strong transcriptional activation domain in the amino-terminal third of the protein |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO protein dimerization activity from the HLH domain. Reason: Dimerization via the HLH motif is central to HAND2 mechanism, including DNA-binding-independent functions mediated only by the HLH. Supporting Evidence: PMID:12070084 digit duplication by dHAND requires neither the transcriptional activation domain nor the basic region, but only the HLH motif PMID:15735646 Dimerization partner choice by Twist1 and Hand2 can be modulated by protein kinase A- and protein phosphatase 2A-regulated phosphorylation of conserved helix I residues |
| GO:0048538 thymus development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from mouse: neural crest Hand2 deletion affects thymus development. Reason: Neural crest-derived pharyngeal contribution; peripheral to core cardiac/limb/autonomic roles. Supporting Evidence: PMID:19008477 Hand2 plays a pivotal role in regulating both cell-autonomous and -nonautonomous functions of the cNC |
| GO:0048538 thymus development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: neural crest Hand2 deletion affects thymus development. Reason: Neural crest-derived pharyngeal contribution; peripheral to core cardiac/limb/autonomic roles. Supporting Evidence: PMID:19008477 Hand2 plays a pivotal role in regulating both cell-autonomous and -nonautonomous functions of the cNC |
| GO:0048706 embryonic skeletal system development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA embryonic skeletal system development from mouse (branchial arch/mandible downstream of endothelin-1). Reason: Hand2 is required in branchial arch mesenchyme and limb skeletal patterning; non-core developmental output. Supporting Evidence: PMID:10804186 identify dHAND as an upstream activator of Shh expression and important transcriptional regulator of limb development |
| GO:0061309 cardiac neural crest cell development involved in outflow tract morphogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: IEA from mouse: Hand2 acts cell-autonomously in cardiac neural crest required for OFT morphogenesis. Reason: Supported by Wnt1-Cre conditional deletion; Hand2 acts within the cNC but not for migration/survival. Supporting Evidence: PMID:19008477 loss of Hand2 in the NC lineage leads to the misalignment of the outflow tract and aortic arch arteries PMID:19008477 Hand2 plays a pivotal role in regulating both cell-autonomous and -nonautonomous functions of the cNC |
| GO:0061309 cardiac neural crest cell development involved in outflow tract morphogenesis | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from mouse: Hand2 acts cell-autonomously in cardiac neural crest required for OFT morphogenesis. Reason: Supported by Wnt1-Cre conditional deletion; Hand2 acts within the cNC but not for migration/survival. Supporting Evidence: PMID:19008477 loss of Hand2 in the NC lineage leads to the misalignment of the outflow tract and aortic arch arteries PMID:19008477 Hand2 plays a pivotal role in regulating both cell-autonomous and -nonautonomous functions of the cNC |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA: HAND2 binds partner DNA-binding TFs (GATA4, MEF2C, PHOX2A, NKX2-5 synergy). Reason: Core MF: HAND2 physically binds GATA4 via its bHLH domain and MEF2C, enabling DNA-binding-independent co-activation of cardiac genes. Supporting Evidence: PMID:11994297 the bHLH domain of dHAND physically interacted with the C-terminal zinc finger domain of GATA4 forming a higher order complex PMID:15486975 full-length MEF2C protein is able to interact with dHAND in vitro and in vivo PMID:11994297 this functional synergy was shown to be GATA site-dependent, but E-box site-independent |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS (rat): HAND2 binds partner DNA-binding TFs (GATA4, MEF2C, PHOX2A, NKX2-5 synergy). Reason: Core MF: HAND2 physically binds GATA4 via its bHLH domain and MEF2C, enabling DNA-binding-independent co-activation of cardiac genes. Supporting Evidence: PMID:11994297 the bHLH domain of dHAND physically interacted with the C-terminal zinc finger domain of GATA4 forming a higher order complex PMID:15486975 full-length MEF2C protein is able to interact with dHAND in vitro and in vivo PMID:11994297 this functional synergy was shown to be GATA site-dependent, but E-box site-independent |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS (mouse): HAND2 binds partner DNA-binding TFs (GATA4, MEF2C, PHOX2A, NKX2-5 synergy). Reason: Core MF: HAND2 physically binds GATA4 via its bHLH domain and MEF2C, enabling DNA-binding-independent co-activation of cardiac genes. Supporting Evidence: PMID:11994297 the bHLH domain of dHAND physically interacted with the C-terminal zinc finger domain of GATA4 forming a higher order complex PMID:15486975 full-length MEF2C protein is able to interact with dHAND in vitro and in vivo PMID:11994297 this functional synergy was shown to be GATA site-dependent, but E-box site-independent |
| GO:0070374 positive regulation of ERK1 and ERK2 cascade | IMP PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | UNDECIDED | Summary: IMP positive regulation of ERK1/2 cascade from the Hand2 heart-failure study. Reason: Abstract-only; likely a signalling readout of hypertrophy rather than direct HAND2 participation, but this cannot be verified without the full text. Supporting Evidence: PMID:24161931 mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy |
