{"gene":"MYOCD","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2020,"finding":"MYOCD directly interacts with SMAD3 and sustains the formation of TGF-β-induced nuclear SMAD3/SMAD4 complex, facilitating TGF-β/SMAD3-induced transactivation of Snail; conversely, the SMAD3/SMAD4 complex transcriptionally activates MYOCD, forming a positive feedback loop driving EMT in NSCLC cells.","method":"Co-immunoprecipitation, overexpression/knockdown with reporter assays, CRISPR/Cas9 silencing of SMAD3/SMAD4, in vivo metastasis assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, genetic loss-of-function (CRISPR), overexpression with defined transcriptional readouts, multiple orthogonal methods in one study","pmids":["32029901"],"is_preprint":false},{"year":2021,"finding":"MYOCD localizes to the TGFBR2 promoter region and recruits the PRMT5/MEP50 complex to epigenetically silence TGFBR2 transcription, functioning as a tumor suppressor that inhibits stemness of lung cancer stem cells.","method":"Chromatin immunoprecipitation (ChIP), in vitro and in vivo functional assays, promoter occupancy analysis","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP showing promoter binding and complex recruitment, single lab, single study","pmids":["33995678"],"is_preprint":false},{"year":2024,"finding":"MYOCD and SRF cooperatively bind to the MLCK promoter to drive MLCK transcription, thereby conferring ferroptosis resistance and hyperactivation of polymorphonuclear neutrophils in sepsis-related acute lung injury.","method":"RNA sequencing, promoter binding assay, knockdown of MYOCD/SRF/MLCK in mouse ALI model with ferroptosis marker readouts","journal":"Immunologic research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — promoter binding demonstrated, functional knockdown with defined ferroptosis phenotype, single lab","pmids":["39196520"],"is_preprint":false},{"year":2023,"finding":"Sall4 and MYOCD form a transcriptional complex with SRF, and this complex directly binds to upstream regulatory regions of CDK and cyclin genes (Cdk1 and Ccnb1) to promote cardiomyocyte proliferation.","method":"Co-immunoprecipitation, ChIP-sequencing, RNA-sequencing in ΔSall4 loss-of-function mice","journal":"Development","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP-seq showing direct binding, reciprocal Co-IP demonstrating complex, genetic loss-of-function with proliferation phenotype, multiple orthogonal methods","pmids":["38014633"],"is_preprint":false},{"year":2022,"finding":"GATA6, acting downstream of BMP4 signaling and cooperating with FOXF1, is required for Myocd expression in ureteric smooth muscle cell precursors; conditional loss of Gata6 reduces Myocd expression and delays SMC differentiation and peristaltic activity.","method":"Conditional knockout mouse model, molecular profiling, gain-of-function experiments","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via conditional KO plus gain-of-function, multiple readouts, single lab","pmids":["35905011"],"is_preprint":false},{"year":2024,"finding":"Colchicine inhibits FOXO3A expression, which relieves FOXO3A-MSX1/2-mediated repression of the SRF–MYOCD complex, thereby increasing SRF–MYOCD activation and promoting VSMC contractile phenotype; the SRF–MYOCD complex drives expression of contractile genes in VSMCs.","method":"In vivo carotid ligation model, in vitro VSMC phenotype assays, molecular mechanistic studies of FOXO3A–MSX1/2–SRF–MYOCD axis","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined molecular pathway with in vivo and in vitro validation, single lab, moderate mechanistic depth from abstract","pmids":["39663419"],"is_preprint":false},{"year":2015,"finding":"miR-9 directly binds to the 3'-UTR of myocardin (Myocd/MYOCD) mRNA and represses its expression, thereby inducing phenotypic switching and proliferation of pulmonary artery smooth muscle cells; knockdown of miR-9 or overexpression of myocardin reverses this effect.","method":"miRNA functional analysis, luciferase reporter assay (3'-UTR), miR-9 knockdown and overexpression in rat PASMCs","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — luciferase 3'-UTR assay plus functional rescue, single lab","pmids":["26147104"],"is_preprint":false},{"year":2022,"finding":"miR-139-5p directly targets the 3'-UTR of MYOCD mRNA to suppress its expression; DBP upregulates miR-139-5p, leading to MYOCD suppression and subsequent phenotypic switching of VSMCs from contractile to synthetic.","method":"Dual-luciferase reporter assay (3'-UTR), qRT-PCR, western blotting in A7r5 VSMC cells","journal":"Toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — luciferase 3'-UTR assay plus expression validation, single lab, single cell line","pmids":["35926758"],"is_preprint":false},{"year":2023,"finding":"Myocd deletion in lung mesenchyme-specific knockout mice mitigates airway smooth muscle cell hypertrophy and hyperplasia in a chronic asthma