MEF2C (myocyte enhancer factor 2C) is a MADS-box transcription factor of the MEF2 family. Its N-terminal MADS and MEF2 domains mediate homo- and heterodimerization with other MEF2 proteins and binding to A/T-rich MEF2 sites (CTA(A/T)4TAG) in promoters and enhancers of muscle, cardiac, neuronal, lymphoid and skeletal genes. The C-terminal transactivation domains activate RNA polymerase II transcription with coactivators such as p300 and MAML1. MEF2C binds partner DNA-binding factors through its DNA-binding domain: myogenic bHLH proteins (MyoD, myogenin), HAND1/HAND2, TBX5, NKX2-5, SOX10 and SMADs. These partners synergistically activate targets such as NPPA (ANF) and MYH6. Class II histone deacetylases (HDAC4/5/7/9) bind MEF2C and repress it; calcium/calmodulin-dependent kinase signalling releases them. p38 MAPK, ERK5 and skMLCK phosphorylation and SUMOylation modulate its activity. Mef2c is expressed in cardiac precursors and the second heart field, where it is a direct ISL1/GATA target. Mef2c-null mice fail to undergo heart looping, lack the right ventricle and do not express a subset of cardiac genes. MEF2C and NKX2-5 up-regulate each other. MEF2C also amplifies MyoD-driven skeletal myogenesis. Outside muscle it controls chondrocyte hypertrophy and endochondral ossification, vascular development, megakaryopoiesis and B-cell proliferation/survival after BCR stimulation. In the brain it governs cortical neuron differentiation and limits excitatory synapse number. Heterozygous loss of MEF2C causes a severe neurodevelopmental disorder (MEF2C haploinsufficiency syndrome) with intellectual disability, absent speech, hypotonia, stereotypic movements and seizures.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:18079734 MEF2C is activated by multiple mechanisms in a subset of T-a... | KEEP AS NON CORE | Summary: MEF2C represses NR4A1/NUR77 in T-ALL cell lines and is seen in nuclear speckles interpreted as repression complexes. Reason: MEF2C can repress targets when bound by class II HDACs, so repression is a real but context-dependent output; the primary role is activation. Evidence here is from leukaemia lines with ectopic MEF2C. Supporting Evidence: PMID:18079734 MEF2C consistently inhibits expression of NR4A1/NUR77 PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation |
| GO:0000165 MAPK cascade | IDA PMID:9858528 Regulation of the MEF2 family of transcription factors by p3... | MARK AS OVER ANNOTATED | Summary: MAPK cascade, based on p38 regulation of MEF2 factors. Reason: MEF2C is a downstream substrate of p38 MAPK (p38 phosphorylation raises its transactivation activity). It does not act as a kinase tier in the cascade. Being acted on by a cascade is not participation in it. A response or regulation term would fit better, so this is an over-annotation. The cited paper mainly concerns MEF2A. Supporting Evidence: PMID:9858528 We showed previously that the transactivation activity of MEF2C is stimulated by p38 mitogen-activated protein (MAP) kinase PMID:9069290 LPS increases the transactivation activity of MEF2C through p38-catalysed phosphorylation |
| GO:0000165 MAPK cascade | IMP PMID:11160896 Smad proteins function as co-modulators for MEF2 transcripti... | MARK AS OVER ANNOTATED | Summary: MAPK cascade, from Smad/MEF2 co-modulation in TGF-beta signalling. Reason: The paper shows Smad2/4 boost GAL4-MEF2C activity, and p38 phospho-acceptor sites are needed for this. MEF2C is a transcriptional target of these signals, not a component of the MAPK kinase cascade. Supporting Evidence: PMID:11160896 The over-expression of Smad2 and 4 (Smad2/4) was found to increase the activities of both GAL4βMEF2A and GAL4βMEF2C in high TGF-Ξ² conditions |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based chromatin location for a sequence-specific DNA-binding TF. Reason: MEF2C binds MEF2 sites in promoters and enhancers (e.g. ANP, MYH6, SOST enhancer), so chromatin is where it acts. Supporting Evidence: PMID:15486975 we show that dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP PMID:19204083 they physically associate through their DNA-binding domains to form a complex on the MYH6 promoter |
| GO:0000976 transcription cis-regulatory region binding | ISS GO_REF:0000024 | ACCEPT | Summary: Transcription cis-regulatory region binding, transferred from mouse. Reason: Correct but less specific than GO:0000978. MEF2C binds A/T-rich MEF2 elements in promoters and enhancers. Supporting Evidence: PMID:9162005 Members of the myocyte enhancer factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, serum response factor)-box transcription factors bind an A-T-rich DNA sequence associated with muscle-specific genes PMID:19204083 they physically associate through their DNA-binding domains to form a complex on the MYH6 promoter |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | ACCEPT | Summary: Original cloning paper showing hMEF2C products bind the MEF2 site and transactivate. Reason: Direct DNA-binding data for the MEF2 site in muscle gene regulatory regions. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA sequence-specific Pol II regulatory region DNA binding from the MEF2-like N-terminal domain. Reason: Consistent with the experimental data; the MADS/MEF2 domain is the DNA-binding domain. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors PMID:9162005 Members of the myocyte enhancer factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, serum response factor)-box transcription factors bind an A-T-rich DNA sequence associated with muscle-specific genes |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA Pol II cis-regulatory region sequence-specific DNA binding across the MADS-box family. Reason: Phylogenetically sound; MEF2C binds MEF2 cis-elements in promoters and enhancers. Supporting Evidence: PMID:19204083 they physically associate through their DNA-binding domains to form a complex on the MYH6 promoter PMID:15486975 we show that dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA Pol II-specific DNA-binding TF activity for the MADS-box/MEF2 clade; human MEF2C is one of the experimental donors. Reason: This is the core molecular function. MEF2C binds MEF2 sites and activates transcription by RNA polymerase II. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors PMID:9162005 Members of the myocyte enhancer factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, serum response factor)-box transcription factors bind an A-T-rich DNA sequence associated with muscle-specific genes |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IDA PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | ACCEPT | Summary: hMEF2C products have DNA-binding and transactivating activity. Reason: Direct evidence for the core activity. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA-predicted Pol II DbTF activity. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: TFClass-based DbTF assignment (MADS/MEF2 class 5.1.1). Reason: Consistent with experimental evidence. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISS PMID:21610032 The MADS box transcription factor MEF2C regulates melanocyte... | ACCEPT | Summary: ISS DbTF activity, from the mouse melanocyte/neural crest study. Reason: MEF2C binds a MEF2 site and activates the Mef2c neural crest enhancer, consistent with Pol II DbTF activity. Supporting Evidence: PMID:21610032 SOX10 and MEF2C physically interact and function cooperatively to activate the Mef2c gene in a feed-forward transcriptional circuit PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IDA PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | ACCEPT | Summary: MEF2C activates the ANP promoter, synergistically with HAND2, by binding A/T elements. Reason: Direct evidence that MEF2C is an activator. Activation is its predominant mode. Supporting Evidence: PMID:15486975 dHAND and MEF2C synergistically activated expression of the atrial naturetic peptide gene (ANP) in transfected HeLa cells PMID:15486975 we show that dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP |
| GO:0001568 blood vessel development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Blood vessel development, transferred from mouse. Reason: Mef2c-null mice have vascular defects, and UniProt notes a role in vascular development. This is a real developmental role but pleiotropic and downstream of the TF activity. Supporting Evidence: file:human/MEF2C/MEF2C-uniprot.txt involved in vascular development |
| GO:0001649 osteoblast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Osteoblast differentiation, transferred from mouse. Reason: MEF2C acts in the bone lineage (it controls the osteocyte SOST enhancer and chondrocyte hypertrophy). An osteoblast differentiation role is plausible but pleiotropic and not well supported here. Supporting Evidence: PMID:17696759 SOST expression in osteocytes of adult bone and its inhibition by PTH is mediated by MEF2A, C, and D transcription factors controlling the SOST bone enhancer PMID:17336904 controls bone development by activating the gene program for chondrocyte hypertrophy |
