{"gene":"MYOG","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2006,"finding":"MYOG and MYOD have distinct regulatory roles at a common set of target genes in skeletal muscle. MYOD binds first and recruits histone acetyltransferases to initiate regional histone modification at late-expressed genes, but is not sufficient for their full expression. MYOG does not bind these late genes efficiently without prior MYOD binding; transcriptional activation of late genes requires the combined activity of MYOD and MYOG. Thus MYOG's role in terminal differentiation is to enhance expression of a subset of genes previously initiated by MYOD.","method":"Genome-wide ChIP, promoter-specific DNA binding assays, expression analysis, histone modification profiling in myoblasts/myotubes","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP combined with promoter-specific binding and expression analyses, multiple orthogonal methods in a single focused study","pmids":["16437161"],"is_preprint":false},{"year":2018,"finding":"Oncogenic RAS, acting through the RAF-MEK-ERK MAPK pathway, represses MYOG expression by causing ERK2-dependent promoter-proximal stalling of RNA polymerase II at the MYOG locus. MEK inhibition with trametinib removes ERK2 from the MYOG promoter, releases transcriptional stalling, and restores MYOG expression. Restored MYOG subsequently opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation.","method":"ChIP for ERK2 and Pol II at MYOG promoter, small-molecule inhibitor treatment (trametinib), RNA-seq, ATAC-seq, xenograft tumor models","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal ChIP, multiple orthogonal genomic methods (ChIP-seq, ATAC-seq, RNA-seq), and in vivo validation","pmids":["29973406"],"is_preprint":false},{"year":1991,"finding":"The MYOG (Myf4) promoter is regulated by multiple signaling pathways: (1) MyoD1, Myf5, and Myf6 transactivate the Myf4 promoter in fibroblasts; (2) serum components, bFGF, TGF-β, and EGF down-regulate Myf4 gene activity; (3) cAMP-elevating agents (dibutyryl-cAMP, forskolin, cholera toxin) inhibit the Myf4 promoter; (4) pertussis toxin (which inactivates Gi protein) stimulates Myf4 expression, indicating positive control through a Gi protein-dependent pathway. A minimal ~200 bp upstream region is sufficient for cell-type-specific expression.","method":"CAT/LacZ reporter assays with 5' deletion constructs, forced expression of MRFs in 10T1/2 fibroblasts, pharmacological perturbation with pertussis toxin, cholera toxin, forskolin, dibutyryl-cAMP","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple reporter and pharmacological approaches in a single lab, no independent replication cited","pmids":["1659574"],"is_preprint":false},{"year":2008,"finding":"The proto-oncogene Ski is required for muscle terminal differentiation and directly activates transcription of MYOG. Ski occupies the endogenous MYOG regulatory region and activates its transcription primarily through a MEF3 site bound by Six1, not through MyoD or MEF2 binding sites. This requires direct physical interaction of Ski with Six1 and Eya3, mediated by the Dachshund homology domain of Ski.","method":"Conditional retroviral overexpression and knockdown of Ski in C2C12 myoblasts, ChIP at the MYOG locus, transcriptional reporter assays, co-immunoprecipitation of Ski-Six1-Eya3 complex","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP at endogenous locus, reporter assays, Co-IP of complex, and functional KD/OE with defined phenotype, multiple orthogonal methods in one study","pmids":["19008232"],"is_preprint":false},{"year":2015,"finding":"MYOD and MYOG bind to a conserved E-box element proximal to the Myomaker transcription start site and induce Myomaker transcription, thereby promoting myoblast fusion.","method":"Luciferase reporter assays with E-box mutants, ChIP for MYOD and MYOG at the Myomaker promoter in chicken primary myoblasts","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay with E-box mutation, single lab, two orthogonal methods (chicken model, ortholog included)","pmids":["26540045"],"is_preprint":false},{"year":2022,"finding":"Actin-related protein 5 (Arp5) acts as an inhibitory regulator of MYOG (and MYOD) by binding to their cysteine-rich (CR) region, which overlaps with the region essential for their epigenetic/chromatin-remodeling functions. Arp5 competes with the Pbx1-Meis1 homeodomain heterodimer for binding to the CR region of MYOG, thereby disturbing MyoD-mediated chromatin remodeling. This inhibitory function is independent of the INO80 chromatin remodeling complex. In rhabdomyosarcoma, elevated Arp5 expression contributes to dysregulation of MYOG activity.","method":"Co-immunoprecipitation, overexpression and siRNA knockdown of Arp5 in myoblasts and RMS cells, chromatin remodeling assays, myotube formation assays, in vivo overexpression in mouse hind limbs","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional KO/OE, in vivo validation, competition assay with defined binding region, multiple orthogonal methods","pmids":["35348112"],"is_preprint":false},{"year":2011,"finding":"PTPLa (protein tyrosine phosphatase-like A) is required for myoblast differentiation; cells lacking PTPLa fail to differentiate into myotubes due to repressed MYOG expression. PTPLa loss does not affect MyoD levels but specifically impairs MYOG induction, placing PTPLa upstream of MYOG in the myogenic differentiation pathway.","method":"siRNA knockdown of PTPLa in myoblasts, Western blot and qPCR for MYOG expression, differentiation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype and specific gene expression readout, single lab","pmids":["22106411"],"is_preprint":false},{"year":2023,"finding":"The transcriptional repressor TRPS1 directly restricts MYOG expression and thereby inhibits terminal myogenic differentiation. TRPS1 and MYOD1 share common genomic binding sites including the MYOG promoter; TRPS1 occupancy at the MYOG promoter represses MYOG transcription. In embryonal rhabdomyosarcoma, elevated TRPS1 (sustained by miR-1 suppression) impairs myogenic differentiation through this mechanism.","method":"ChIP for TRPS1 and MYOD1 at the MYOG promoter, luciferase reporter assays, TRPS1 overexpression and knockdown in myoblasts and RD cells, in vivo xenograft experiments","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at MYOG promoter, reporter assays, KD/OE with functional readout, in