model, demonstrating Myocd as a key transcriptional coactivator required for asthmatic airway remodeling.","method":"Lung mesenchyme-specific conditional Myocd knockout mice, chronic ovalbumin asthma model, histological and cellular phenotyping","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with specific hypertrophy/hyperplasia phenotype in established disease model, multiple histological readouts","pmids":["36484734"],"is_preprint":false},{"year":2015,"finding":"MYOCD acts as a co-activator for SRF, GATA4, and TBX5; in cardiac stem cells (CSCs) lacking endogenous MYOCD, adding MYOCD to GMT transcription factors triggers cardiac protein expression (α-cardiac actin, ANP, sarcomeric myosin heavy chains), with MYOCD+TBX5 being the most effective pairwise combination for inducing cardiac differentiation.","method":"Doxycycline-inducible lentiviral transduction, high-throughput quantitative RT-PCR, immunofluorescence for cardiac proteins in adult mouse Sca1+ CSCs","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — systematic combinatorial overexpression with protein-level readouts, single lab","pmids":["26047103"],"is_preprint":false},{"year":2025,"finding":"NEXN binds to MYOCD and co-regulates EMT in hepatocellular carcinoma through the WNT/β-catenin signaling pathway; NEXN overexpression reduces β-catenin nuclear accumulation, and this is mediated at least in part through MYOCD interaction.","method":"Co-immunoprecipitation (NEXN–MYOCD binding), overexpression/knockdown with EMT marker readouts, in vivo tumor formation assay","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying binding partner, mechanistic pathway partially inferred, single lab","pmids":["41399508"],"is_preprint":false}],"current_model":"MYOCD (myocardin) is a transcriptional coactivator that partners with SRF and other cardiac/smooth muscle transcription factors (GATA4, TBX5, SALL4) to drive cardiac and smooth muscle gene programs; it directly interacts with SMAD3 to sustain nuclear SMAD3/SMAD4 complex formation and TGF-β-induced transcription (forming a positive feedback loop with SMAD3/SMAD4 in EMT); it occupies the TGFBR2 promoter and recruits PRMT5/MEP50 to epigenetically silence TGFBR2 in lung cancer; it is post-transcriptionally repressed by miR-9 and miR-139-5p via 3'-UTR targeting; and it is required for airway smooth muscle cell hypertrophy/hyperplasia in asthma and for ureteral smooth muscle differentiation downstream of GATA6/BMP4 signaling."},"narrative":{"mechanistic_narrative":"MYOCD (myocardin) is a transcriptional coactivator that partners with SRF and lineage-specific transcription factors to drive smooth muscle and cardiac contractile gene programs and to control cellular phenotype in development and disease [PMID:26047103, PMID:39663419]. In the cardiovascular and smooth muscle context, the SRF–MYOCD complex activates contractile genes and maintains the differentiated VSMC state, with this output gated by upstream regulators such as the FOXO3A–MSX1/2 axis [PMID:39663419]; in cardiomyocytes MYOCD partners with SALL4 and SRF to bind cell-cycle gene loci (Cdk1, Ccnb1) and promote proliferation [PMID:38014633], and in cardiac stem cells MYOCD cooperates with GATA4 and TBX5 to induce cardiac differentiation [PMID:26047103]. MYOCD expression is required for smooth muscle differentiation programs in vivo, acting downstream of BMP4/GATA6/FOXF1 signaling in ureteric smooth muscle precursors [PMID:35905011] and being required for airway smooth muscle hypertrophy and hyperplasia in chronic asthma [PMID:36484734]. MYOCD activity is tuned post-transcriptionally by miRNAs miR-9 and miR-139-5p, which bind its 3'-UTR to repress expression and promote contractile-to-synthetic phenotypic switching [PMID:26147104, PMID:35926758]. In cancer, MYOCD has context-dependent roles: it directly binds SMAD3 and sustains nuclear SMAD3/SMAD4 complexes in a positive feedback loop that drives TGF-β-induced EMT and metastasis in NSCLC [PMID:32029901], while at the TGFBR2 promoter it recruits the PRMT5/MEP50 complex to epigenetically silence TGFBR2 and suppress lung cancer stemness [PMID:33995678].","teleology":[{"year":2015,"claim":"Established that MYOCD acts as a combinatorial cardiac coactivator, defining which transcription-factor partners convert progenitor cells toward cardiac identity.","evidence":"Inducible lentiviral overexpression of MYOCD with GATA4/MEF2C/TBX5 combinations and cardiac protein readouts in adult mouse Sca1+ cardiac stem cells","pmids":["26047103"],"confidence":"Medium","gaps":["Does not define the genomic loci directly bound by MYOCD in these cells","Pairwise efficacy measured by marker expression, not functional cardiomyocyte conversion"]},{"year":2015,"claim":"Showed MYOCD is post-transcriptionally repressible, identifying miR-9 as a direct 3'-UTR regulator that drives smooth muscle phenotypic switching.","evidence":"Luciferase 3'-UTR reporter assay with miR-9 