| GO:0001764 neuron migration | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuron migration, transferred from mouse. Reason: Nestin-Cre Mef2c conditional knockouts show abnormal neuronal compaction and distribution in the neocortex. This is a pleiotropic neural phenotype downstream of transcriptional control. Supporting Evidence: PMID:18599437 conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size PMID:18599437 Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex |
| GO:0001782 B cell homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: B cell homeostasis, transferred from mouse. Reason: Mef2c-deficient mice show an age-dependent loss of B-cell progenitors. This is a real but non-core haematopoietic role. Supporting Evidence: PMID:19211936 an Scl-independent requirement for Mef2C in B-lymphoid homeostasis was observed in Mef2C-deficient mice |
| GO:0001947 heart looping | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Heart looping, transferred from mouse. Reason: Mef2c-null hearts fail to loop. Looping is a morphogenetic consequence of MEF2C's transcriptional control of myocardial genes, so it is kept as non-core. Supporting Evidence: PMID:9162005 In mice homozygous for a null mutation of MEF2C, the heart tube did not undergo looping morphogenesis, the future right ventricle did not form, and a subset of cardiac muscle genes was not expressed |
| GO:0001958 endochondral ossification | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Endochondral ossification, transferred from mouse. Reason: Mef2c deletion in cartilage impairs hypertrophy and ossification. This is a real developmental role outside the muscle/heart core. Supporting Evidence: PMID:17336904 Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice |
| GO:0001974 blood vessel remodeling | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Blood vessel remodeling, transferred from mouse. Reason: Consistent with the vascular requirement for MEF2C. Pleiotropic. Supporting Evidence: file:human/MEF2C/MEF2C-uniprot.txt involved in vascular development |
| GO:0002062 chondrocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Chondrocyte differentiation, transferred from mouse. Reason: MEF2C activates the chondrocyte hypertrophy gene program (GO:0003415 chondrocyte hypertrophy would be more precise). It is a non-core skeletal role. Supporting Evidence: PMID:17336904 controls bone development by activating the gene program for chondrocyte hypertrophy PMID:17336904 Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice |
| GO:0002467 germinal center formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Germinal center formation, transferred from mouse. Reason: Mef2c-deficient B cells give reduced germinal center formation in vivo. Non-core immune role. Supporting Evidence: PMID:18438409 loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell-dependent antibody responses and germinal center formation in vivo |
| GO:0002634 regulation of germinal center formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of germinal center formation, transferred from mouse. Reason: Same evidence as germinal center formation. Non-core. Supporting Evidence: PMID:18438409 loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell-dependent antibody responses and germinal center formation in vivo |
| GO:0002931 response to ischemia | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Response to ischemia, transferred from rat Mef2c. Reason: This is a stress-response expression association. It does not describe a function of the MEF2C transcription factor. No cited evidence shows MEF2C carrying out an ischemic response. |
| GO:0003138 primary heart field specification | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Primary heart field specification, transferred from mouse. Reason: Mef2c-null embryos form a linear heart tube from the primary heart field. The defect is in looping, right ventricle formation and myocardial gene expression, i.e. differentiation and morphogenesis rather than specification. MEF2 acts in differentiation, not specification, as in Drosophila. Supporting Evidence: PMID:9162005 In mice homozygous for a null mutation of MEF2C, the heart tube did not undergo looping morphogenesis, the future right ventricle did not form, and a subset of cardiac muscle genes was not expressed PMID:8548800 Members of the myocyte enhancer factor-2 (MEF2) family of MADS domain transcription factors cannot induce myogenesis in transfected fibroblasts |
| GO:0003139 secondary heart field specification | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Secondary heart field specification, transferred from mouse. Reason: Mef2c is a direct ISL1/GATA target in the anterior (second) heart field and is needed for SHF-derived outflow tract and right ventricle. Whether it specifies SHF cells or acts in their later differentiation is uncertain; Nkx2-5;Mef2c double mutants still express SHF markers. Kept as non-core. Supporting Evidence: PMID:15253934 The MADS domain transcription factor MEF2C is required for proper formation of the cardiac outflow tract and right ventricle, suggesting a key role in anterior heart field development PMID:15253934 establish Mef2c as the first direct transcriptional target of ISL1 in the anterior heart field PMID:19035347 Co-immunoprecipitation and mammalian two-hybrid experiments revealed a direct molecular interaction between Nkx2.5 and Mef2c |
| GO:0003151 outflow tract morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Outflow tract morphogenesis, transferred from mouse. Reason: MEF2C is required for proper outflow tract formation. A real developmental phenotype, downstream of the core TF activity. Supporting Evidence: PMID:15253934 The MADS domain transcription factor MEF2C is required for proper formation of the cardiac outflow tract and right ventricle, suggesting a key role in anterior heart field development |
| GO:0003185 sinoatrial valve morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: Sinoatrial valve morphogenesis, transferred from mouse. Reason: No accessible evidence for a sinoatrial valve role of MEF2C. The mouse source annotation could not be checked. |
| GO:0003211 cardiac ventricle formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cardiac ventricle formation, transferred from mouse. Reason: The future right ventricle does not form in Mef2c-null mice, and Nkx2-5;Mef2c double mutants lack ventricles. This is a hallmark phenotype but at the organ level, downstream of cardiomyocyte differentiation control. Kept as non-core. Supporting Evidence: PMID:9162005 In mice homozygous for a null mutation of MEF2C, the heart tube did not undergo looping morphogenesis, the future right ventricle did not form, and a subset of cardiac muscle genes was not expressed PMID:9162005 MEF2C is an essential regulator of cardiac myogenesis and right ventricular development |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based DNA binding. Reason: Correct but uninformative. Sequence-specific Pol II cis-regulatory binding (GO:0000978) already captures it. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0003680 minor groove of adenine-thymine-rich DNA binding | IDA PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | KEEP AS NON CORE | Summary: Minor groove of A/T-rich DNA binding, from ANP promoter ChIP/EMSA data. Reason: MEF2C binds A/T-rich MEF2 sites (CTA(A/T)4TAG), which is consistent with this term. Kept as a mechanistic detail rather than the core function term. Supporting Evidence: PMID:15486975 we show that dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP PMID:9162005 Members of the myocyte enhancer factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, serum response factor)-box transcription factors bind an A-T-rich DNA sequence associated with muscle-specific genes |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:16043483 MEF2-dependent recruitment of the HAND1 transcription factor... | ACCEPT | Summary: DNA-binding TF activity, from the HAND1/MEF2 synergy study. Reason: MEF2 binding sites are sufficient for synergistic activation, so MEF2C acts as a DNA-binding TF. GO:0000981 is the more specific equivalent. Supporting Evidence: PMID:16043483 MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy |
| GO:0005515 protein binding | IPI PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | MODIFY | Summary: MEF2C binds HAND2 (dHAND) and the two synergistically activate the ANP promoter. Reason: Generic protein binding is uninformative. HAND2 is a Pol II DNA-binding TF, so this is DNA-binding TF partner binding. 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:16510869 The Notch coactivator, MAML1, functions as a novel coactivat... | MODIFY | Summary: MEF2C binds the coactivator MAML1, which enhances MEF2C-dependent transcription and myogenesis. Reason: Generic protein binding is uninformative. MAML1 acts as a MEF2C coactivator. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:16510869 we determined that MAML1 interacts with MEF2C (myocyte enhancer factor 2C), functioning as its potent co-transcriptional regulator |
| GO:0005515 protein binding | IPI PMID:18588859 TGF-beta activates ERK5 in human renal epithelial cells. | REMOVE | Summary: TGF-beta increases association of MEK5 with phospho-ERK5 and MEF2C in renal epithelial cells. Reason: Generic protein binding is uninformative. The association is a co-precipitating signalling complex with no defined direct partner. It adds nothing beyond MEF2C being a target of ERK5 signalling. Supporting Evidence: PMID:18588859 TGF-beta increased the association of MEK5 with phospho-ERK5 and MEF2C |
| GO:0005515 protein binding | IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous... | MODIFY | Summary: High-throughput TF interaction atlas: MEF2C-HDAC9. MEF2C binds class II HDACs (HDAC4/5/7/9). They repress MEF2-dependent transcription and are released on differentiation. Reason: Generic protein binding is uninformative. The partner is a class II HDAC, and binding of class II HDACs is a central regulatory interaction of MEF2C. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation file:human/MEF2C/MEF2C-uniprot.txt Interacts with HDAC4 and HDAC9; the interaction with HDACs |
| GO:0005515 protein binding | IPI PMID:20211142 An atlas of combinatorial transcriptional regulation in mous... | MODIFY | Summary: High-throughput TF interaction atlas: MEF2C-HDAC5. MEF2C binds class II HDACs (HDAC4/5/7/9). They repress MEF2-dependent transcription and are released on differentiation. Reason: Generic protein binding is uninformative. The partner is a class II HDAC. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation file:human/MEF2C/MEF2C-uniprot.txt Forms a complex with class II HDACs in undifferentiating |
| GO:0005515 protein binding | IPI PMID:20936779 A human MAP kinase interactome. | MODIFY | Summary: MAP kinase interactome screen: MEF2C-HDAC9. MEF2C binds class II HDACs (HDAC4/5/7/9). They repress MEF2-dependent transcription and are released on differentiation. Reason: Generic protein binding is uninformative. The partner is a class II HDAC. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation file:human/MEF2C/MEF2C-uniprot.txt Interacts with HDAC4 and HDAC9; the interaction with HDACs |
| GO:0005515 protein binding | IPI PMID:21556048 Skeletal myosin light chain kinase regulates skeletal myogen... | MODIFY | Summary: MEF2C interacts with mouse p300 (Ep300). Phosphorylation of MEF2C on T80 by skMLCK is needed to recruit p300 to skeletal muscle promoters. Reason: Generic protein binding is uninformative. The partner is the histone acetyltransferase/coactivator p300, recruited by MEF2C. Proposed replacements: histone acetyltransferase binding Supporting Evidence: PMID:21556048 MEFT80A was deficient in recruitment of p300 to skeletal but not cardiac muscle promoters PMID:21556048 skMLCK regulates MRF expression by controlling the MEF2C-dependent recruitment of histone acetyltransferases to skeletal muscle promoters |
| GO:0005515 protein binding | IPI PMID:21556048 Skeletal myosin light chain kinase regulates skeletal myogen... | MODIFY | Summary: MEF2C binds mouse skMLCK (Mylk2), which phosphorylates MEF2C T80. Reason: Generic protein binding is uninformative. The partner is a protein kinase that binds and phosphorylates MEF2C. Proposed replacements: protein kinase binding Supporting Evidence: PMID:21556048 phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis |
| GO:0005515 protein binding | IPI PMID:21556048 Skeletal myosin light chain kinase regulates skeletal myogen... | MODIFY | Summary: MEF2C binds human skMLCK (MYLK2). Reason: Generic protein binding is uninformative. The partner is a protein kinase that binds and phosphorylates MEF2C. Proposed replacements: protein kinase binding Supporting Evidence: PMID:21556048 phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis |
| GO:0005515 protein binding | IPI PMID:23752268 The functional interactome landscape of the human histone de... | MODIFY | Summary: HDAC interactome: MEF2C co-purifies with class II HDACs. MEF2C binds class II HDACs (HDAC4/5/7/9). They repress MEF2-dependent transcription and are released on differentiation. Reason: Generic protein binding is uninformative. The partner is a class II HDAC. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:23752268 MEF2C, a well-known interaction among the class II HDACs (Lu et al, 2000), was identified in the HDAC immunoisolates PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation |
| GO:0005515 protein binding | IPI PMID:31988313 Genetic interaction screen for severe neurodevelopmental dis... | MODIFY | Summary: UBE3A and MEF2C co-immunoprecipitate from HEK293 cells, following a fly genetic interaction screen. Reason: Generic protein binding is uninformative. The partner is the E3 ubiquitin ligase UBE3A. Its functional significance is unclear (no transcriptional cross-regulation was found). Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:31988313 we could show that UBE3A and MEF2C can be co-immunoprecipitated from HEK293 cells co-transfected with Myc-tagged UBE3A and HA-tagged MEF2C |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: HuRI binary Y2H screen: MEF2C-HDAC4. MEF2C binds class II HDACs (HDAC4/5/7/9). They repress MEF2-dependent transcription and are released on differentiation. Reason: Generic protein binding is uninformative. The partner is a class II HDAC, and the MEF2C-HDAC4 balance controls bone development. Proposed replacements: histone deacetylase binding Supporting Evidence: PMID:17336904 Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4) file:human/MEF2C/MEF2C-uniprot.txt Interacts with HDAC4 and HDAC9; the interaction with HDACs |
| GO:0005515 protein binding | IPI PMID:37207277 Using brain cell-type-specific protein interactomes to inter... | REMOVE | Summary: Brain cell-type-specific interactome: MEF2C co-precipitates with CACNA1C. Reason: Generic protein binding is uninformative. It is a proteomic co-IP hit with no functional characterization. A nuclear transcription factor binding an L-type channel pore subunit does not inform MEF2C function. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: IBA nucleus. Reason: MEF2C is a nuclear transcription factor. Supporting Evidence: PMID:9770491 Myogenic cells expressing the chimerical MEF2C/nlsSV40, but not wild-type MEF2C, retained this transcription factor in the nucleus and were resistant to the inhibitory action of TGF-beta PMID:21170291 While neurons from control brains show robust MEF2C immunoreactivity in neuronal nuclei |
| GO:0005634 nucleus | IDA PMID:16510869 The Notch coactivator, MAML1, functions as a novel coactivat... | ACCEPT | Summary: Nuclear localization with MAML1 in muscle cells. Reason: MEF2C is a nuclear transcription factor. Supporting Evidence: PMID:16510869 we determined that MAML1 interacts with MEF2C (myocyte enhancer factor 2C), functioning as its potent co-transcriptional regulator |
| GO:0005634 nucleus | IDA PMID:21170291 MicroRNA-21 dysregulates the expression of MEF2C in neurons ... | ACCEPT | Summary: MEF2C immunoreactivity in neuronal nuclei of human and monkey brain. Reason: MEF2C is a nuclear transcription factor. Supporting Evidence: PMID:21170291 While neurons from control brains show robust MEF2C immunoreactivity in neuronal nuclei |
| GO:0005634 nucleus | IDA PMID:24008018 MEF2C exon Ξ±: role in gene activation and differentiation. | ACCEPT | Summary: Nuclear localization of MEF2C splice variants. Reason: MEF2C is a nuclear transcription factor. Supporting Evidence: PMID:24008018 Transactivation experiments show that the presence of exon Ξ± induces a reduction of transcription levels |