vivo validation, multiple orthogonal methods","pmids":["37452493"],"is_preprint":false},{"year":2018,"finding":"DEC1 (Bhlhe40/STRA13) overexpression inhibits myogenic differentiation in bovine satellite cells by inhibiting MYOG promoter activity, as demonstrated by luciferase reporter assays. DEC1 overexpression reduces MYOG mRNA and protein levels.","method":"Adenovirus-mediated DEC1 overexpression, luciferase reporter assay of MYOG promoter, Western blot and qPCR for MYOG in bovine satellite cells","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assay and functional OE, single lab, two orthogonal approaches","pmids":["29350420"],"is_preprint":false},{"year":2022,"finding":"CREB1 directly binds to the proximal promoter region of MYOG and activates its transcription, promoting myogenic differentiation in bovine myoblasts, as shown by dual-luciferase reporter assays.","method":"Dual-luciferase reporter assay with MYOG promoter constructs, CREB1 overexpression/knockdown, ChIP (inferred from promoter analysis)","journal":"International journal of biological macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, promoter-reporter assay only, no direct ChIP confirmation stated in abstract","pmids":["35777504"],"is_preprint":false},{"year":2017,"finding":"MYOG drives transcription of the bovine SIX1 gene indirectly via the MEF3 motif in the SIX1 promoter, as shown by EMSA, ChIP, serial deletion constructs, site-directed mutation, and siRNA interference experiments.","method":"EMSA, ChIP, luciferase reporter with deletion constructs and site-directed mutations, siRNA knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, reporter mutagenesis, siRNA), single lab","pmids":["28974698"],"is_preprint":false},{"year":2022,"finding":"MYOG binds to E-box elements in the core promoter region (-159/+1) of the bovine Myoz2 gene and cooperates with MYOD to regulate its transcription, as demonstrated by ChIP, dual-luciferase assay, site-directed mutagenesis, and siRNA interference.","method":"ChIP, dual-luciferase reporter with deletion constructs and site-directed mutagenesis, siRNA interference","journal":"Research in veterinary science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, reporter mutagenesis, siRNA), single lab","pmids":["36191510"],"is_preprint":false},{"year":2022,"finding":"MEF2A and MYOG cooperate to bind the core promoter region (-248/-56) of the bovine LATS2 gene and regulate its transcription, as identified by site-directed mutations, siRNA interference, and chromatin immunoprecipitation.","method":"Dual-luciferase reporter with deletion/mutation constructs, siRNA interference, ChIP","journal":"Research in veterinary science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter mutagenesis, siRNA, ChIP), single lab","pmids":["36126508"],"is_preprint":false},{"year":2022,"finding":"Vitamin C (VC) promotes muscle differentiation by upregulating nuclear translocation of CSRP3, which then interacts physically with MYOG (and MYOD), linking CSRP3-MYOG interaction to VC-mediated myogenesis.","method":"Co-immunoprecipitation/interaction assay, nuclear fractionation, C2C12 differentiation assays, mouse muscle injury model","journal":"Journal of agricultural and food chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, interaction assay mentioned without detailed mechanistic characterization, abstract does not clarify strength of Co-IP","pmids":["35652451"],"is_preprint":false},{"year":2014,"finding":"Sheep MyoG protein localizes to the nucleus when expressed in transfected cells, and forced expression of MyoG in goat embryonic fibroblasts induces desmin expression, demonstrating its myogenic trans-differentiation activity. MyoG contains a bHLH domain and lacks a signal peptide, identifying it as a non-secretory nuclear transcription factor.","method":"EGFP-tagged MyoG transfection with subcellular localization by fluorescence microscopy, Western blot, RT-PCR; forced expression in GEF cells with desmin immunodetection","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging of nuclear localization plus functional myogenic trans-differentiation assay, single lab","pmids":["24385300"],"is_preprint":false},{"year":2009,"finding":"In zebrafish, myog (unlike mrf4) cannot rescue myogenesis in myod/myf5 double morphants, demonstrating that myog is not sufficient to activate myogenesis de novo in the absence of upstream MRFs. This places myog downstream of myod/myf5 in the zebrafish myogenic hierarchy.","method":"Morpholino knockdown of myod and myf5 in zebrafish, rescue experiments with forced early expression of mrf4 or myog, in vivo imaging of muscle development","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via morpholino double knockdown with rescue experiment in a vertebrate model, single lab","pmids":["19193870"],"is_preprint":false},{"year":1999,"finding":"No causative mutations were detected in the MYOG (myf4) coding region in 37 patients with severe congenital myopathy, indicating that coding mutations in MYOG are not a common cause of severe congenital myopathy. Additional intronic sequences (659 bp in intron 1, 498 bp in intron 2) and a variable (CA)-dinucleotide repeat in intron 2 were characterized.","method":"PCR amplification and automated sequencing of all three MYOG exons in 37 patients and 40 controls","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — negative result (no causative mutations found), single genomic sequencing study","pmids":["10329008"],"is_preprint":false}],"current_model":"MYOG (myogenin/MYF4) is a nuclear bHLH transcription factor that acts downstream of MYOD in the myogenic hierarchy to drive terminal skeletal muscle differentiation: MYOD first binds target promoters and recruits histone acetyltransferases to initiate chromatin remodeling, after which MYOG cooperates with MYOD to fully activate late myogenic genes; MYOG expression is itself transcriptionally regulated by upstream MRFs (MYOD, Myf5, Myf6), repressed by RAS-MEK-ERK signaling via ERK2-mediated RNA Pol II stalling at its promoter, activated through a Ski-Six1-Eya3 complex at a MEF3 element, and inhibited by TRPS1 and DEC1 at its promoter; MYOG activity is further modulated by binding partners including Arp5 (which competes with Pbx1-Meis1 for the MYOG cysteine-rich region to inhibit chromatin remodeling) and CSRP3; and MYOG in turn directly binds E-box elements to transactivate downstream muscle differentiation genes including Myomaker, SIX1, Myoz2, and LATS2."