{"gene":"MEF2D","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2009,"finding":"MEF2D is a substrate of chaperone-mediated autophagy (CMA): MEF2D continuously shuttles to the cytoplasm, interacts with the chaperone Hsc70, and undergoes lysosomal degradation. Inhibition of CMA causes accumulation of inactive MEF2D in the cytoplasm. Alpha-synuclein (wild-type and PD-associated mutant) disrupts MEF2D–Hsc70 binding, blocking CMA-mediated degradation and leading to neuronal death.","method":"Co-immunoprecipitation, subcellular fractionation, CMA inhibition assays, neuronal cell line experiments, alpha-synuclein transgenic mouse model","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional CMA inhibition, in vivo transgenic model, and human PD brain confirmation; replicated across multiple orthogonal methods in one rigorous study","pmids":["19119233"],"is_preprint":false},{"year":2011,"finding":"A portion of MEF2D localizes to neuronal mitochondria via an N-terminal targeting motif and the chaperone mtHsp70, where it binds a MEF2 consensus site in the mitochondrial DNA region containing the ND6 gene (encoding a complex I subunit) and activates ND6 transcription. Blocking mitochondrial MEF2D function decreases complex I activity, increases H2O2, reduces ATP, and sensitizes neurons to stress-induced death.","method":"Immunocytochemistry, immunoelectron microscopy, biochemical fractionation, chromatin immunoprecipitation (ChIP) on mtDNA, luciferase reporter, dominant-negative mitochondrial MEF2D construct, mouse PD model (MPTP), postmortem PD brain analysis","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ICC, IEM, fractionation, ChIP, functional knockdown, in vivo model, human tissue) in one study","pmids":["21393861"],"is_preprint":false},{"year":2009,"finding":"GSK3β directly phosphorylates MEF2D at three specific residues in its transactivation domain, inhibiting MEF2D transcriptional activity. In cerebellar granule neurons, withdrawal of neuronal activity activates nuclear GSK3β, leading to GSK3β-dependent inhibition of MEF2 function and contributing to neuronal death. Expression of a GSK3β-resistant MEF2D mutant protects neurons from GSK3β activation- or activity deprivation-induced toxicity.","method":"In vitro kinase assay, site-directed mutagenesis, cerebellar granule neuron culture, transactivation reporter assays, overexpression of GSK3β-resistant MEF2D mutant","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation with mutagenesis of specific residues, functional rescue in primary neurons","pmids":["19801631"],"is_preprint":false},{"year":2014,"finding":"Oxidative stress (6-OHDA) causes direct oxidative modifications of MEF2D, which increases its binding affinity for Hsc70 and accelerates its CMA-mediated degradation via upregulation of LAMP2A. An oxidation-resistant MEF2D mutant protects dopaminergic neurons from 6-OHDA-induced death. Oxidized MEF2D is elevated in postmortem PD brains.","method":"Biochemical oxidation assays, Co-IP (MEF2D–Hsc70 binding), LAMP2A quantification, MEF2D oxidation-resistant mutant expression, mouse substantia nigra analysis, postmortem PD brain samples","journal":"Antioxidants & Redox Signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical modification assay, mutant rescue, in vivo model, and human tissue confirmation across multiple methods","pmids":["24219011"],"is_preprint":false},{"year":2014,"finding":"ATM kinase phosphorylates MEF2D at four ATM consensus sites following DNA damage, activating MEF2D and promoting neuronal survival. ATM associates with MEF2D after DNA damage; a phosphomimetic MEF2D mutant protects cerebellar granule cells from etoposide-induced death, whereas a non-phosphorylatable mutant does not. Mef2d knockout mice show increased cerebellar susceptibility to DNA damage.","method":"In vitro kinase assay, Co-immunoprecipitation (ATM–MEF2D), shRNA knockdown, phosphomimetic/non-phosphorylatable mutant rescue, Mef2d knockout mouse cerebellar damage model","journal":"Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct kinase assay, mutagenesis, reciprocal Co-IP, and in vivo KO phenotype with multiple orthogonal methods","pmids":["24672010"],"is_preprint":false},{"year":2008,"finding":"MEF2D is required for stress-dependent pathological cardiac remodeling in vivo. MEF2D-null mice are resistant to cardiac hypertrophy, fetal gene