| GO:0005634 nucleus | IDA PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | ACCEPT | Summary: Original characterization of hMEF2C as a nuclear MEF2-site binding factor. Reason: MEF2C is a nuclear transcription factor. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0005634 nucleus | IDA PMID:9770491 Inhibition of myogenesis by transforming growth factor beta ... | ACCEPT | Summary: MEF2C is nuclear in myoblasts; TGF-beta drives MEF2 into the cytoplasm. Reason: MEF2C is a nuclear transcription factor. Supporting Evidence: PMID:9770491 Myogenic cells expressing the chimerical MEF2C/nlsSV40, but not wild-type MEF2C, retained this transcription factor in the nucleus and were resistant to the inhibitory action of TGF-beta |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: IEA nucleus. Reason: MEF2C is a nuclear transcription factor. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: ISS nucleus from rat. Reason: MEF2C is a nuclear transcription factor. Supporting Evidence: PMID:21170291 While neurons from control brains show robust MEF2C immunoreactivity in neuronal nuclei |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-448955 | ACCEPT | Summary: Reactome: p38 phosphorylation of MEF2 in the nucleoplasm. Reason: MEF2C is a nuclear transcription factor. Nucleoplasm is appropriate. Supporting Evidence: PMID:9069290 LPS increases the transactivation activity of MEF2C through p38-catalysed phosphorylation |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-448963 | ACCEPT | Summary: Reactome: MyoD:E protein interaction with MEF2 in the nucleoplasm. Reason: MEF2C is a nuclear transcription factor. Nucleoplasm is appropriate. Supporting Evidence: PMID:8548800 This cooperativity required direct interactions between the DNA-binding domains of MEF2 and the myogenic bHLH factors |
| GO:0005737 cytoplasm | IDA PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | KEEP AS NON CORE | Summary: Cytoplasmic MEF2C, from the original characterization. Reason: Mainly nuclear. Signals such as TGF-beta can send MEF2 to the cytoplasm, which shows a regulated cytoplasmic pool, but this is not where it functions. Supporting Evidence: PMID:9770491 TGF-beta induced translocation of MEF2, but not MyoD, myogenin, or p21, to the cytoplasm of myogenic cells grown to high density |
| GO:0005829 cytosol | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cytosol, transferred from rat. Reason: UniProt records a sarcoplasmic/cytoplasmic pool by similarity to rat. Not the site of function. Supporting Evidence: file:human/MEF2C/MEF2C-uniprot.txt Cytoplasm, sarcoplasm PMID:9770491 TGF-beta induced translocation of MEF2, but not MyoD, myogenin, or p21, to the cytoplasm of myogenic cells grown to high density |
| GO:0006355 regulation of DNA-templated transcription | IDA PMID:24008018 MEF2C exon Ξ±: role in gene activation and differentiation. | ACCEPT | Summary: Exon alpha-containing MEF2C variants show reduced transactivation. Reason: MEF2C regulates transcription. Correct, though general. Supporting Evidence: PMID:24008018 Transactivation experiments show that the presence of exon Ξ± induces a reduction of transcription levels |
| GO:0006959 humoral immune response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Humoral immune response, transferred from mouse. Reason: Mef2c-deficient B cells give lower T cell-dependent antibody responses. Non-core immune role. Supporting Evidence: PMID:18438409 loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell-dependent antibody responses and germinal center formation in vivo |
| GO:0007399 nervous system development | TAS PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | KEEP AS NON CORE | Summary: Nervous system development (TAS) based on brain expression of hMEF2C. Reason: MEF2C is needed for neocortical neuron differentiation and distribution, and haploinsufficiency causes a severe neurodevelopmental disorder. A real but pleiotropic role. Supporting Evidence: PMID:8455629 a potentially important role of hMEF2C factors in myogenesis and neurogenesis PMID:18599437 Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex PMID:19592390 haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations |
| GO:0007507 heart development | IBA GO_REF:0000033 | ACCEPT | Summary: IBA heart development for the vertebrate MEF2 clade. Reason: MEF2C is essential for cardiac myogenesis and right ventricular development. Heart development is a core process (the cardiac specification network output). Supporting Evidence: PMID:9162005 MEF2C is an essential regulator of cardiac myogenesis and right ventricular development PMID:9857019 These findings indicate the presence of a positive regulatory network between Nkx2-5 and MEF2C and show that both factors can direct early stages of cell differentiation into a cardiomyogenic pathway |
| GO:0007507 heart development | IEP PMID:10458488 Expression of MEF2 genes during human cardiac development. | ACCEPT | Summary: Heart development, from expression of MEF2 transcripts throughout human heart development. Reason: Expression alone is weak evidence, but the term is correct and core given knockout and gain-of-function data. Supporting Evidence: PMID:10458488 Expression of all four MEF2 transcripts (MEF2A, MEF2B, MEF2C, and MEF2D) were detected in all developmental stage of the human heart PMID:9162005 MEF2C is an essential regulator of cardiac myogenesis and right ventricular development |
| GO:0007507 heart development | ISS GO_REF:0000024 | ACCEPT | Summary: Heart development, transferred from mouse. Reason: Core; mouse Mef2c is essential for heart development. Supporting Evidence: PMID:9162005 In mice homozygous for a null mutation of MEF2C, the heart tube did not undergo looping morphogenesis, the future right ventricle did not form, and a subset of cardiac muscle genes was not expressed PMID:9162005 MEF2C is an essential regulator of cardiac myogenesis and right ventricular development |
| GO:0007507 heart development | NAS PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | ACCEPT | Summary: Heart development (NAS) from the HAND2/MEF2C ANP study. Reason: Core; consistent with genetic data. Supporting Evidence: PMID:9162005 MEF2C is an essential regulator of cardiac myogenesis and right ventricular development |
| GO:0007517 muscle organ development | TAS PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | ACCEPT | Summary: Muscle organ development (TAS). Reason: MEF2C is a key muscle differentiation factor in skeletal and cardiac muscle; it is induced during myogenesis and cooperates with myogenic bHLH factors. Supporting Evidence: PMID:8455629 The hMEF2C gene is induced late during myogenic differentiation, and its expression is limited to a subset of cortical neurons PMID:8548800 This cooperativity required direct interactions between the DNA-binding domains of MEF2 and the myogenic bHLH factors |
| GO:0007519 skeletal muscle tissue development | ISS GO_REF:0000024 | ACCEPT | Summary: Skeletal muscle tissue development, transferred from mouse. Reason: MEF2C cooperates with MyoD/myogenin, and its phosphorylation by skMLCK drives skeletal myogenesis. Core muscle differentiation role. Supporting Evidence: PMID:8548800 This cooperativity required direct interactions between the DNA-binding domains of MEF2 and the myogenic bHLH factors PMID:21556048 phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis |
| GO:0007521 muscle cell fate determination | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Muscle cell fate determination, transferred from mouse. Reason: MEF2 factors amplify and execute differentiation after myogenic bHLH factors have determined fate. MEF2 alone cannot induce myogenesis, so 'fate determination' overstates its role. Supporting Evidence: PMID:8548800 Members of the myocyte enhancer factor-2 (MEF2) family of MADS domain transcription factors cannot induce myogenesis in transfected fibroblasts |
| GO:0007611 learning or memory | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Learning or memory, transferred from mouse. Reason: CNS deletion of Mef2c impairs hippocampal learning and memory. This is a behavioural-level phenotype downstream of control of synapse number. Supporting Evidence: PMID:18599438 deletion of the MEF2C transcription factor in the CNS of mice impairs hippocampal-dependent learning and memory PMID:18599438 MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampal-dependent learning and memory |
| GO:0010628 positive regulation of gene expression | IDA PMID:21556048 Skeletal myosin light chain kinase regulates skeletal myogen... | ACCEPT | Summary: skMLCK-phosphorylated MEF2C activates myogenic regulatory factor gene expression. Reason: MEF2C activates target gene expression; general but correct. Supporting Evidence: PMID:21556048 skMLCK regulates MRF expression by controlling the MEF2C-dependent recruitment of histone acetyltransferases to skeletal muscle promoters |
| GO:0010628 positive regulation of gene expression | IDA PMID:9857019 Myocyte enhancer factor 2C and Nkx2-5 up-regulate each other... | ACCEPT | Summary: MEF2C up-regulates Nkx2-5, GATA4 and cardiac structural genes in P19 cells. Reason: Direct support for positive regulation of cardiac gene expression in the NKX2-5/MEF2C positive loop. Supporting Evidence: PMID:9857019 Similar to Nkx2-5, MEF2C expression initiated cardiomyogenesis, resulting in the up-regulation of Brachyury T, bone morphogenetic protein-4, Nkx2-5, GATA-4, cardiac alpha-actin, and myosin heavy chain expression PMID:9857019 These findings indicate the presence of a positive regulatory network between Nkx2-5 and MEF2C and show that both factors can direct early stages of cell differentiation into a cardiomyogenic pathway |