knockdown/overexpression and myocardin rescue in rat pulmonary artery smooth muscle cells","pmids":["26147104"],"confidence":"Medium","gaps":["Single cell type; whether miR-9 regulation operates in vivo not established","Downstream contractile targets affected not enumerated"]},{"year":2020,"claim":"Resolved a direct mechanistic link between MYOCD and TGF-β signaling, showing MYOCD sustains SMAD3/SMAD4 nuclear complexes in a feed-forward loop driving EMT.","evidence":"Reciprocal Co-IP, reporter assays, CRISPR silencing of SMAD3/SMAD4 and in vivo metastasis assay in NSCLC cells","pmids":["32029901"],"confidence":"High","gaps":["The MYOCD domain mediating SMAD3 binding not mapped","Reconciliation with MYOCD's tumor-suppressive role in lung cancer not addressed"]},{"year":2021,"claim":"Demonstrated a chromatin-level repressive function for MYOCD, occupying the TGFBR2 promoter and recruiting PRMT5/MEP50 to silence it.","evidence":"ChIP promoter occupancy and complex recruitment with in vitro/in vivo functional assays in lung cancer stem cells","pmids":["33995678"],"confidence":"Medium","gaps":["Single study, single lab","How MYOCD switches between coactivator and repressor at different loci is unresolved"]},{"year":2022,"claim":"Placed Myocd within a developmental signaling cascade, showing it is a required transcriptional output of BMP4/GATA6/FOXF1 for ureteric smooth muscle differentiation.","evidence":"Conditional Gata6 knockout with molecular profiling and gain-of-function in mouse ureteric smooth muscle precursors","pmids":["35905011"],"confidence":"Medium","gaps":["Direct binding of GATA6 to the Myocd locus not shown","Whether Myocd loss alone phenocopies Gata6 loss not tested here"]},{"year":2022,"claim":"Identified a second miRNA, miR-139-5p, as a direct MYOCD 3'-UTR repressor linking toxicant exposure to VSMC phenotype switching.","evidence":"Dual-luciferase 3'-UTR assay with qRT-PCR and western blot in A7r5 VSMCs","pmids":["35926758"],"confidence":"Medium","gaps":["Single cell line","In vivo relevance of DBP–miR-139-5p–MYOCD axis not established"]},{"year":2023,"claim":"Extended MYOCD's coactivator function into cell-cycle control, showing a SALL4–MYOCD–SRF complex directly drives proliferation genes in cardiomyocytes.","evidence":"Co-IP, ChIP-seq and RNA-seq in ΔSall4 loss-of-function mice with proliferation readouts at Cdk1/Ccnb1 loci","pmids":["38014633"],"confidence":"High","gaps":["Relative contribution of MYOCD versus SALL4 to complex targeting not dissected","Whether this proliferative role is reactivatable for cardiac regeneration untested"]},{"year":2023,"claim":"Provided in vivo genetic proof that Myocd is required for pathological airway smooth muscle remodeling.","evidence":"Lung mesenchyme-specific conditional Myocd knockout in a chronic ovalbumin asthma model with histological phenotyping","pmids":["36484734"],"confidence":"High","gaps":["Direct transcriptional targets mediating hypertrophy/hyperplasia not identified","Whether MYOCD acts through SRF in this setting not addressed"]},{"year":2024,"claim":"Defined upstream control of the SRF–MYOCD contractile output via a FOXO3A–MSX1/2 repressive axis relieved pharmacologically.","evidence":"Carotid ligation model plus VSMC phenotype assays dissecting the FOXO3A–MSX1/2–SRF–MYOCD axis with colchicine","pmids":["39663419"],"confidence":"Medium","gaps":["Direct molecular mechanism of MSX1/2 repression of the complex not fully resolved","Single lab"]},{"year":2024,"claim":"Linked SRF–MYOCD to MLCK transcription as a determinant of ferroptosis resistance in neutrophils during acute lung injury.","evidence":"RNA-seq, promoter binding and MYOCD/SRF/MLCK knockdown in a mouse ALI model with ferroptosis markers","pmids":["39196520"],"confidence":"Medium","gaps":["Single study","Mechanism connecting MLCK to ferroptosis resistance not fully defined"]},{"year":2025,"claim":"Identified NEXN as a physical MYOCD partner modulating EMT via WNT/β-catenin in hepatocellular carcinoma.","evidence":"Co-IP for NEXN–MYOCD binding with overexpression/knockdown EMT readouts and in vivo tumor assay","pmids":["41399508"],"confidence":"Low","gaps":["Single Co-IP without reciprocal/structural validation of the interaction","Mechanistic link to β-catenin only partially inferred"]},{"year":null,"claim":"How MYOCD is switched between transcriptional coactivation, chromatin-level repression, and partner-dependent context outputs at the molecular level remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of MYOCD with its partners","No unified mechanism explaining its opposing tumor-promoting (SMAD3) versus tumor-suppressing (TGFBR2 silencing) roles in lung cancer","Domains mediating distinct partner interactions not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,5,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,9]}],"complexes":["SRF–MYOCD coactivator complex","SALL4–MYOCD–SRF