| GO:0070888 E-box binding | IDA PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | ACCEPT | Summary: IDA E-box binding by EMSA in the dHAND/MEF2C study. Reason: Consistent with established heterodimeric E-box binding. Supporting Evidence: PMID:15486975 MEF2C and dHAND do not influence each other's DNA binding activity PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0070888 E-box binding | IEA GO_REF:0000107 | ACCEPT | Summary: IEA E-box binding from mouse. Reason: Established mouse IDA. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0070888 E-box binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS E-box binding (contributes_to) from mouse. Reason: Heterodimer-dependent E-box binding. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0071300 cellular response to retinoic acid | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: IEA cellular response to retinoic acid from rat. Reason: Likely reflects RA-responsive expression; no evidence HAND2 executes a function within RA response. Supporting Evidence: PMID:11812799 HAND2 functions as a transcription activator by binding a subset of E-boxes as a heterodimer with E-proteins |
| GO:0160108 animal gross anatomical part developmental process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA animal gross anatomical part developmental process. Reason: Uninformative high-level grouping term; specific developmental processes are annotated. Supporting Evidence: PMID:9171826 the first demonstration of a single gene controlling the formation of the mesodermally derived right ventricle and the neural crest-derived aortic arches PMID:10804186 identify dHAND as an upstream activator of Shh expression and important transcriptional regulator of limb development |
| GO:1900745 positive regulation of p38MAPK cascade | IMP PMID:24161931 Nfat and miR-25 cooperate to reactivate the transcription fa... | UNDECIDED | Summary: IMP positive regulation of p38MAPK cascade from the heart-failure study. Reason: Abstract-only; probably an indirect signalling readout, cannot verify. Supporting Evidence: PMID:24161931 mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: IDA sequence-specific dsDNA binding from methylation-SELEX of 542 human TFs. Reason: HAND2 data are in the supplementary SELEX motifs (not in cached text); consistent with E-box binding. Deferred to curator. Supporting Evidence: PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX (systematic evolution of ligands by exponential enrichment), we found that there are also many TFs that prefer CpG-methylated sequences |
| GO:2001262 positive regulation of semaphorin-plexin signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: IEA from mouse: neural crest Hand2 regulates Sema3c-dependent signalling from cNC. Reason: Reflects HAND2-dependent target gene expression in cNC (non-autonomous signalling); valid but non-core. Supporting Evidence: PMID:19008477 Hand2 functions in part by regulating signaling from the cNC to other cardiac lineages but not by regulating migration or survival of the cNC |
| GO:2001262 positive regulation of semaphorin-plexin signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS from mouse: neural crest Hand2 regulates Sema3c-dependent signalling from cNC. Reason: Reflects HAND2-dependent target gene expression in cNC (non-autonomous signalling); valid but non-core. Supporting Evidence: PMID:19008477 Hand2 functions in part by regulating signaling from the cNC to other cardiac lineages but not by regulating migration or survival of the cNC |
| GO:0048485 sympathetic nervous system development | IMP PMID:18501887 Conditional deletion of Hand2 reveals critical functions in ... | NEW | Summary: Hand2 is required in neural crest-derived sympathetic precursors for neurogenesis and noradrenergic gene expression and can activate the autonomic neuronal program. Reason: Mouse conditional knockout and gain-of-function show HAND2 acting as a TF within sympathetic precursors (cell-autonomous); mouse Hand2 carries this term (IDA, PMID:16145670). Supporting Evidence: PMID:18501887 conditional disruption of Hand2 results in a significant and progressive loss of neurons as well as a significant loss of TH expression PMID:18501887 Hand2 is a multifunctional DNA binding protein affecting differentiation and cell type-specific gene expression in neural crest-derived noradrenergic sympathetic ganglion neurons PMID:16145670 ectopic expression of Hand 2 activates the neuronal program and promotes the acquisition of a phenotype corresponding to peripheral neurons including neurons of the SNS lineage |
| GO:0060173 limb development | IMP PMID:10804186 The bHLH transcription factor dHAND controls Sonic hedgehog ... | NEW | Summary: dHAND is expressed in posterior limb mesenchyme, required for Shh expression and sufficient to induce an ectopic ZPA. Reason: HAND2 is a posterior-limb TF upstream of Shh (with roles independent of DNA binding via the HLH); human HAND2 lacks a limb term despite strong mouse genetics. Supporting Evidence: PMID:10804186 identify dHAND as an upstream activator of Shh expression and important transcriptional regulator of limb development PMID:12070084 digit duplication by dHAND requires neither the transcriptional activation domain nor the basic region, but only the HLH motif |
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Download this section (compressed HTML)Q: Which HAND2 target genes are regulated through direct E-box binding by HAND2/E-protein heterodimers versus DNA-binding-independent recruitment by GATA4, MEF2C or NKX2-5, and does this differ between heart, limb and sympathetic neurons?
Q: Should GO represent the progesterone-HAND2-FGF stromal pathway in endometrium (embryo implantation/decidualization) as a HAND2 process, given that HAND2 acts by regulating paracrine FGF expression?
Q: Are the ERK1/2 and p38 cascade annotations from the heart failure study direct HAND2 effects or downstream readouts of hypertrophy?
Experiment: Knock in a basic-domain mutant HAND2 in human iPSC-derived cardiomyocytes and neural crest; profile HAND2, GATA4 and E-protein occupancy by CUT&RUN and transcriptome by RNA-seq.
Hypothesis: A DNA-binding-deficient (basic region mutant) HAND2 retains GATA4-dependent activation of cardiac targets but loses E-box-dependent targets.
Type: genome-wide DNA-binding and transcriptomic profiling
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