| GO:0010629 negative regulation of gene expression | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of gene expression, transferred from mouse. Reason: MEF2C can repress (e.g. NR4A1) when bound by class II HDACs; context-dependent and non-core. Supporting Evidence: PMID:18079734 MEF2C consistently inhibits expression of NR4A1/NUR77 PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation |
| GO:0014033 neural crest cell differentiation | ISS PMID:21610032 The MADS box transcription factor MEF2C regulates melanocyte... | KEEP AS NON CORE | Summary: Neural crest cell differentiation (ISS) from the neural crest-specific Mef2c knockout. Reason: Neural crest Mef2c inactivation impairs melanocyte differentiation. Real but pleiotropic. Supporting Evidence: PMID:21610032 Inactivation of Mef2c in the neural crest of mice results in reduced expression of melanocyte genes during development and a significant loss of pigmentation at birth due to defective differentiation and reduced abundance of melanocytes |
| GO:0014902 myotube differentiation | IEP PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | KEEP AS NON CORE | Summary: hMEF2C expression is induced late in myogenic differentiation. Reason: IEP evidence. MEF2C functions in muscle differentiation (see positive regulation of myoblast differentiation), but expression alone shows correlation, not participation. Supporting Evidence: PMID:8455629 The hMEF2C gene is induced late during myogenic differentiation, and its expression is limited to a subset of cortical neurons |
| GO:0016528 sarcoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Sarcoplasm, from the UniProt subcellular location mapping (by similarity to rat). Reason: A cytoplasmic pool exists, but MEF2C functions in the nucleus. Supporting Evidence: file:human/MEF2C/MEF2C-uniprot.txt Cytoplasm, sarcoplasm |
| GO:0016607 nuclear speck | IDA PMID:18079734 MEF2C is activated by multiple mechanisms in a subset of T-a... | KEEP AS NON CORE | Summary: GFP-MEF2C in nuclear speckles in T-ALL cell lines. Reason: Overexpressed fusion protein localization, interpreted as repression complexes. A sub-nuclear detail; not core. Supporting Evidence: PMID:18079734 Fusion constructs with green fluorescent protein permitted subcellular detection of MEF2C protein in nuclear speckles interpretable as repression complexes |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cell differentiation for MEF2 clade. Reason: Correct high-level process; MEF2 factors drive muscle and other differentiation programs. Supporting Evidence: PMID:9162005 MEF2C is an essential regulator of cardiac myogenesis and right ventricular development PMID:8548800 This cooperativity required direct interactions between the DNA-binding domains of MEF2 and the myogenic bHLH factors |
| GO:0030154 cell differentiation | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA cell differentiation. Reason: Correct high-level process, consistent with the IBA; specific differentiation terms are reviewed separately. Supporting Evidence: PMID:8548800 This cooperativity required direct interactions between the DNA-binding domains of MEF2 and the myogenic bHLH factors |
| GO:0030182 neuron differentiation | IEP PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | KEEP AS NON CORE | Summary: Neuron differentiation (IEP) from brain-restricted expression. Reason: Supported genetically by the Nestin-Cre knockout. Non-core relative to the muscle/heart role. Supporting Evidence: PMID:8455629 The hMEF2C gene is induced late during myogenic differentiation, and its expression is limited to a subset of cortical neurons PMID:18599437 conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size |
| GO:0030182 neuron differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuron differentiation, transferred from mouse. Reason: Supported by conditional knockout data. Supporting Evidence: PMID:18599437 conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size PMID:18599437 Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex |
| GO:0030220 platelet formation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Platelet formation, transferred from mouse. Reason: Haematopoietic Mef2c deletion causes platelet defects and impaired megakaryopoiesis. Non-core. Supporting Evidence: PMID:19211936 adult VavCre(+)Mef2C(fl/fl) mice exhibited platelet defects similar to those observed in Scl-deficient mice PMID:19211936 Furthermore, megakaryopoiesis was severely impaired in vitro |
| GO:0030279 negative regulation of ossification | IDA PMID:17696759 Control of the SOST bone enhancer by PTH using MEF2 transcri... | MARK AS OVER ANNOTATED | Summary: MEF2 factors drive the SOST (sclerostin) bone enhancer; PTH suppresses this. Reason: The IDA is a reporter/knockdown study of SOST regulation. Inferring 'negative regulation of ossification' requires the downstream sclerostin effect, which was not measured. In vivo, MEF2C promotes endochondral ossification. The annotation overstates what the data show. Supporting Evidence: PMID:17696759 Enhancer activity was stimulated by MEF2C overexpression and inhibited by co-expression of a dominant negative MEF2C mutant PMID:17696759 SOST expression in osteocytes of adult bone and its inhibition by PTH is mediated by MEF2A, C, and D transcription factors controlling the SOST bone enhancer PMID:17336904 Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice |
| GO:0030318 melanocyte differentiation | ISS PMID:21610032 The MADS box transcription factor MEF2C regulates melanocyte... | KEEP AS NON CORE | Summary: Melanocyte differentiation (ISS) from the neural crest knockout. Reason: Loss of Mef2c in neural crest reduces melanocyte differentiation. Non-core. Supporting Evidence: PMID:21610032 Inactivation of Mef2c in the neural crest of mice results in reduced expression of melanocyte genes during development and a significant loss of pigmentation at birth due to defective differentiation and reduced abundance of melanocytes |
| GO:0030501 positive regulation of bone mineralization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of bone mineralization, transferred from mouse. Reason: MEF2C promotes chondrocyte hypertrophy and ossification. Non-core skeletal role. Supporting Evidence: PMID:17336904 Genetic deletion of Mef2c or expression of a dominant-negative MEF2C mutant in endochondral cartilage impairs hypertrophy, cartilage angiogenesis, ossification, and longitudinal bone growth in mice |
| GO:0030890 positive regulation of B cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of B cell proliferation, transferred from mouse. Reason: Mef2c is required for BCR-induced B cell proliferation. Non-core. Supporting Evidence: PMID:18438409 loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell-dependent antibody responses and germinal center formation in vivo |
| GO:0032991 protein-containing complex | IDA PMID:15486975 Cooperative activation of atrial naturetic peptide promoter ... | MODIFY | Summary: MEF2C and HAND2 form a protein complex on the ANP promoter. Reason: Protein-containing complex is uninformative. The complex is a DNA-bound transcription factor complex on a Pol II promoter. Proposed replacements: RNA polymerase II transcription regulator complex Supporting Evidence: PMID:15486975 we show that dHAND interact with MEF2C to form protein complex and bind A/T sequence in promoter of ANP |
| GO:0035984 cellular response to trichostatin A | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Cellular response to trichostatin A, transferred from mouse. Reason: A pharmacological response. It reflects HDAC inhibitor relief of class II HDAC repression, not a MEF2C function in its own right. Supporting Evidence: PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation |
| GO:0042100 B cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: B cell proliferation, transferred from mouse. Reason: Mef2c is required for BCR-induced proliferation. Non-core. Supporting Evidence: PMID:18438409 loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell-dependent antibody responses and germinal center formation in vivo |
| GO:0042826 histone deacetylase binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA histone deacetylase binding for vertebrate MEF2. Reason: Binding of class II HDACs is the main switch controlling MEF2 activity (repression in undifferentiated cells, released on differentiation). It is a core regulatory interaction. Supporting Evidence: PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation PMID:10983972 These HDACs do not interact directly with MyoD, yet they suppress its myogenic activity through association with MEF2 PMID:17336904 Endochondral bone formation is exquisitely sensitive to the balance between MEF2C and the corepressor histone deacetylase 4 (HDAC4) |