complex"],"partners":["SRF","SMAD3","SALL4","TBX5","GATA4","PRMT5","MEP50","NEXN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IZQ8","full_name":"Myocardin","aliases":[],"length_aa":938,"mass_kda":102.0,"function":"Smooth muscle cells (SM) and cardiac muscle cells-specific transcriptional factor which uses the canonical single or multiple CArG boxes DNA sequence. Acts as a cofactor of serum response factor (SRF) with the potential to modulate SRF-target genes. Plays a crucial role in cardiogenesis, urinary bladder development, and differentiation of the smooth muscle cell lineage (myogenesis) (By similarity). Positively regulates the transcription of genes involved in vascular smooth muscle contraction (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8IZQ8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYOCD","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYOCD","total_profiled":1310},"omim":[{"mim_id":"621305","title":"CARDIAC MESODERM ENHANCER-ASSOCIATED NONCODING RNA; CARMN","url":"https://www.omim.org/entry/621305"},{"mim_id":"620941","title":"SYNAPTOPODIN 2; SYNPO2","url":"https://www.omim.org/entry/620941"},{"mim_id":"619730","title":"ACTIN-RELATED PROTEIN 5; ACTR5","url":"https://www.omim.org/entry/619730"},{"mim_id":"618976","title":"MYOCARDIN-INDUCED SMOOTH MUSCLE LONG NONCODING RNA, INDUCER OF DIFFERENTIATION; MYOSLID","url":"https://www.omim.org/entry/618976"},{"mim_id":"618719","title":"MEGABLADDER, CONGENITAL; MGBL","url":"https://www.omim.org/entry/618719"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":25.4}],"url":"https://www.proteinatlas.org/search/MYOCD"},"hgnc":{"alias_symbol":["MYCD"],"prev_symbol":[]},"alphafold":{"accession":"Q8IZQ8","domains":[{"cath_id":"-","chopping":"19-72","consensus_level":"medium","plddt":93.2219,"start":19,"end":72}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZQ8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZQ8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IZQ8-F1-predicted_aligned_error_v6.png","plddt_mean":54.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYOCD","jax_strain_url":"https://www.jax.org/strain/search?query=MYOCD"},"sequence":{"accession":"Q8IZQ8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IZQ8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IZQ8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IZQ8"}},"corpus_meta":[{"pmid":"23704920","id":"PMC_23704920","title":"Transcription factors MYOCD, SRF, Mesp1 and SMARCD3 enhance the cardio-inducing effect of GATA4, TBX5, and MEF2C during direct cellular reprogramming.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23704920","citation_count":127,"is_preprint":false},{"pmid":"27144530","id":"PMC_27144530","title":"MEF2C-MYOCD and Leiomodin1 Suppression by miRNA-214 Promotes Smooth Muscle Cell Phenotype Switching in Pulmonary Arterial Hypertension.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27144530","citation_count":50,"is_preprint":false},{"pmid":"32029901","id":"PMC_32029901","title":"MYOCD and SMAD3/SMAD4 form a positive feedback loop and drive TGF-β-induced epithelial-mesenchymal transition in non-small cell lung cancer.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32029901","citation_count":44,"is_preprint":false},{"pmid":"23144723","id":"PMC_23144723","title":"Cardiac gene activation analysis in mammalian non-myoblasic cells by Nkx2-5, Tbx5, Gata4 and Myocd.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23144723","citation_count":29,"is_preprint":false},{"pmid":"20560679","id":"PMC_20560679","title":"Response to methadone maintenance treatment is associated with the MYOCD and GRM6 genes.","date":"2010","source":"Molecular diagnosis & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20560679","citation_count":23,"is_preprint":false},{"pmid":"33909498","id":"PMC_33909498","title":"Rho/ROCK-MYOCD in regulating airway smooth muscle growth and remodeling.","date":"2021","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33909498","citation_count":21,"is_preprint":false},{"pmid":"33718351","id":"PMC_33718351","title":"Sall4 and Myocd Empower Direct Cardiac Reprogramming From Adult Cardiac Fibroblasts After Injury.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33718351","citation_count":20,"is_preprint":false},{"pmid":"33995678","id":"PMC_33995678","title":"Targeting hyperactive TGFBR2 for treating MYOCD deficient lung cancer.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/33995678","citation_count":17,"is_preprint":false},{"pmid":"35926758","id":"PMC_35926758","title":"Di-n-butyl phthalate regulates vascular smooth muscle cells phenotypic switching by MiR-139-5p-MYOCD pathways.","date":"2022","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35926758","citation_count":13,"is_preprint":false},{"pmid":"36484734","id":"PMC_36484734","title":"Myocd regulates airway smooth muscle cell remodeling in response to chronic asthmatic injury.","date":"2023","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36484734","citation_count":10,"is_preprint":false},{"pmid":"26047103","id":"PMC_26047103","title":"Forward Programming of Cardiac Stem Cells by Homogeneous Transduction with MYOCD plus TBX5.