activation, and fibrosis in response to pressure overload and beta-adrenergic stimulation. Conversely, transgenic overexpression of MEF2D is sufficient to drive the fetal gene program and pathological cardiac remodeling.","method":"Conditional MEF2D knockout mouse, pressure overload model, chronic adrenergic stimulation, MEF2D transgenic overexpression mouse","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo KO and gain-of-function transgenic models with defined cardiac phenotypes","pmids":["18079970"],"is_preprint":false},{"year":1995,"finding":"MEF2D is the predominant HeLa cell protein binding the MEF2 site in the c-jun promoter and is required for serum-inducible c-jun expression. Transfection of MEF2D into low-MEF2-activity NIH 3T3 cells reconstitutes serum induction. The MEF2D DNA-binding domain fused to a heterologous activation domain is sufficient for serum induction, suggesting a shared mechanism with SRF-mediated c-fos serum response.","method":"DNA-binding assays (EMSA), transfection reconstitution in NIH 3T3 cells, deletion analysis/domain swap","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — EMSA, functional reconstitution, and domain deletion analysis with multiple orthogonal approaches","pmids":["7760790"],"is_preprint":false},{"year":2006,"finding":"At the onset of skeletal muscle specification, MEF2D appears at late muscle gene loci concomitant with the SWI/SNF ATPase Brg1 and chromatin opening. Ectopic co-expression of myogenin and MEF2D (without MyoD) is sufficient to induce muscle differentiation in a manner entirely dependent on Brg1, showing that MEF2D cooperates with myogenin to recruit Brg1 for chromatin remodeling at muscle-specific genes.","method":"ChIP in cultured cells and embryonic tissue, ectopic co-expression, Brg1 dominant-negative and knockdown, chromatin accessibility assays","journal":"EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP in cells and embryonic tissue, functional co-expression rescue, and Brg1 dependency demonstrated by multiple methods","pmids":["16424906"],"is_preprint":false},{"year":2015,"finding":"In the retina, MEF2D binds retina-specific enhancers by cooperating with the tissue-specific factor CRX, which recruits MEF2D away from canonical MEF2-binding sites and redirects it to retina-specific enhancers lacking the consensus MEF2 sequence. MEF2D and CRX then co-activate photoreceptor-specific genes critical for retinal function.","method":"ChIP-seq, genome-wide MEF2D binding analysis, MEF2D and CRX co-immunoprecipitation, retinal gene expression analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq with genome-wide scope, Co-IP of MEF2D–CRX interaction, functional co-activation demonstrated","pmids":["25801704"],"is_preprint":false},{"year":2001,"finding":"14-3-3tau physically interacts with MEF2D (identified by yeast two-hybrid and confirmed by co-precipitation in vivo) and specifically enhances MEF2 transactivational activity by competitively inhibiting HDAC4 from binding to MEF2D, thereby promoting muscle cell differentiation.","method":"Yeast two-hybrid, co-immunoprecipitation, transient transfection reporter assay, HDAC4 competition experiment","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP in vivo, functional transactivation assay; single lab, two orthogonal methods","pmids":["11433030"],"is_preprint":false},{"year":2014,"finding":"Rbfox2 RNA-binding protein regulates alternative splicing of Mef2d. Restoration of Rbfox2-dependent Mef2d splicing isoforms rescues myoblast fusion in Rbfox2-depleted cultures, demonstrating that Mef2d isoform switching downstream of Rbfox2 is functionally required for myoblast fusion during myogenesis.","method":"RNA-seq, Rbfox2 iCLIP, shRNA depletion, splicing isoform rescue experiments in myoblast fusion assays","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — iCLIP defines direct splicing targets, RNA-seq quantifies transitions, rescue of fusion phenotype by specific isoforms; multiple orthogonal methods","pmids":["25087874"],"is_preprint":false},{"year":2013,"finding":"MEF2D is required for normal myogenesis; its loss in rhabdomyosarcoma cells prevents muscle differentiation. Re-expression of MEF2D in RMS cells activates muscle-specific gene expression (including myosin heavy chain), upregulates p21, inhibits proliferation and motility, and abolishes tumorigenicity in xenograft