},"narrative":{"mechanistic_narrative":"MYOG (myogenin/MYF4) is a nuclear basic helix-loop-helix transcription factor that operates downstream of the upstream myogenic regulatory factors to drive terminal skeletal muscle differentiation [PMID:24385300, PMID:19193870]. It functions cooperatively with MYOD rather than independently: MYOD binds late-expressed muscle genes first and recruits histone acetyltransferases to initiate regional histone modification, after which MYOG enhances and fully activates expression of this MYOD-initiated subset of genes [PMID:16437161]. Epistasis in zebrafish confirms that MYOG is not sufficient to activate myogenesis de novo without MYOD/Myf5 [PMID:19193870]. Acting through E-box elements, MYOG directly transactivates downstream differentiation and fusion genes including Myomaker [PMID:26540045] and Myoz2 [PMID:36191510], and drives additional targets such as SIX1 via a MEF3 motif [PMID:28974698] and LATS2 in concert with MEF2A [PMID:36126508]. MYOG expression is itself a tightly controlled node: it is activated by upstream MRFs and a Ski–Six1–Eya3 complex acting at a MEF3 site [PMID:1659574, PMID:19008232], and is repressed by oncogenic RAS–MEK–ERK signaling, which drives ERK2-dependent promoter-proximal RNA polymerase II stalling at the MYOG locus, as well as by the transcriptional repressor TRPS1 [PMID:29973406, PMID:37452493]. At the protein level, MYOG activity is constrained by Arp5, which competes with the Pbx1–Meis1 heterodimer for binding to MYOG's cysteine-rich region to disturb MYOD-mediated chromatin remodeling, a mechanism dysregulated in rhabdomyosarcoma [PMID:35348112]. No causative coding mutations in MYOG were found in severe congenital myopathy [PMID:10329008].","teleology":[{"year":1991,"claim":"Established that the MYOG promoter is a convergence point for myogenic and signaling inputs, defining how the differentiation program is gated upstream of MYOG itself.","evidence":"Reporter assays with 5' deletions plus forced MRF expression and pharmacological perturbation in 10T1/2 fibroblasts","pmids":["1659574"],"confidence":"Medium","gaps":["Direct factor occupancy at the promoter not demonstrated","Identity of the Gi-protein-coupled effectors unresolved","Mostly heterologous fibroblast context"]},{"year":1999,"claim":"Tested whether MYOG coding mutations cause severe congenital myopathy, addressing a possible disease role; the negative result argued against MYOG coding variants as a common cause.","evidence":"PCR sequencing of all three MYOG exons in 37 patients and 40 controls","pmids":["10329008"],"confidence":"Low","gaps":["Negative result does not exclude regulatory/intronic variants","Limited cohort size","No functional follow-up"]},{"year":2006,"claim":"Resolved how MYOG and MYOD divide labor at shared targets, showing MYOG acts as an amplifier of a MYOD-initiated chromatin program rather than an independent pioneer factor.","evidence":"Genome-wide ChIP with promoter-specific binding, expression, and histone modification profiling in myoblasts/myotubes","pmids":["16437161"],"confidence":"High","gaps":["Precise coactivators recruited by MYOG not defined","Does not specify how MYOG binding is licensed by prior MYOD occupancy"]},{"year":2008,"claim":"Identified an upstream activating complex driving MYOG transcription, showing Ski activates MYOG through a MEF3/Six1 element via direct Ski-Six1-Eya3 interaction.","evidence":"Conditional OE/KD of Ski in C2C12, ChIP at the MYOG locus, reporter assays, and Co-IP of the Ski-Six1-Eya3 complex","pmids":["19008232"],"confidence":"High","gaps":["How Ski integrates with MRF inputs at the promoter unclear","In vivo requirement during development not addressed"]},{"year":2009,"claim":"Placed MYOG genetically downstream of MYOD/Myf5 by showing it cannot rescue myogenesis de novo, clarifying its non-redundant late position in the hierarchy.","evidence":"Morpholino knockdown of myod/myf5 in zebrafish with mrf4 vs myog rescue and in vivo imaging","pmids":["19193870"],"confidence":"Medium","gaps":["Morpholino specificity caveats","Does not define which targets require MYOG specifically"]},{"year":2011,"claim":"Identified PTPLa as a specific upstream activator of MYOG induction, separating MYOG control from MYOD levels during differentiation.","evidence":"siRNA knockdown of PTPLa in myoblasts with MYOG expression readouts and differentiation assays","pmids":["22106411"],"confidence":"Medium","gaps":["Molecular mechanism linking PTPLa to MYOG promoter unknown","Whether effect is direct not established"]},{"year":2014,"claim":"Confirmed MYOG as a nuclear, non-secretory bHLH factor with intrinsic myogenic trans-differentiation activity capable of inducing muscle markers in non-muscle cells.","evidence":"EGFP-tagged localization microscopy and forced expression inducing desmin in goat embryonic fibroblasts","pmids":["24385300"],"confidence":"Medium","gaps":["Single ortholog/cell context","Does not map nuclear import signals"]},{"year":2015,"claim":"Connected MYOG to the fusion machinery, showing MYOD and MYOG co-activate Myomaker via a conserved E-box to promote myoblast fusion.","evidence":"Luciferase reporter with E-box mutants and ChIP for MYOD/MYOG at the Myomaker promoter in chicken myoblasts","pmids":["26540045"],"confidence":"Medium","gaps":["Relative contributions of MYOD vs MYOG not separated","Single avian model"]},{"year":2017,"claim":"Extended the MYOG regulon to SIX1, revealing a feed-forward loop in which MYOG drives SIX1 through a MEF3 motif.","evidence":"EMSA, ChIP, reporter deletion/mutation, and siRNA in bovine cells","pmids":["28974698"],"confidence":"Medium","gaps":["Indirect mechanism at MEF3 not fully resolved","Single lab/species"]},{"year":2018,"claim":"Defined a clinically actionable repression mechanism, showing oncogenic RAS-MEK-ERK silences MYOG via ERK2-driven Pol II stalling that is reversible by MEK inhibition.","evidence":"ChIP for ERK2/Pol II at the MYOG promoter, trametinib treatment, RNA-seq, ATAC-seq, and xenografts","pmids":["29973406"],"confidence":"High","gaps":["How ERK2 is recruited to the promoter not fully defined","Generality across muscle contexts beyond the tumor models"]},{"year":2018,"claim":"Identified DEC1 as an additional repressor acting at the MYOG promoter to block differentiation.","evidence":"Adenoviral DEC1 overexpression with MYOG