| GO:0043410 positive regulation of MAPK cascade | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of MAPK cascade, transferred from rat. Reason: MEF2C is a downstream target of p38/ERK5 MAPK signalling, not an upstream regulator of the cascade. Not supported. Supporting Evidence: PMID:9069290 LPS increases the transactivation activity of MEF2C through p38-catalysed phosphorylation |
| GO:0043523 regulation of neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of neuron apoptotic process, transferred from mouse. Reason: MEF2 factors promote neuronal survival, and caspase cleavage of MEF2C accompanies neurotoxic apoptosis (UniProt). Non-core. |
| GO:0043524 negative regulation of neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of neuron apoptotic process, transferred from rat. Reason: As above; non-core neuronal survival role. |
| GO:0043524 negative regulation of neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of neuron apoptotic process, transferred from mouse. Reason: As above; non-core. |
| GO:0043537 negative regulation of blood vessel endothelial cell migration | IGI PMID:26184978 MiR-135b-5p and MiR-499a-3p Promote Cell Proliferation and M... | KEEP AS NON CORE | Summary: miR-135b-5p/miR-499a-3p target MEF2C; MEF2C overexpression counteracts the miRNA effects on endothelial migration. Reason: Cell-culture miRNA/overexpression study of atherosclerosis-related phenotypes. An indirect outcome of MEF2C transcriptional activity; non-core. Supporting Evidence: PMID:26184978 the enhanced proliferation and migration in response to the miRNAs-mediated MEF2C suppression were demonstrated in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) |
| GO:0045652 regulation of megakaryocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of megakaryocyte differentiation, transferred from mouse. Reason: Mef2c is needed for megakaryopoiesis. Non-core. Supporting Evidence: PMID:19211936 Furthermore, megakaryopoiesis was severely impaired in vitro |
| GO:0045663 positive regulation of myoblast differentiation | IMP PMID:9770491 Inhibition of myogenesis by transforming growth factor beta ... | ACCEPT | Summary: Forcing MEF2C into the nucleus (nlsSV40) makes myoblasts resistant to TGF-beta inhibition of myogenesis. Reason: MEF2C promotes myoblast differentiation. This is a core skeletal muscle function, also supported by MEF2/MyoD cooperativity and HDAC repression data. Supporting Evidence: PMID:9770491 Myogenic cells expressing the chimerical MEF2C/nlsSV40, but not wild-type MEF2C, retained this transcription factor in the nucleus and were resistant to the inhibitory action of TGF-beta PMID:10983972 class II histone deacetylases (HDACs), which interact with MEF2, specifically suppress myoblast differentiation |
| GO:0045666 positive regulation of neuron differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of neuron differentiation, transferred from mouse. Reason: Conditional knockout impairs neuronal differentiation. Non-core. Supporting Evidence: PMID:18599437 conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size PMID:18599437 Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex |
| GO:0045669 positive regulation of osteoblast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of osteoblast differentiation, transferred from mouse. Reason: MEF2C acts in bone-lineage gene regulation. Plausible but pleiotropic; the source data could not be checked. Supporting Evidence: PMID:17696759 SOST expression in osteocytes of adult bone and its inhibition by PTH is mediated by MEF2A, C, and D transcription factors controlling the SOST bone enhancer |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:17696759 Control of the SOST bone enhancer by PTH using MEF2 transcri... | ACCEPT | Summary: MEF2C overexpression stimulates the SOST bone enhancer through a MEF2 site. Reason: Direct evidence of MEF2C-dependent activation of a target enhancer. Supporting Evidence: PMID:17696759 Enhancer activity was stimulated by MEF2C overexpression and inhibited by co-expression of a dominant negative MEF2C mutant |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA positive regulation of transcription by Pol II across MEF2/MADS family. Reason: Core: MEF2C is primarily a transcriptional activator. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors 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:15486975 Cooperative activation of atrial naturetic peptide promoter ... | ACCEPT | Summary: MEF2C and HAND2 cooperatively activate the ANP promoter. Reason: Core activator function. 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:16043483 MEF2-dependent recruitment of the HAND1 transcription factor... | ACCEPT | Summary: MEF2 recruits HAND1 for synergistic activation of MEF2-dependent promoters. Reason: Core activator function. Supporting Evidence: PMID:16043483 MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:8455629 hMEF2C gene encodes skeletal muscle- and brain-specific tran... | ACCEPT | Summary: hMEF2C products transactivate via MEF2 sites. Reason: Core activator function. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000120 | ACCEPT | Summary: IEA positive regulation of transcription by Pol II. Reason: Consistent with experimental evidence. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:11160896 Smad proteins function as co-modulators for MEF2 transcripti... | ACCEPT | Summary: Smad2/4 cooperate with GAL4-MEF2C in TGF-beta-responsive cells. Reason: MEF2C activates Pol II transcription; the study shows its activation domain is modulated by signalling. Supporting Evidence: PMID:11160896 The over-expression of Smad2 and 4 (Smad2/4) was found to increase the activities of both GAL4βMEF2A and GAL4βMEF2C in high TGF-Ξ² conditions |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:21556048 Skeletal myosin light chain kinase regulates skeletal myogen... | ACCEPT | Summary: Phosphorylation-deficient MEF2C T80A fails to recruit p300 to skeletal muscle promoters, and myogenic regulatory factor expression falls. Reason: Core activator function in skeletal myogenesis. Supporting Evidence: PMID:21556048 skMLCK regulates MRF expression by controlling the MEF2C-dependent recruitment of histone acetyltransferases to skeletal muscle promoters PMID:21556048 MEFT80A was deficient in recruitment of p300 to skeletal but not cardiac muscle promoters |
| GO:0046928 regulation of neurotransmitter secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of neurotransmitter secretion, transferred from mouse. Reason: CNS Mef2c deletion potentiates basal and evoked synaptic transmission. MEF2C acts through transcriptional control of synapse number, so this is non-core and indirect. Supporting Evidence: PMID:18599438 these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission |
| GO:0046982 protein heterodimerization activity | IPI PMID:9858528 Regulation of the MEF2 family of transcription factors by p3... | ACCEPT | Summary: MEF2C heterodimerizes with MEF2D. Reason: MEF2 factors bind DNA as homo- and heterodimers through the MADS/MEF2 domain, so dimerization is intrinsic to MEF2C DNA binding. Supporting Evidence: PMID:9858528 Members of the MEF2 family of transcription factors bind as homo- and heterodimers to the MEF2 site |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro protein dimerization activity (MADS domain). Reason: Correct; redundant with heterodimerization. Supporting Evidence: PMID:9858528 Members of the MEF2 family of transcription factors bind as homo- and heterodimers to the MEF2 site |
| GO:0048167 regulation of synaptic plasticity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of synaptic plasticity, transferred from mouse. Reason: MEF2C limits synapse formation during activity-dependent refinement. Non-core neuronal role. Supporting Evidence: PMID:18599438 MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampal-dependent learning and memory |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA animal organ development. Reason: Too general to be informative; specific developmental terms are present. |
| GO:0048643 positive regulation of skeletal muscle tissue development | IMP PMID:9770491 Inhibition of myogenesis by transforming growth factor beta ... | KEEP AS NON CORE | Summary: Nuclear-retained MEF2C rescues TGF-beta inhibition of myogenesis. Reason: Redundant with positive regulation of myoblast differentiation; tissue-level framing. Non-core. Supporting Evidence: PMID:9770491 Myogenic cells expressing the chimerical MEF2C/nlsSV40, but not wild-type MEF2C, retained this transcription factor in the nucleus and were resistant to the inhibitory action of TGF-beta |