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26047103","citation_count":10,"is_preprint":false},{"pmid":"26147104","id":"PMC_26147104","title":"Requirement of miR-9-dependent regulation of Myocd in PASMCs phenotypic modulation and proliferation induced by hepatopulmonary syndrome rat serum.","date":"2015","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26147104","citation_count":10,"is_preprint":false},{"pmid":"39663419","id":"PMC_39663419","title":"Colchicine reduces neointima formation and VSMC phenotype transition by modulating SRF-MYOCD activation and autophagy.","date":"2024","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/39663419","citation_count":8,"is_preprint":false},{"pmid":"35905011","id":"PMC_35905011","title":"GATA6 is a crucial factor for Myocd expression in the visceral smooth muscle cell differentiation program of the murine ureter.","date":"2022","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/35905011","citation_count":8,"is_preprint":false},{"pmid":"34606735","id":"PMC_34606735","title":"Improvement of Heart Function After Transplantation of Encapsulated Stem Cells Induced with miR-1/Myocd in Myocardial Infarction Model of Rat.","date":"2021","source":"Cell transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/34606735","citation_count":7,"is_preprint":false},{"pmid":"38014633","id":"PMC_38014633","title":"Sall1 and Sall4 cooperatively interact with Myocd and SRF to promote cardiomyocyte proliferation by regulating CDK and cyclin genes.","date":"2023","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38014633","citation_count":6,"is_preprint":false},{"pmid":"39196520","id":"PMC_39196520","title":"MYOCD and SRF-mediated MLCK transcription prevents polymorphonuclear neutrophils from ferroptosis in sepsis-related acute lung injury.","date":"2024","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/39196520","citation_count":4,"is_preprint":false},{"pmid":"34697065","id":"PMC_34697065","title":"Fusion of the Paired Box 3 (PAX3) and Myocardin (MYOCD) Genes in Pediatric Rhabdomyosarcoma.","date":"2021","source":"Cancer genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/34697065","citation_count":4,"is_preprint":false},{"pmid":"39260358","id":"PMC_39260358","title":"The Function of RhoA/ROCK Pathway and MYOCD in Airway Remodeling in Asthma.","date":"2024","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39260358","citation_count":3,"is_preprint":false},{"pmid":"41399508","id":"PMC_41399508","title":"NEXN targeting MYOCD by facilitating EMT-related β-catenin nuclear translocation modulates the metastasis of hepatocellular carcinoma.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/41399508","citation_count":0,"is_preprint":false},{"pmid":"40159973","id":"PMC_40159973","title":"[The splicing factor HNRNPH1 regulates Circ-MYOCD back-splicing to modulate the course of cardiac hypertrophy].","date":"2025","source":"Nan fang yi ke da xue xue bao = Journal of Southern Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/40159973","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.25.24317869","title":"Genomic predictors of response to antidepressants in Major depressive disorder (MDD): A GWAS-Based Study on Indian cohort","date":"2024-11-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.25.24317869","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.11.24310260","title":"Dysregulations in Cardiogenic Mechanisms by TGF-beta and Angiotensin II in Cardiac Remodeling Post-Ischemic Injury: a systematic review","date":"2024-07-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.11.24310260","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15152,"output_tokens":2676,"usd":0.042798,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9937,"output_tokens":3762,"usd":0.071868,"stage2_stop_reason":"end_turn"},"total_usd":0.114666,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"MYOCD directly interacts with SMAD3 and sustains the formation of TGF-β-induced nuclear SMAD3/SMAD4 complex, facilitating TGF-β/SMAD3-induced transactivation of Snail; conversely, the SMAD3/SMAD4 complex transcriptionally activates MYOCD, forming a positive feedback loop driving EMT in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown with reporter assays, CRISPR/Cas9 silencing of SMAD3/SMAD4, in vivo metastasis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, genetic loss-of-function (CRISPR), overexpression with defined transcriptional readouts, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32029901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYOCD localizes to the TGFBR2 promoter region and recruits the PRMT5/MEP50 complex to epigenetically silence TGFBR2 transcription, functioning as a tumor suppressor that inhibits stemness of lung cancer stem cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), in vitro and in vivo functional assays, promoter occupancy analysis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP showing promoter binding and complex recruitment, single lab, single study\",\n      \"pmids\": [\"33995678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYOCD and SRF cooperatively bind to the MLCK promoter to drive MLCK transcription, thereby conferring ferroptosis resistance and hyperactivation of polymorphonuclear neutrophils in sepsis-related acute lung injury.