promoter luciferase assay in bovine satellite cells","pmids":["29350420"],"confidence":"Medium","gaps":["Direct DEC1 promoter occupancy not shown","Endogenous loss-of-function not tested"]},{"year":2022,"claim":"Uncovered post-translational restraint of MYOG, showing Arp5 competes with Pbx1-Meis1 at the cysteine-rich region to block MYOD-mediated chromatin remodeling, with relevance to rhabdomyosarcoma.","evidence":"Reciprocal Co-IP, competition assays, OE/siRNA, chromatin remodeling and myotube assays, and in vivo mouse limb overexpression","pmids":["35348112"],"confidence":"High","gaps":["Structural basis of CR-region competition not solved","How Arp5 levels are set in normal myogenesis unclear"]},{"year":2022,"claim":"Expanded the direct MYOG target set to Myoz2 and LATS2, reinforcing MYOG's cooperative regulation with MYOD and MEF2A at downstream muscle genes.","evidence":"ChIP, dual-luciferase with deletion/mutation, and siRNA for Myoz2 and LATS2 in bovine cells","pmids":["36191510","36126508"],"confidence":"Medium","gaps":["Physiological consequence of LATS2/Myoz2 regulation not tested in vivo","Single species"]},{"year":2022,"claim":"Added candidate activating inputs to MYOG, with CREB1 binding the proximal promoter and CSRP3 interacting with MYOG to mediate vitamin-C-driven myogenesis.","evidence":"Dual-luciferase reporter (CREB1) and Co-IP/nuclear fractionation with C2C12 and injury models (CSRP3)","pmids":["35777504","35652451"],"confidence":"Low","gaps":["CREB1 ChIP confirmation not stated","CSRP3-MYOG Co-IP not deeply characterized","Functional consequences of the interactions incompletely defined"]},{"year":2023,"claim":"Established TRPS1 as a direct repressor of MYOG that shares MYOD1 binding sites at the promoter and impairs differentiation in embryonal rhabdomyosarcoma.","evidence":"ChIP for TRPS1/MYOD1 at the MYOG promoter, reporter assays, OE/KD in myoblasts and RD cells, and xenografts","pmids":["37452493"],"confidence":"High","gaps":["How TRPS1 competes with or displaces MYOD at shared sites not resolved","Upstream control of TRPS1 beyond miR-1 incompletely mapped"]},{"year":null,"claim":"How the multiple repressive (RAS-ERK, TRPS1, DEC1, Arp5) and activating (MRFs, Ski-Six1-Eya3, CREB1, PTPLa) inputs are integrated quantitatively at the MYOG locus to time terminal differentiation, and the structural basis of MYOG cofactor competition, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating activators and repressors","No structural model of MYOG with Arp5/Pbx1-Meis1 or with MYOD","MYOG-specific in vivo target requirements incompletely defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,10,11,12,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,10,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,4,15]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,7]}],"complexes":[],"partners":["MYOD1","MEF2A","ARP5","CSRP3","TRPS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15173","full_name":"Myogenin","aliases":["Class C basic helix-loop-helix protein 3","bHLHc3","Myogenic factor 4","Myf-4"],"length_aa":224,"mass_kda":25.0,"function":"Acts as a transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation, cell cycle exit and muscle atrophy. Essential for the development of functional embryonic skeletal fiber muscle differentiation. However is dispensable for postnatal skeletal muscle growth; phosphorylation by CAMK2G inhibits its transcriptional activity in respons to muscle activity. Required for the recruitment of the FACT complex to muscle-specific promoter regions, thus promoting gene expression initiation. During terminal myoblast differentiation, plays a role as a strong activator of transcription at loci with an open chromatin structure previously initiated by MYOD1. Together with MYF5 and MYOD1, co-occupies muscle-specific gene promoter core regions during myogenesis. Also cooperates with myocyte-specific enhancer factor MEF2D and BRG1-dependent recruitment of SWI/SNF chromatin-remodeling enzymes to alter chromatin structure at myogenic late gene promoters. Facilitates cell cycle exit during terminal muscle differentiation through the up-regulation of miR-20a expression, which in turn represses genes involved in cell cycle progression. Binds to the E-box containing (E1) promoter region of the miR-20a gene. Also plays a role in preventing reversal of muscle cell differentiation. Contributes to the atrophy-related gene expression in adult denervated muscles. Induces fibroblasts to differentiate into myoblasts (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P15173/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYOG","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYOG","total_profiled":1310},"omim":[{"mim_id":"618617","title":"ZINC FINGER HIT DOMAIN-CONTAINING PROTEIN 1; ZNHIT1","url":"https://www.omim.org/entry/618617"},{"mim_id":"618255","title":"MYOGENESIS-REGULATING GLYCOSIDASE; MYORG","url":"https://www.omim.org/entry/618255"},{"mim_id":"615671","title":"SET DOMAIN-CONTAINING PROTEIN 3; SETD3","url":"https://www.omim.org/entry/615671"},{"mim_id":"615581","title":"DOUBLE HOMEOBOX 4-LIKE 9; DUX4L9","url":"https://www.omim.org/entry/615581"},{"mim_id":"614933","title":"LONG INTERGENIC NONCODING RNA, MUSCLE DIFFERENTIATION 1; LINCMD1","url":"https://www.omim.org/entry/614933"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skeletal muscle","ntpm":98.4},{"tissue":"tongue","ntpm":43.5}],"url":"https://www.proteinatlas.org/search/MYOG"},"hgnc":{"alias_symbol":["bHLHc3"],"prev_symbol":["MYF4"]},"alphafold":{"accession":"P15173","domains":[{"cath_id":"4.10.280.10","chopping":"64-148","consensus_level":"medium","plddt":94.8922,"start":64,"end":148}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15173","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15173-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15173-F1-predicted_aligned_error_v6.png","plddt_mean":67.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYOG","jax_strain_url":"https://www.jax.org/strain/search?query=MYOG"},"sequence":{"accession":"P15173","fasta_url":"https://rest.uniprot.org/uniprotkb/P15173.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15173/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15173"}},"corpus_meta":[{"pmid":"16437161","id":"PMC_16437161","title":"Global and gene-specific analyses show distinct roles for Myod and Myog at a common set of promoters.