| GO:0048666 neuron development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuron development, transferred from mouse. Reason: Non-core neural role. Supporting Evidence: PMID:18599437 conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size |
| GO:0048667 cell morphogenesis involved in neuron differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cell morphogenesis involved in neuron differentiation, transferred from mouse. Reason: Mef2c conditional knockout neurons have smaller somal size. Non-core. Supporting Evidence: PMID:18599437 conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size |
| GO:0050853 B cell receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: B cell receptor signaling pathway, transferred from mouse. Reason: Mef2c is a calcineurin-regulated TF effector needed for BCR-induced proliferation and survival. Non-core. Supporting Evidence: PMID:18438409 Here we demonstrate a function for the calcineurin-regulated transcription factor Mef2c in B cells PMID:18438409 loss of Mef2c caused defects in B cell proliferation and survival after BCR stimulation in vitro and lower T cell-dependent antibody responses and germinal center formation in vivo |
| GO:0051145 smooth muscle cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Smooth muscle cell differentiation, transferred from mouse. Reason: Consistent with the vascular requirement for MEF2C. Non-core. Supporting Evidence: file:human/MEF2C/MEF2C-uniprot.txt involved in vascular development |
| GO:0051963 regulation of synapse assembly | ISS GO_REF:0000024 | MODIFY | Summary: Regulation of synapse assembly, transferred from mouse. Reason: MEF2C limits excitatory synapse number: deletion increases synapses and a superactive form reduces them. The direction is negative, so the more specific term fits. Non-core neuronal role. Proposed replacements: negative regulation of synapse assembly Supporting Evidence: PMID:18599438 MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampal-dependent learning and memory PMID:18599438 these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission |
| GO:0051966 regulation of synaptic transmission, glutamatergic | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of glutamatergic synaptic transmission, transferred from mouse. Reason: CNS Mef2c deletion potentiates excitatory transmission. Non-core, indirect via synapse number. Supporting Evidence: PMID:18599438 these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission |
| GO:0055012 ventricular cardiac muscle cell differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: Ventricular cardiac muscle cell differentiation, transferred from mouse. Reason: Mef2c-null hearts lack the right ventricle and fail to express a subset of cardiac muscle genes. Nkx2-5;Mef2c double mutants lack ventricles because ventricular cell differentiation is defective. This is a core cardiac differentiation role. Supporting Evidence: PMID:9162005 In mice homozygous for a null mutation of MEF2C, the heart tube did not undergo looping morphogenesis, the future right ventricle did not form, and a subset of cardiac muscle genes was not expressed PMID:19035347 ventricular hypoplasia is the result of defective ventricular cell differentiation |
| GO:0060025 regulation of synaptic activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of synaptic activity, transferred from mouse. Reason: Non-core; indirect via synapse number. Supporting Evidence: PMID:18599438 these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission |
| GO:0060045 positive regulation of cardiac muscle cell proliferation | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of cardiac muscle cell proliferation, transferred from mouse. Reason: Genetic analyses of the Mef2c ventricular phenotype attribute it to defective differentiation rather than proliferation. A proliferation role is not well supported. Supporting Evidence: PMID:19035347 ventricular hypoplasia is the result of defective ventricular cell differentiation |
| GO:0060079 excitatory postsynaptic potential | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Excitatory postsynaptic potential, transferred from mouse. Reason: MEF2C is a nuclear TF that changes synapse number. It does not take part in generating the postsynaptic potential. Supporting Evidence: PMID:18599438 MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampal-dependent learning and memory |
| GO:0060998 regulation of dendritic spine development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of dendritic spine development, transferred from mouse. Reason: MEF2C restrains excitatory synapse (spine) number. Non-core. Supporting Evidence: PMID:18599438 MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampal-dependent learning and memory |
| GO:0061333 renal tubule morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: Renal tubule morphogenesis, transferred from mouse. Reason: No accessible evidence for a kidney tubule role of MEF2C; the mouse source could not be checked. |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IPI PMID:16043483 MEF2-dependent recruitment of the HAND1 transcription factor... | ACCEPT | Summary: MEF2C binds HAND1, recruiting it to MEF2-dependent promoters for synergistic activation. Reason: Core partner-TF interaction. MEF2C also binds HAND2, TBX5, NKX2-5 and myogenic bHLH factors through its DNA-binding domain. Supporting Evidence: PMID:16043483 HAND1 is recruited to the promoter via physical interaction with MEF2 proteins PMID:16043483 MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy PMID:19204083 we report a physical interaction between TBX5 and MEF2C leading to a synergistic activation of the alpha-cardiac myosin heavy chain (MYH6) |
| GO:0071222 cellular response to lipopolysaccharide | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to LPS, transferred from mouse. Reason: In monocytes, LPS activates MEF2C via p38 phosphorylation, raising c-jun transcription. Non-core. Supporting Evidence: PMID:9069290 LPS increases the transactivation activity of MEF2C through p38-catalysed phosphorylation PMID:9069290 One consequence of MEF2C activation is increased c-jun gene transcription |
| GO:0071277 cellular response to calcium ion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to calcium ion, transferred from mouse. Reason: MEF2C is a calcineurin/CaM kinase-regulated TF, so calcium signals act through it. Non-core. Supporting Evidence: PMID:18438409 Here we demonstrate a function for the calcineurin-regulated transcription factor Mef2c in B cells |
| GO:0071374 cellular response to parathyroid hormone stimulus | IDA PMID:17696759 Control of the SOST bone enhancer by PTH using MEF2 transcri... | KEEP AS NON CORE | Summary: PTH suppresses MEF2-driven SOST enhancer activity in osteoblast-like cells. Reason: A signalling response in bone cells. Non-core. Supporting Evidence: PMID:17696759 SOST expression in osteocytes of adult bone and its inhibition by PTH is mediated by MEF2A, C, and D transcription factors controlling the SOST bone enhancer |
| GO:0071466 cellular response to xenobiotic stimulus | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Cellular response to xenobiotic stimulus, transferred from mouse. Reason: Uninformative; no evidence that MEF2C is part of a xenobiotic response. |
| GO:0071498 cellular response to fluid shear stress | ISS GO_REF:0000024 | UNDECIDED | Summary: Cellular response to fluid shear stress, transferred from mouse. Reason: MEF2 factors are reported downstream of ERK5 in endothelial shear signalling, but the evidence could not be checked here. |
| GO:0071560 cellular response to transforming growth factor beta stimulus | IDA PMID:9770491 Inhibition of myogenesis by transforming growth factor beta ... | KEEP AS NON CORE | Summary: TGF-beta translocates MEF2 to the cytoplasm, inhibiting myogenesis. Reason: MEF2C localization responds to TGF-beta. Non-core. Supporting Evidence: PMID:9770491 TGF-beta induced translocation of MEF2, but not MyoD, myogenin, or p21, to the cytoplasm of myogenic cells grown to high density PMID:9770491 Myogenic cells expressing the chimerical MEF2C/nlsSV40, but not wild-type MEF2C, retained this transcription factor in the nucleus and were resistant to the inhibitory action of TGF-beta |
| GO:0072102 glomerulus morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: Glomerulus morphogenesis, transferred from mouse. Reason: No accessible evidence for a kidney glomerulus role; the source could not be checked. |
| GO:0072160 nephron tubule epithelial cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: Nephron tubule epithelial cell differentiation, transferred from mouse. Reason: No accessible evidence; the source could not be checked. |