models.","method":"Stable transfection, ChIP (showing absence of MEF2D at muscle gene promoters in RMS), luciferase reporter, proliferation assay, scratch assay, soft agar assay, xenograft tumor model","journal":"Molecular Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, functional rescue in cell lines and in vivo xenograft; single lab, multiple orthogonal methods","pmids":["24279793"],"is_preprint":false},{"year":2019,"finding":"MEF2D binds the CD274 (PD-L1) gene promoter and activates its transcription in hepatocellular carcinoma cells. Upon IFN-γ stimulation, p300 acetyltransferase acetylates MEF2D and promotes its binding (with acetylated histones) to the CD274 promoter. SIRT7 forms a complex with MEF2D under basal conditions and deacetylates it to attenuate PD-L1 expression; IFN-γ disrupts MEF2D–SIRT7 interaction by inducing p300 binding to MEF2D.","method":"ChIP, co-immunoprecipitation, pull-down assays, dual luciferase reporter, MEF2D/SIRT7 knockout cells, allograft tumor models in immune-competent and immune-deficient mice","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, reciprocal Co-IP, pull-down, luciferase reporter, KO models with in vivo immune-competent tumor models; multiple orthogonal methods in one study","pmids":["31678303"],"is_preprint":false},{"year":2009,"finding":"MEF2D regulates expression of the anti-apoptotic bcl-w gene in dorsal root ganglia sensory neurons downstream of a target-derived neurotrophin–Trk–ERK5/MEF2 pathway, constituting a retrograde survival signaling program. ERK5 activation by distal-axon neurotrophin stimulation induces MEF2D-dependent mef2d and bcl-w expression to promote sensory neuron survival.","method":"Neurotrophin compartmentalized axon stimulation, MEF2D expression analysis, ERK5 pathway inhibition, bcl-w reporter and expression assays, sensory neuron survival assays","journal":"Journal of Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pathway analysis in primary neurons with pathway inhibitor and distal-axon stimulation; single lab, multiple methods","pmids":["19458239"],"is_preprint":false},{"year":2007,"finding":"MEF2D is activated by the calcineurin/NFATc1 pathway in muscle cells during calcium-ionophore treatment. MEF2D, NFATc1, and MyoD co-activate the beta-MyHC promoter in a calcineurin-dependent manner; MEF2D binds to the MyoD complex at the promoter and is recruited with p300. This was shown by EMSA, ChIP, and nuclear complex co-immunoprecipitation.","method":"EMSA, ChIP, nuclear complex co-immunoprecipitation (NCcoIP), transient transfection reporter assay, calcineurin inhibitor experiments","journal":"Journal of Cellular Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP confirm binding at promoter; multiple methods, single lab","pmids":["17111365"],"is_preprint":false},{"year":2013,"finding":"CDK5 phosphorylation of MEF2D at Ser444 contributes to MEF2D inactivation and neuronal apoptosis following intracerebral hemorrhage. Knockdown of CDK5 suppresses neuronal apoptosis with concurrent reduction in MEF2D phosphorylation at Ser444.","method":"CDK5 kinase activity assay, phospho-specific immunostaining, CDK5 siRNA knockdown, rat intracerebral hemorrhage model, primary cortical neuron culture","journal":"Journal of Molecular Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific phosphorylation evidence with KD phenotype in primary neurons and in vivo model; single lab","pmids":["25417143"],"is_preprint":false},{"year":2013,"finding":"MEF2D constitutively binds the Nur77 (NR4A1) promoter in neurons under basal conditions; this binding is lost following MPP+ treatment. MEF2D loss leads to decreased Nur77 expression, sensitizing dopaminergic neurons to MPTP-induced death. Ectopic Nur77 expression in nigrostriatal neurons rescues dopaminergic loss in Nur77-deficient MPTP-treated mice, placing Nur77 downstream of MEF2D in a neuronal survival pathway.","method":"ChIP (MEF2D binding to Nur77 promoter), in vivo MPTP mouse model, Nur77 knockout mice, lentiviral Nur77 rescue, striatal dopamine/DOPAC measurement","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrates direct promoter binding, in vivo epistasis via Nur77 KO and rescue, multiple orthogonal approaches","pmids":["23536182"],"is_preprint":false},{"year":2006,"finding":"In hippocampal neurons, cAMP inhibits Ca2+-activated MEF2D-mediated gene expression by antagonizing HDAC5 nuclear export (blocking MEF2D derepression) and inhibiting nuclear import of the MEF2 co-activator NFAT3/c4. Unlike CREB, MEF2D is not directly activated by cAMP.","method":"Neuronal transfection reporter assays, nuclear/cytoplasmic fractionation, pharmacological cAMP elevation, Ca2+ manipulation in hippocampal neurons","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic steps tested in primary neurons; single lab, two orthogonal methods","pmids":["16870618"],"is_preprint":false},{"year":2016,"finding":"MEF2D directly regulates transcription of ZEB1 (an EMT driver gene) and facilitates histone acetylation at the ZEB1 promoter in colorectal cancer cells. MEF2D acts as a central integrator of multiple tumor microenvironment signals to activate ZEB1, promoting cancer cell invasion and EMT.","method":"ChIP (MEF2D binding to ZEB1 promoter), luciferase reporter, MEF2D knockdown/overexpression, invasion assay, in vivo metastasis model","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct ZEB1 promoter binding, functional phenotype in cells and in vivo; single lab","pmids":["27364559"],"is_preprint":false},{"year":2015,"finding":"MEF2D loss in neonatal cardiomyocytes triggers cell cycle re-entry and programmed cell death. Genome-wide transcriptome analysis showed that MEF2D depletion upregulates positive cell cycle regulators. PTEN, the primary negative regulator of PI3K/Akt, is a direct MEF2D target gene; MEF2D-deficient cardiomyocytes show reduced PTEN and activated PI3K/Akt signaling.","method":"siRNA knockdown of MEF2D in neonatal cardiomyocytes, RNA-seq/transcriptome profiling, ChIP (PTEN as direct target), cell cycle analysis, apoptosis assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms PTEN as direct target, RNA-seq provides genome-wide transcriptome data, KD with defined cell cycle/death phenotype; single lab","pmids":["26294766"],"is_preprint":false},{"year":2021,"finding":"In MLL-rearranged AML, MEF2D binds to and suppresses chromatin accessibility of CEBPE cis-regulatory regions, thereby blocking a CEBPE-centered myeloid differentiation program. Knockout of MEF2D activates CEBPE expression, induces myeloid differentiation, and impairs leukemia growth. CEBPE depletion partially rescues cell growth defects caused by MEF2D loss, placing MEF2D upstream of CEBPE in a leukemia self-renewal circuit.","method":"MEF2D knockout (CRISPR), RNA-seq, ATAC-seq/chromatin profiling (ChIP), CEBPE depletion rescue, in vivo leukemia progression model","journal":"Blood Advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — chromatin profiling, KO and rescue epistasis, in vivo leukemia model; multiple orthogonal methods in one study","pmids":["34597364"],"is_preprint":false},{"year":2022,"finding":"The MEF2D-HNRNPUL1 (MH) fusion protein acquires increased chromatin-binding ability at MEF2D-responsive element (MRE) motifs. X-ray crystallography of the MEF2D-MRE complex revealed atomic-resolution structure. Disrupting MH–DNA interaction alleviated aberrant target gene expression and B-cell differentiation arrest. The HNRNPUL1 C-terminal moiety contributes to trans-regulatory activity, cofactor recruitment, and homodimerization of the fusion protein.","method":"Knock-in mouse model, RNA-seq, ChIP-seq, X-ray crystallography, MH–DNA interaction mutagenesis, HDAC inhibitor treatment, xenograft/in vivo leukemia model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — X-ray crystal structure with functional mutagenesis, ChIP-seq, knock-in mouse, and in vivo therapeutic validation; multiple rigorous orthogonal methods","pmids":["35544603"],"is_preprint":false},{"year":2013,"finding":"O-GlcNAc glycosylation of MEF2D (specifically the Mef2D1a splice variant, in both its DNA-binding and transactivation domains) negatively regulates MEF2D recruitment to the myogenin promoter. Decreased O-GlcNAc glycosylation upon myogenic stimulus is required for MEF2D binding to the myogenin promoter and subsequent myogenin expression.","method":"O-GlcNAc glycosylation assays, deletion mutant analysis, O-GlcNAc transferase/hydrolase inhibitors, ChIP (MEF2D at myogenin promoter), C2C12 differentiation model","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct glycosylation biochemistry, domain mapping, ChIP confirming promoter recruitment change; single lab","pmids":["23523791"],"is_preprint":false},{"year":2002,"finding":"MEF2D forms a protein complex