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16437161","citation_count":217,"is_preprint":false},{"pmid":"29973406","id":"PMC_29973406","title":"MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma.","date":"2018","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29973406","citation_count":119,"is_preprint":false},{"pmid":"26540045","id":"PMC_26540045","title":"Myomaker, Regulated by MYOD, MYOG and miR-140-3p, Promotes Chicken Myoblast Fusion.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26540045","citation_count":96,"is_preprint":false},{"pmid":"1659574","id":"PMC_1659574","title":"Transcription of the muscle regulatory gene Myf4 is regulated by serum components, peptide growth factors and signaling pathways involving G proteins.","date":"1991","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1659574","citation_count":82,"is_preprint":false},{"pmid":"32060262","id":"PMC_32060262","title":"CASZ1 induces skeletal muscle and rhabdomyosarcoma differentiation through a feed-forward loop with MYOD and MYOG.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32060262","citation_count":44,"is_preprint":false},{"pmid":"16682754","id":"PMC_16682754","title":"Polymorphisms in coding and regulatory regions of the porcine MYF6 and MYOG genes and expression of the MYF6 gene in m. longissimus dorsi versus productive traits in pigs.","date":"2006","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16682754","citation_count":39,"is_preprint":false},{"pmid":"19008232","id":"PMC_19008232","title":"Ski regulates muscle terminal differentiation by transcriptional activation of Myog in a complex with Six1 and Eya3.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19008232","citation_count":36,"is_preprint":false},{"pmid":"30118770","id":"PMC_30118770","title":"A new hypoglycemic mechanism of catalpol revealed by enhancing MyoD/MyoG-mediated myogenesis.","date":"2018","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30118770","citation_count":33,"is_preprint":false},{"pmid":"19193870","id":"PMC_19193870","title":"Induced early expression of mrf4 but not myog rescues myogenesis in the myod/myf5 double-morphant zebrafish embryo.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19193870","citation_count":29,"is_preprint":false},{"pmid":"22106411","id":"PMC_22106411","title":"Protein tyrosine phosphatase-like A regulates myoblast proliferation and differentiation through MyoG and the cell cycling signaling pathway.","date":"2011","source":"Molecular and cellular 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MYOD binds first and recruits histone acetyltransferases to initiate regional histone modification at late-expressed genes, but is not sufficient for their full expression. MYOG does not bind these late genes efficiently without prior MYOD binding; transcriptional activation of late genes requires the combined activity of MYOD and MYOG. Thus MYOG's role in terminal differentiation is to enhance expression of a subset of genes previously initiated by MYOD.\",\n      \"method\": \"Genome-wide ChIP, promoter-specific DNA binding assays, expression analysis, histone modification profiling in myoblasts/myotubes\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP combined with promoter-specific binding and expression analyses, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"16437161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Oncogenic RAS, acting through the RAF-MEK-ERK MAPK pathway, represses MYOG expression by causing ERK2-dependent promoter-proximal stalling of RNA polymerase II at the MYOG locus. MEK inhibition with trametinib removes ERK2 from the MYOG promoter, releases transcriptional stalling, and restores MYOG expression. Restored MYOG subsequently opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation.\",\n      \"method\": \"ChIP for ERK2 and Pol II at MYOG promoter, small-molecule inhibitor treatment (trametinib), RNA-seq, ATAC-seq, xenograft tumor models\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal ChIP, multiple orthogonal genomic methods (ChIP-seq, ATAC-seq, RNA-seq), and in vivo validation\",\n      \"pmids\": [\"29973406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The MYOG (Myf4) promoter is regulated by multiple signaling pathways: (1) MyoD1, Myf5, and Myf6 transactivate the Myf4 promoter in fibroblasts; (2) serum components, bFGF, TGF-β, and EGF down-regulate Myf4 gene activity; (3) cAMP-elevating agents (dibutyryl-cAMP, forskolin, cholera toxin) inhibit the Myf4 promoter; (4) pertussis toxin (which inactivates Gi protein) stimulates Myf4 expression, indicating positive control through a Gi protein-dependent pathway. A minimal ~200 bp upstream region is sufficient for cell-type-specific expression.\",\n      \"method\": \"CAT/LacZ reporter assays with 5' deletion constructs, forced expression of MRFs in 10T1/2 fibroblasts, pharmacological perturbation with pertussis toxin, cholera toxin, forskolin, dibutyryl-cAMP\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple reporter and pharmacological approaches in a single lab, no independent replication cited\",\n      \"pmids\": [\"1659574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The proto-oncogene Ski is required for muscle terminal differentiation and directly activates transcription of MYOG. Ski occupies the endogenous MYOG regulatory region and activates its transcription primarily through a MEF3 site bound by Six1, not through MyoD or MEF2 binding sites. This requires direct physical interaction of Ski with Six1 and Eya3, mediated by the Dachshund homology domain of Ski.\",\n      \"method\": \"Conditional retroviral overexpression and knockdown of Ski in C2C12 myoblasts, ChIP at the MYOG locus, transcriptional reporter assays, co-immunoprecipitation of Ski-Six1-Eya3 complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at endogenous locus, reporter assays, Co-IP of complex, and functional KD/OE with defined phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19008232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYOD and MYOG bind to a conserved E-box element proximal to the Myomaker transcription start site and induce Myomaker transcription, thereby promoting myoblast fusion.