| GO:0098794 postsynapse | IEA GO_REF:0000108 | REMOVE | Summary: Postsynapse, inferred automatically from the excitatory postsynaptic potential annotation. Reason: MEF2C is a nuclear transcription factor and is not located at the postsynapse. This IEA is an inter-ontology inference from an over-annotated process term. Supporting Evidence: PMID:21170291 While neurons from control brains show robust MEF2C immunoreactivity in neuronal nuclei PMID:18599438 MEF2C limits excessive synapse formation during activity-dependent refinement of synaptic connectivity and thus facilitates hippocampal-dependent learning and memory |
| GO:0098989 NMDA selective glutamate receptor signaling pathway | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: NMDA receptor signaling pathway (acts upstream, negative effect), transferred from mouse. Reason: Changes in glutamatergic signalling after Mef2c loss arise from altered synapse number. MEF2C does not act in the receptor signalling pathway. Supporting Evidence: PMID:18599438 these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission |
| GO:0098990 AMPA selective glutamate receptor signaling pathway | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: AMPA receptor signaling pathway (acts upstream, negative effect), transferred from mouse. Reason: As for NMDA; indirect via synapse number. Supporting Evidence: PMID:18599438 these behavioral changes were accompanied by a marked increase in the number of excitatory synapses and potentiation of basal and evoked synaptic transmission |
| GO:0140297 DNA-binding transcription factor binding | IPI PMID:11160896 Smad proteins function as co-modulators for MEF2 transcripti... | ACCEPT | Summary: Smad2 interacts with MEF2C in GST pull-down assays. Reason: Smad2 is a DNA-binding transcription factor, and its cooperation with MEF2 activity is shown. This is a non-trivial partner-TF interaction. Supporting Evidence: PMID:11160896 In vitro translated and 35 S-labelled MEF2A or MEF2C were incubated with immobilised GST or GSTβSmad2 PMID:11160896 The over-expression of Smad2 and 4 (Smad2/4) was found to increase the activities of both GAL4βMEF2A and GAL4βMEF2C in high TGF-Ξ² conditions |
| GO:1904706 negative regulation of vascular associated smooth muscle cell proliferation | IDA PMID:28799067 MiR-448 promotes vascular smooth muscle cell proliferation a... | KEEP AS NON CORE | Summary: MEF2C overexpression counteracts miR-448-induced VSMC proliferation. Reason: Cell-culture overexpression study; an indirect consequence of MEF2C transcriptional activity. Non-core. Supporting Evidence: PMID:28799067 overexpression of MEF2C decreased miR-448-induced VSMCs proliferation and migration |
| GO:1904706 negative regulation of vascular associated smooth muscle cell proliferation | IGI PMID:26184978 MiR-135b-5p and MiR-499a-3p Promote Cell Proliferation and M... | KEEP AS NON CORE | Summary: miR-135b-5p/miR-499a-3p-mediated MEF2C suppression increases VSMC proliferation. Reason: As above; non-core. Supporting Evidence: PMID:26184978 the enhanced proliferation and migration in response to the miRNAs-mediated MEF2C suppression were demonstrated in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) |
| GO:1904753 negative regulation of vascular associated smooth muscle cell migration | IDA PMID:28799067 MiR-448 promotes vascular smooth muscle cell proliferation a... | KEEP AS NON CORE | Summary: MEF2C overexpression counteracts miR-448-induced VSMC migration. Reason: Non-core. Supporting Evidence: PMID:28799067 overexpression of MEF2C decreased miR-448-induced VSMCs proliferation and migration |
| GO:1904753 negative regulation of vascular associated smooth muscle cell migration | IGI PMID:26184978 MiR-135b-5p and MiR-499a-3p Promote Cell Proliferation and M... | KEEP AS NON CORE | Summary: miRNA-mediated MEF2C suppression increases VSMC migration. Reason: Non-core. Supporting Evidence: PMID:26184978 the enhanced proliferation and migration in response to the miRNAs-mediated MEF2C suppression were demonstrated in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) |
| GO:1905563 negative regulation of vascular endothelial cell proliferation | IGI PMID:26184978 MiR-135b-5p and MiR-499a-3p Promote Cell Proliferation and M... | KEEP AS NON CORE | Summary: miRNA-mediated MEF2C suppression increases endothelial cell proliferation. Reason: Non-core. Supporting Evidence: PMID:26184978 the enhanced proliferation and migration in response to the miRNAs-mediated MEF2C suppression were demonstrated in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: Methyl-SELEX/HT-SELEX DNA-binding specificity profiling of human TFs includes MEF2C. Reason: Consistent with MEF2C sequence-specific binding to A/T-rich MEF2 sites. Supporting Evidence: PMID:8455629 The products of this gene have DNA-binding and trans-activating activities indistinguishable from those of the previously reported MEF2 factors PMID:9162005 Members of the myocyte enhancer factor-2 (MEF2) family of MADS (MCM1, agamous, deficiens, serum response factor)-box transcription factors bind an A-T-rich DNA sequence associated with muscle-specific genes |
| GO:2000111 positive regulation of macrophage apoptotic process | ISS GO_REF:0000024 | UNDECIDED | Summary: Positive regulation of macrophage apoptotic process, transferred from mouse. Reason: No accessible evidence; the mouse source could not be checked. |
| GO:2000727 positive regulation of cardiac muscle cell differentiation | IDA PMID:9857019 Myocyte enhancer factor 2C and Nkx2-5 up-regulate each other... | ACCEPT | Summary: MEF2C overexpression initiates cardiomyogenesis in P19 cells and up-regulates Nkx2-5 and GATA4 in a positive loop. Reason: Core: MEF2C drives cardiac muscle cell differentiation as the transcriptional effector of the cardiac network. Matches the module annoton process. Supporting Evidence: PMID:9857019 Similar to Nkx2-5, MEF2C expression initiated cardiomyogenesis, resulting in the up-regulation of Brachyury T, bone morphogenetic protein-4, Nkx2-5, GATA-4, cardiac alpha-actin, and myosin heavy chain expression PMID:9857019 These findings indicate the presence of a positive regulatory network between Nkx2-5 and MEF2C and show that both factors can direct early stages of cell differentiation into a cardiomyogenic pathway |
| GO:2000987 positive regulation of behavioral fear response | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of behavioral fear response, transferred from mouse. Reason: A behavioural phenotype distal to MEF2C transcriptional function; not informative. |
| GO:2001013 epithelial cell proliferation involved in renal tubule morphogenesis | ISS GO_REF:0000024 | UNDECIDED | Summary: Epithelial cell proliferation involved in renal tubule morphogenesis, transferred from mouse. Reason: No accessible evidence; the source could not be checked. |
| GO:2001016 positive regulation of skeletal muscle cell differentiation | IDA PMID:21556048 Skeletal myosin light chain kinase regulates skeletal myogen... | ACCEPT | Summary: skMLCK phosphorylation of MEF2C T80 enhances skeletal myogenesis. Reason: Core skeletal muscle differentiation role. Supporting Evidence: PMID:21556048 phosphorylation of MEF2C on T(80) by skeletal myosin light chain kinase (skMLCK) enhances skeletal and not cardiac myogenesis PMID:21556048 skMLCK regulates MRF expression by controlling the MEF2C-dependent recruitment of histone acetyltransferases to skeletal muscle promoters |
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Download this section (compressed HTML)Q: Does MEF2C act in second heart field specification, or only in differentiation of SHF-derived right ventricle and outflow tract myocardium? Mef2c-null and Nkx2-5;Mef2c double mutants still express SHF markers.
Q: Which direct MEF2C target genes in excitatory neurons mediate its restraint of synapse number, and which of these explain the MEF2C haploinsufficiency syndrome?
Q: Should GO represent MEF2C as having input from p38/ERK5/skMLCK signalling (on the kinase) rather than annotating MEF2C to 'MAPK cascade'?
Experiment: Do CUT&RUN for MEF2C, ISL1 and GATA4 in staged human iPSC-derived SHF progenitors and right-ventricle-like cardiomyocytes. Combine with an inducible MEF2C knockout and single-cell RNA-seq to separate specification from differentiation defects.
Hypothesis: MEF2C binding at second heart field enhancers depends on ISL1/GATA4 co-occupancy and is needed for right-ventricular myocyte differentiation but not for SHF progenitor specification.
Type: genome-wide DNA-binding and single-cell transcriptomic profiling
Experiment: Measure DNA binding (EMSA/SELEX), dimerization, partner binding (HAND2, TBX5, HDAC4/5) and reporter activation for a panel of NEDHSIL variants. Rescue synapse number in MEF2C+/- human iPSC-derived neurons.
Hypothesis: Patient MEF2C missense variants in the MADS/MEF2 domain impair DNA binding or partner-TF/HDAC binding and reduce activation of neuronal synapse-pruning targets.
Type: variant functional characterization
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