\",\n      \"method\": \"RNA sequencing, promoter binding assay, knockdown of MYOCD/SRF/MLCK in mouse ALI model with ferroptosis marker readouts\",\n      \"journal\": \"Immunologic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — promoter binding demonstrated, functional knockdown with defined ferroptosis phenotype, single lab\",\n      \"pmids\": [\"39196520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Sall4 and MYOCD form a transcriptional complex with SRF, and this complex directly binds to upstream regulatory regions of CDK and cyclin genes (Cdk1 and Ccnb1) to promote cardiomyocyte proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-sequencing, RNA-sequencing in ΔSall4 loss-of-function mice\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP-seq showing direct binding, reciprocal Co-IP demonstrating complex, genetic loss-of-function with proliferation phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"38014633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GATA6, acting downstream of BMP4 signaling and cooperating with FOXF1, is required for Myocd expression in ureteric smooth muscle cell precursors; conditional loss of Gata6 reduces Myocd expression and delays SMC differentiation and peristaltic activity.\",\n      \"method\": \"Conditional knockout mouse model, molecular profiling, gain-of-function experiments\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via conditional KO plus gain-of-function, multiple readouts, single lab\",\n      \"pmids\": [\"35905011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Colchicine inhibits FOXO3A expression, which relieves FOXO3A-MSX1/2-mediated repression of the SRF–MYOCD complex, thereby increasing SRF–MYOCD activation and promoting VSMC contractile phenotype; the SRF–MYOCD complex drives expression of contractile genes in VSMCs.\",\n      \"method\": \"In vivo carotid ligation model, in vitro VSMC phenotype assays, molecular mechanistic studies of FOXO3A–MSX1/2–SRF–MYOCD axis\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined molecular pathway with in vivo and in vitro validation, single lab, moderate mechanistic depth from abstract\",\n      \"pmids\": [\"39663419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-9 directly binds to the 3'-UTR of myocardin (Myocd/MYOCD) mRNA and represses its expression, thereby inducing phenotypic switching and proliferation of pulmonary artery smooth muscle cells; knockdown of miR-9 or overexpression of myocardin reverses this effect.\",\n      \"method\": \"miRNA functional analysis, luciferase reporter assay (3'-UTR), miR-9 knockdown and overexpression in rat PASMCs\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — luciferase 3'-UTR assay plus functional rescue, single lab\",\n      \"pmids\": [\"26147104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-139-5p directly targets the 3'-UTR of MYOCD mRNA to suppress its expression; DBP upregulates miR-139-5p, leading to MYOCD suppression and subsequent phenotypic switching of VSMCs from contractile to synthetic.\",\n      \"method\": \"Dual-luciferase reporter assay (3'-UTR), qRT-PCR, western blotting in A7r5 VSMC cells\",\n      \"journal\": \"Toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — luciferase 3'-UTR assay plus expression validation, single lab, single cell line\",\n      \"pmids\": [\"35926758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Myocd deletion in lung mesenchyme-specific knockout mice mitigates airway smooth muscle cell hypertrophy and hyperplasia in a chronic asthma model, demonstrating Myocd as a key transcriptional coactivator required for asthmatic airway remodeling.\",\n      \"method\": \"Lung mesenchyme-specific conditional Myocd knockout mice, chronic ovalbumin asthma model, histological and cellular phenotyping\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with specific hypertrophy/hyperplasia phenotype in established disease model, multiple histological readouts\",\n      \"pmids\": [\"36484734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYOCD acts as a co-activator for SRF, GATA4, and TBX5; in cardiac stem cells (CSCs) lacking endogenous MYOCD, adding MYOCD to GMT transcription factors triggers cardiac protein expression (α-cardiac actin, ANP, sarcomeric myosin heavy chains), with MYOCD+TBX5 being the most effective pairwise combination for inducing cardiac differentiation.