\",\n      \"method\": \"Luciferase reporter assays with E-box mutants, ChIP for MYOD and MYOG at the Myomaker promoter in chicken primary myoblasts\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay with E-box mutation, single lab, two orthogonal methods (chicken model, ortholog included)\",\n      \"pmids\": [\"26540045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Actin-related protein 5 (Arp5) acts as an inhibitory regulator of MYOG (and MYOD) by binding to their cysteine-rich (CR) region, which overlaps with the region essential for their epigenetic/chromatin-remodeling functions. Arp5 competes with the Pbx1-Meis1 homeodomain heterodimer for binding to the CR region of MYOG, thereby disturbing MyoD-mediated chromatin remodeling. This inhibitory function is independent of the INO80 chromatin remodeling complex. In rhabdomyosarcoma, elevated Arp5 expression contributes to dysregulation of MYOG activity.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and siRNA knockdown of Arp5 in myoblasts and RMS cells, chromatin remodeling assays, myotube formation assays, in vivo overexpression in mouse hind limbs\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional KO/OE, in vivo validation, competition assay with defined binding region, multiple orthogonal methods\",\n      \"pmids\": [\"35348112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTPLa (protein tyrosine phosphatase-like A) is required for myoblast differentiation; cells lacking PTPLa fail to differentiate into myotubes due to repressed MYOG expression. PTPLa loss does not affect MyoD levels but specifically impairs MYOG induction, placing PTPLa upstream of MYOG in the myogenic differentiation pathway.\",\n      \"method\": \"siRNA knockdown of PTPLa in myoblasts, Western blot and qPCR for MYOG expression, differentiation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype and specific gene expression readout, single lab\",\n      \"pmids\": [\"22106411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The transcriptional repressor TRPS1 directly restricts MYOG expression and thereby inhibits terminal myogenic differentiation. TRPS1 and MYOD1 share common genomic binding sites including the MYOG promoter; TRPS1 occupancy at the MYOG promoter represses MYOG transcription. In embryonal rhabdomyosarcoma, elevated TRPS1 (sustained by miR-1 suppression) impairs myogenic differentiation through this mechanism.\",\n      \"method\": \"ChIP for TRPS1 and MYOD1 at the MYOG promoter, luciferase reporter assays, TRPS1 overexpression and knockdown in myoblasts and RD cells, in vivo xenograft experiments\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at MYOG promoter, reporter assays, KD/OE with functional readout, in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"37452493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DEC1 (Bhlhe40/STRA13) overexpression inhibits myogenic differentiation in bovine satellite cells by inhibiting MYOG promoter activity, as demonstrated by luciferase reporter assays. DEC1 overexpression reduces MYOG mRNA and protein levels.\",\n      \"method\": \"Adenovirus-mediated DEC1 overexpression, luciferase reporter assay of MYOG promoter, Western blot and qPCR for MYOG in bovine satellite cells\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reporter assay and functional OE, single lab, two orthogonal approaches\",\n      \"pmids\": [\"29350420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CREB1 directly binds to the proximal promoter region of MYOG and activates its transcription, promoting myogenic differentiation in bovine myoblasts, as shown by dual-luciferase reporter assays.\",\n      \"method\": \"Dual-luciferase reporter assay with MYOG promoter constructs, CREB1 overexpression/knockdown, ChIP (inferred from promoter analysis)\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, promoter-reporter assay only, no direct ChIP confirmation stated in abstract\",\n      \"pmids\": [\"35777504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYOG drives transcription of the bovine SIX1 gene indirectly via the MEF3 motif in the SIX1 promoter, as shown by EMSA, ChIP, serial deletion constructs, site-directed mutation, and siRNA interference experiments.\",\n      \"method\": \"EMSA, ChIP, luciferase reporter with deletion constructs and site-directed mutations, siRNA knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (EMSA, ChIP, reporter mutagenesis, siRNA), single lab\",\n      \"pmids\": [\"28974698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYOG binds to E-box elements in the core promoter region (-159/+1) of the bovine Myoz2 gene and cooperates with MYOD to regulate its transcription, as demonstrated by ChIP, dual-luciferase assay, site-directed mutagenesis, and siRNA interference.\",\n      \"method\": \"ChIP, dual-luciferase reporter with deletion constructs and site-directed mutagenesis, siRNA interference\",\n      \"journal\": \"Research in veterinary science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, reporter mutagenesis, siRNA), single lab\",\n      \"pmids\": [\"36191510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MEF2A and MYOG cooperate to bind the core promoter region (-248/-56) of the bovine LATS2 gene and regulate its transcription, as identified by site-directed mutations, siRNA interference, and chromatin immunoprecipitation.\",\n      \"method\": \"Dual-luciferase reporter with deletion/mutation constructs, siRNA interference, ChIP\",\n      \"journal\": \"Research in veterinary science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter mutagenesis, siRNA, ChIP), single lab\",\n      \"pmids\": [\"36126508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Vitamin C (VC) promotes muscle differentiation by upregulating nuclear translocation of CSRP3, which then interacts physically with MYOG (and MYOD), linking CSRP3-MYOG interaction to VC-mediated myogenesis.\",\n      \"method\": \"Co-immunoprecipitation/interaction assay, nuclear fractionation, C2C12 differentiation assays, mouse muscle injury model\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, interaction assay mentioned without detailed mechanistic characterization, abstract does not clarify strength of Co-IP\",\n      \"pmids\": [\"35652451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Sheep MyoG protein localizes to the nucleus when expressed in transfected cells, and forced expression of MyoG in goat embryonic fibroblasts induces desmin expression, demonstrating its myogenic trans-differentiation activity. MyoG contains a bHLH domain and lacks a signal peptide, identifying it as a non-secretory nuclear transcription factor.\",\n      \"method\": \"EGFP-tagged MyoG transfection with subcellular localization by fluorescence microscopy, Western blot, RT-PCR; forced expression in GEF cells with desmin immunodetection\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging of nuclear localization plus functional myogenic trans-differentiation assay, single lab\",\n      \"pmids\": [\"24385300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In zebrafish, myog (unlike mrf4) cannot rescue myogenesis in myod/myf5 double morphants, demonstrating that myog is not sufficient to activate myogenesis de novo in the absence of upstream MRFs. This places myog downstream of myod/myf5 in the zebrafish myogenic hierarchy.\",\n      \"method\": \"Morpholino knockdown of myod and myf5 in zebrafish, rescue experiments with forced early expression of mrf4 or myog, in vivo imaging of muscle development\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via morpholino double knockdown with rescue experiment in a vertebrate model, single lab\",\n      \"pmids\": [\"19193870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"No causative mutations were detected in the MYOG (myf4) coding region in 37 patients with severe congenital myopathy, indicating that coding mutations in MYOG are not a common cause of severe congenital myopathy. Additional intronic sequences (659 bp in intron 1, 498 bp in intron 2) and a variable (CA)-dinucleotide repeat in intron 2 were characterized.\",\n      \"method\": \"PCR amplification and automated sequencing of all three MYOG exons in 37 patients and 40 controls\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — negative result (no causative mutations found), single genomic sequencing study\",\n      \"pmids\": [\"10329008\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYOG (myogenin/MYF4) is a nuclear bHLH transcription factor that acts downstream of MYOD in the myogenic hierarchy to drive terminal skeletal muscle differentiation: MYOD first binds target promoters and recruits histone acetyltransferases to initiate chromatin remodeling, after which MYOG cooperates with MYOD to fully activate late myogenic genes; MYOG expression is itself transcriptionally regulated by upstream MRFs (MYOD, Myf5, Myf6), repressed by RAS-MEK-ERK signaling via ERK2-mediated RNA Pol II stalling at its promoter, activated through a Ski-Six1-Eya3 complex at a MEF3 element, and inhibited by TRPS1 and DEC1 at its promoter; MYOG activity is further modulated by binding partners including Arp5 (which competes with Pbx1-Meis1 for the MYOG cysteine-rich region to inhibit chromatin remodeling) and CSRP3; and MYOG in turn directly binds E-box elements to transactivate downstream muscle differentiation genes including Myomaker, SIX1, Myoz2, and LATS2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYOG (myogenin/MYF4) is a nuclear basic helix-loop-helix transcription factor that operates downstream of the upstream myogenic regulatory factors to drive terminal skeletal muscle differentiation [#14, #15]. It functions cooperatively with MYOD rather than independently: MYOD binds late-expressed muscle genes first and recruits histone acetyltransferases to initiate regional histone modification, after which MYOG enhances and fully activates expression of this MYOD-initiated subset of genes [#0]. Epistasis in zebrafish confirms that MYOG is not sufficient to activate myogenesis de novo without MYOD/Myf5 [#15]. Acting through E-box elements, MYOG directly transactivates downstream differentiation and fusion genes including Myomaker [#4] and Myoz2 [#11], and drives additional targets such as SIX1 via a MEF3 motif [#10] and LATS2 in concert with MEF2A [#12]. MYOG expression is itself a tightly controlled node: it is activated by upstream MRFs and a Ski–Six1–Eya3 complex acting at a MEF3 site [#2, #3], and is repressed by oncogenic RAS–MEK–ERK signaling, which drives ERK2-dependent promoter-proximal RNA polymerase II stalling at the MYOG locus, as well as by the transcriptional repressor TRPS1 [#1, #7]. At the protein level, MYOG activity is constrained by Arp5, which competes with the Pbx1–Meis1 heterodimer for binding to MYOG's cysteine-rich region to disturb MYOD-mediated chromatin remodeling, a mechanism dysregulated in rhabdomyosarcoma [#5]. No causative coding mutations in MYOG were found in severe congenital myopathy [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that the MYOG promoter is a convergence point for myogenic and signaling inputs, defining how the differentiation program is gated upstream of MYOG itself.\",\n      \"evidence\": \"Reporter assays with 5' deletions plus forced MRF expression and pharmacological perturbation in 10T1/2 fibroblasts\",\n      \"pmids\": [\"1659574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct factor occupancy at the promoter not demonstrated\", \"Identity of the Gi-protein-coupled effectors unresolved\", \"Mostly heterologous fibroblast context\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Tested whether MYOG coding mutations cause severe congenital myopathy, addressing a possible disease role; the negative result argued against MYOG coding variants as a common cause.\",\n      \"evidence\": \"PCR sequencing of all three MYOG exons in 37 patients and 40 controls\",\n      \"pmids\": [\"10329008\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Negative result does not exclude regulatory/intronic variants\", \"Limited cohort size\", \"No functional follow-up\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved how MYOG and MYOD divide labor at shared targets, showing MYOG acts as an amplifier of a MYOD-initiated chromatin program rather than an independent pioneer factor.\",\n      \"evidence\": \"Genome-wide ChIP with promoter-specific binding, expression, and histone modification profiling in myoblasts/myotubes\",\n      \"pmids\": [\"16437161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise coactivators recruited by MYOG not defined\", \"Does not specify how MYOG binding is licensed by prior MYOD occupancy\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified an upstream activating complex driving MYOG transcription, showing Ski activates MYOG through a MEF3/Six1 element via direct Ski-Six1-Eya3 interaction.