\",\n      \"method\": \"Doxycycline-inducible lentiviral transduction, high-throughput quantitative RT-PCR, immunofluorescence for cardiac proteins in adult mouse Sca1+ CSCs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — systematic combinatorial overexpression with protein-level readouts, single lab\",\n      \"pmids\": [\"26047103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NEXN binds to MYOCD and co-regulates EMT in hepatocellular carcinoma through the WNT/β-catenin signaling pathway; NEXN overexpression reduces β-catenin nuclear accumulation, and this is mediated at least in part through MYOCD interaction.\",\n      \"method\": \"Co-immunoprecipitation (NEXN–MYOCD binding), overexpression/knockdown with EMT marker readouts, in vivo tumor formation assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying binding partner, mechanistic pathway partially inferred, single lab\",\n      \"pmids\": [\"41399508\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYOCD (myocardin) is a transcriptional coactivator that partners with SRF and other cardiac/smooth muscle transcription factors (GATA4, TBX5, SALL4) to drive cardiac and smooth muscle gene programs; it directly interacts with SMAD3 to sustain nuclear SMAD3/SMAD4 complex formation and TGF-β-induced transcription (forming a positive feedback loop with SMAD3/SMAD4 in EMT); it occupies the TGFBR2 promoter and recruits PRMT5/MEP50 to epigenetically silence TGFBR2 in lung cancer; it is post-transcriptionally repressed by miR-9 and miR-139-5p via 3'-UTR targeting; and it is required for airway smooth muscle cell hypertrophy/hyperplasia in asthma and for ureteral smooth muscle differentiation downstream of GATA6/BMP4 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYOCD (myocardin) is a transcriptional coactivator that partners with SRF and lineage-specific transcription factors to drive smooth muscle and cardiac contractile gene programs and to control cellular phenotype in development and disease [#9, #5]. In the cardiovascular and smooth muscle context, the SRF\\u2013MYOCD complex activates contractile genes and maintains the differentiated VSMC state, with this output gated by upstream regulators such as the FOXO3A\\u2013MSX1/2 axis [#5]; in cardiomyocytes MYOCD partners with SALL4 and SRF to bind cell-cycle gene loci (Cdk1, Ccnb1) and promote proliferation [#3], and in cardiac stem cells MYOCD cooperates with GATA4 and TBX5 to induce cardiac differentiation [#9]. MYOCD expression is required for smooth muscle differentiation programs in vivo, acting downstream of BMP4/GATA6/FOXF1 signaling in ureteric smooth muscle precursors [#4] and being required for airway smooth muscle hypertrophy and hyperplasia in chronic asthma [#8]. MYOCD activity is tuned post-transcriptionally by miRNAs miR-9 and miR-139-5p, which bind its 3'-UTR to repress expression and promote contractile-to-synthetic phenotypic switching [#6, #7]. In cancer, MYOCD has context-dependent roles: it directly binds SMAD3 and sustains nuclear SMAD3/SMAD4 complexes in a positive feedback loop that drives TGF-\\u03b2-induced EMT and metastasis in NSCLC [#0], while at the TGFBR2 promoter it recruits the PRMT5/MEP50 complex to epigenetically silence TGFBR2 and suppress lung cancer stemness [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that MYOCD acts as a combinatorial cardiac coactivator, defining which transcription-factor partners convert progenitor cells toward cardiac identity.\",\n      \"evidence\": \"Inducible lentiviral overexpression of MYOCD with GATA4/MEF2C/TBX5 combinations and cardiac protein readouts in adult mouse Sca1+ cardiac stem cells\",\n      \"pmids\": [\"26047103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the genomic loci directly bound by MYOCD in these cells\", \"Pairwise efficacy measured by marker expression, not functional cardiomyocyte conversion\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed MYOCD is post-transcriptionally repressible, identifying miR-9 as a direct 3'-UTR regulator that drives smooth muscle phenotypic switching.\",\n      \"evidence\": \"Luciferase 3'-UTR reporter assay with miR-9 knockdown/overexpression and myocardin rescue in rat pulmonary artery smooth muscle cells\",\n      \"pmids\": [\"26147104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell type; whether miR-9 regulation operates in vivo not established\", \"Downstream contractile targets affected not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved a direct mechanistic link between MYOCD and TGF-\\u03b2 signaling, showing MYOCD sustains SMAD3/SMAD4 nuclear complexes in a feed-forward loop driving EMT.\",\n      \"evidence\": \"Reciprocal Co-IP, reporter assays, CRISPR silencing of SMAD3/SMAD4 and in vivo metastasis assay in NSCLC cells\",\n      \"pmids\": [\"32029901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The MYOCD domain mediating SMAD3 binding not mapped\", \"Reconciliation with MYOCD's tumor-suppressive role in lung cancer not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a chromatin-level repressive function for MYOCD, occupying the TGFBR2 promoter and recruiting PRMT5/MEP50 to silence it.\",\n      \"evidence\": \"ChIP promoter occupancy and complex recruitment with in vitro/in vivo functional assays in lung cancer stem cells\",\n      \"pmids\": [\"33995678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single lab\", \"How MYOCD switches between coactivator and repressor at different loci is unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed Myocd within a developmental signaling cascade, showing it is a required transcriptional output of BMP4/GATA6/FOXF1 for ureteric smooth muscle differentiation.\",\n      \"evidence\": \"Conditional Gata6 knockout with molecular profiling and gain-of-function in mouse ureteric smooth muscle precursors\",\n      \"pmids\": [\"35905011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of GATA6 to the Myocd locus not shown\", \"Whether Myocd loss alone phenocopies Gata6 loss not tested here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a second miRNA, miR-139-5p, as a direct MYOCD 3'-UTR repressor linking toxicant exposure to VSMC phenotype switching.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR assay with qRT-PCR and western blot in A7r5 VSMCs\",\n      \"pmids\": [\"35926758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line\", \"In vivo relevance of DBP\\u2013miR-139-5p\\u2013MYOCD axis not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended MYOCD's coactivator function into cell-cycle control, showing a SALL4\\u2013MYOCD\\u2013SRF complex directly drives proliferation genes in cardiomyocytes.\",\n      \"evidence\": \"Co-IP, ChIP-seq and RNA-seq in \\u0394Sall4 loss-of-function mice with proliferation readouts at Cdk1/Ccnb1 loci\",\n      \"pmids\": [\"38014633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of MYOCD versus SALL4 to complex targeting not dissected\", \"Whether this proliferative role is reactivatable for cardiac regeneration untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided in vivo genetic proof that Myocd is required for pathological airway smooth muscle remodeling.\",\n      \"evidence\": \"Lung mesenchyme-specific conditional Myocd knockout in a chronic ovalbumin asthma model with histological phenotyping\",\n      \"pmids\": [\"36484734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating hypertrophy/hyperplasia not identified\", \"Whether MYOCD acts through SRF in this setting not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined upstream control of the SRF\\u2013MYOCD contractile output via a FOXO3A\\u2013MSX1/2 repressive axis relieved pharmacologically.\",\n      \"evidence\": \"Carotid ligation model plus VSMC phenotype assays dissecting the FOXO3A\\u2013MSX1/2\\u2013SRF\\u2013MYOCD axis with colchicine\",\n      \"pmids\": [\"39663419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism of MSX1/2 repression of the complex not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked SRF\\u2013MYOCD to MLCK transcription as a determinant of ferroptosis resistance in neutrophils during acute lung injury.\",\n      \"evidence\": \"RNA-seq, promoter binding and MYOCD/SRF/MLCK knockdown in a mouse ALI model with ferroptosis markers\",\n      \"pmids\": [\"39196520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Mechanism connecting MLCK to ferroptosis resistance not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified NEXN as a physical MYOCD partner modulating EMT via WNT/\\u03b2-catenin in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP for NEXN\\u2013MYOCD binding with overexpression/knockdown EMT readouts and in vivo tumor assay\",\n      \"pmids\": [\"41399508\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal/structural validation of the interaction\", \"Mechanistic link to \\u03b2-catenin only partially inferred\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYOCD is switched between transcriptional coactivation, chromatin-level repression, and partner-dependent context outputs at the molecular level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of MYOCD with its partners\", \"No unified mechanism explaining its opposing tumor-promoting (SMAD3) versus tumor-suppressing (TGFBR2 silencing) roles in lung cancer\", \"Domains mediating distinct partner interactions not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 5, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 9]}\n    ],\n    \"complexes\": [\"SRF\\u2013MYOCD coactivator complex\", \"SALL4\\u2013MYOCD\\u2013SRF complex\"],\n    \"partners\": [\"SRF\", \"SMAD3\", \"SALL4\", \"TBX5\", \"GATA4\", \"PRMT5\", \"MEP50\", \"NEXN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}