\",\n      \"evidence\": \"Conditional OE/KD of Ski in C2C12, ChIP at the MYOG locus, reporter assays, and Co-IP of the Ski-Six1-Eya3 complex\",\n      \"pmids\": [\"19008232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ski integrates with MRF inputs at the promoter unclear\", \"In vivo requirement during development not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placed MYOG genetically downstream of MYOD/Myf5 by showing it cannot rescue myogenesis de novo, clarifying its non-redundant late position in the hierarchy.\",\n      \"evidence\": \"Morpholino knockdown of myod/myf5 in zebrafish with mrf4 vs myog rescue and in vivo imaging\",\n      \"pmids\": [\"19193870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino specificity caveats\", \"Does not define which targets require MYOG specifically\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified PTPLa as a specific upstream activator of MYOG induction, separating MYOG control from MYOD levels during differentiation.\",\n      \"evidence\": \"siRNA knockdown of PTPLa in myoblasts with MYOG expression readouts and differentiation assays\",\n      \"pmids\": [\"22106411\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking PTPLa to MYOG promoter unknown\", \"Whether effect is direct not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed MYOG as a nuclear, non-secretory bHLH factor with intrinsic myogenic trans-differentiation activity capable of inducing muscle markers in non-muscle cells.\",\n      \"evidence\": \"EGFP-tagged localization microscopy and forced expression inducing desmin in goat embryonic fibroblasts\",\n      \"pmids\": [\"24385300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single ortholog/cell context\", \"Does not map nuclear import signals\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected MYOG to the fusion machinery, showing MYOD and MYOG co-activate Myomaker via a conserved E-box to promote myoblast fusion.\",\n      \"evidence\": \"Luciferase reporter with E-box mutants and ChIP for MYOD/MYOG at the Myomaker promoter in chicken myoblasts\",\n      \"pmids\": [\"26540045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of MYOD vs MYOG not separated\", \"Single avian model\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the MYOG regulon to SIX1, revealing a feed-forward loop in which MYOG drives SIX1 through a MEF3 motif.\",\n      \"evidence\": \"EMSA, ChIP, reporter deletion/mutation, and siRNA in bovine cells\",\n      \"pmids\": [\"28974698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Indirect mechanism at MEF3 not fully resolved\", \"Single lab/species\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a clinically actionable repression mechanism, showing oncogenic RAS-MEK-ERK silences MYOG via ERK2-driven Pol II stalling that is reversible by MEK inhibition.\",\n      \"evidence\": \"ChIP for ERK2/Pol II at the MYOG promoter, trametinib treatment, RNA-seq, ATAC-seq, and xenografts\",\n      \"pmids\": [\"29973406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ERK2 is recruited to the promoter not fully defined\", \"Generality across muscle contexts beyond the tumor models\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified DEC1 as an additional repressor acting at the MYOG promoter to block differentiation.\",\n      \"evidence\": \"Adenoviral DEC1 overexpression with MYOG promoter luciferase assay in bovine satellite cells\",\n      \"pmids\": [\"29350420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DEC1 promoter occupancy not shown\", \"Endogenous loss-of-function not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered post-translational restraint of MYOG, showing Arp5 competes with Pbx1-Meis1 at the cysteine-rich region to block MYOD-mediated chromatin remodeling, with relevance to rhabdomyosarcoma.\",\n      \"evidence\": \"Reciprocal Co-IP, competition assays, OE/siRNA, chromatin remodeling and myotube assays, and in vivo mouse limb overexpression\",\n      \"pmids\": [\"35348112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CR-region competition not solved\", \"How Arp5 levels are set in normal myogenesis unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded the direct MYOG target set to Myoz2 and LATS2, reinforcing MYOG's cooperative regulation with MYOD and MEF2A at downstream muscle genes.\",\n      \"evidence\": \"ChIP, dual-luciferase with deletion/mutation, and siRNA for Myoz2 and LATS2 in bovine cells\",\n      \"pmids\": [\"36191510\", \"36126508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequence of LATS2/Myoz2 regulation not tested in vivo\", \"Single species\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added candidate activating inputs to MYOG, with CREB1 binding the proximal promoter and CSRP3 interacting with MYOG to mediate vitamin-C-driven myogenesis.\",\n      \"evidence\": \"Dual-luciferase reporter (CREB1) and Co-IP/nuclear fractionation with C2C12 and injury models (CSRP3)\",\n      \"pmids\": [\"35777504\", \"35652451\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"CREB1 ChIP confirmation not stated\", \"CSRP3-MYOG Co-IP not deeply characterized\", \"Functional consequences of the interactions incompletely defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established TRPS1 as a direct repressor of MYOG that shares MYOD1 binding sites at the promoter and impairs differentiation in embryonal rhabdomyosarcoma.\",\n      \"evidence\": \"ChIP for TRPS1/MYOD1 at the MYOG promoter, reporter assays, OE/KD in myoblasts and RD cells, and xenografts\",\n      \"pmids\": [\"37452493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TRPS1 competes with or displaces MYOD at shared sites not resolved\", \"Upstream control of TRPS1 beyond miR-1 incompletely mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple repressive (RAS-ERK, TRPS1, DEC1, Arp5) and activating (MRFs, Ski-Six1-Eya3, CREB1, PTPLa) inputs are integrated quantitatively at the MYOG locus to time terminal differentiation, and the structural basis of MYOG cofactor competition, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating activators and repressors\", \"No structural model of MYOG with Arp5/Pbx1-Meis1 or with MYOD\", \"MYOG-specific in vivo target requirements incompletely defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 10, 11, 12, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 4, 15]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYOD1\", \"MEF2A\", \"Arp5\", \"CSRP3\", \"TRPS1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}