with Sp1 in U937 promyeloid cells. Co-expression of MEF2D and Sp1 synergistically activates the CD14 promoter during monocytic differentiation, providing a mechanism for MEF2D to regulate gene expression at promoters lacking canonical MEF2-binding sites.","method":"Co-immunoprecipitation (MEF2D–Sp1 complex), transient transfection reporter assay, CD14 promoter activation analysis","journal":"Molecular Immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP and functional reporter assay confirm complex and synergistic activation; single lab, two methods","pmids":["12213324"],"is_preprint":false},{"year":2010,"finding":"MEF2D forms high-level MEF2A–MEF2D heterodimers in macrophage-differentiated HL60 cells. MEF2A/D dimers strongly interact with HDAC1 (and to a lesser extent HDAC7) in macrophages, and only in differentiated macrophages does endogenous p300 associate with MEF2A—suggesting that MEF2A/D can act as either repressors (via HDAC1/7) or activators (via p300) of target genes including c-Jun.","method":"Co-immunoprecipitation, ChIP (MEF2A on c-Jun promoter), HDAC inhibitor experiments, differentiation assays","journal":"Biochemical Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP in primary cells and differentiated lines; single lab, multiple methods","pmids":["20590529"],"is_preprint":false},{"year":1999,"finding":"MEF2D is required for monocyte/macrophage differentiation: expression of a dominant-negative MEF2D (lacking transactivation domain) in HL60 cells significantly decreases CD14 surface expression and NBT reduction ability upon VitD3-induced differentiation.","method":"Dominant-negative MEF2D stable expression, flow cytometry (CD14), NBT reduction assay, HL60 differentiation model","journal":"Molecular Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative loss-of-function with defined differentiation phenotype; single lab, two orthogonal readouts","pmids":["10684960"],"is_preprint":false},{"year":2012,"finding":"In Xenopus, Mef2d acts upstream of MyoD to transactivate Myod expression in lateral presomitic cells required for lateral myogenesis, and also cooperates with Paraxis (Tcf15) to directly activate Meox2 expression upstream of Pax3 in dermomyotome formation progenitors. Gain- and loss-of-function experiments establish Mef2d as an upstream regulator coupling lateral myogenesis to dermomyotome formation.","method":"Gain-of-function (mRNA injection) and loss-of-function (morpholino) in Xenopus, cell tracing, in situ hybridization, promoter reporter assays for Myod and Meox2","journal":"PLOS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by gain and loss of function in Xenopus embryo with reporter assays and cell tracing; single lab","pmids":["23300648"],"is_preprint":false},{"year":2021,"finding":"MEF2D activates transcription of NR4A1 (Nur77) and the reticulophagy receptor FAM134B2 gene under amino acid deficiency, as part of a MEF2D–NR4A1–FAM134B2-mediated reticulophagy pathway that contributes to amino acid homeostasis.","method":"Luciferase reporter assays, MEF2D ChIP, amino acid deprivation experiments, reticulophagy flux assays","journal":"Autophagy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — abstract provides limited mechanistic detail; pathway assignment based on reporter and ChIP but only briefly described","pmids":["34517786"],"is_preprint":false},{"year":2017,"finding":"In hepatocellular carcinoma, MEF2D in complex with HDAC4 directly binds the SPRY4 promoter and suppresses SPRY4 transcription, thereby relieving SPRY4-mediated inhibition of the MAPK/ERK pathway and contributing to sorafenib resistance.","method":"ChIP (MEF2D and HDAC4 binding to SPRY4 promoter), Co-immunoprecipitation (MEF2D–HDAC4 complex), HDAC4 inhibitor experiments, sorafenib resistance assays, in vivo tumor model","journal":"Cancer Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP confirm direct promoter binding of MEF2D–HDAC4 complex; single lab, two orthogonal methods","pmids":["34339801"],"is_preprint":false},{"year":2020,"finding":"In CD4+Foxp3+ Treg cells, MEF2D interacts with Foxp3 and is released from canonical HDAC partners, gaining new functions. MEF2D is required for expression of IL-10, CTLA4, and Icos and for effector Treg phenotype acquisition, acting downstream of Blimp1. Conditional MEF2D deletion in Tregs impairs long-term allograft survival and enhances anti-tumor immunity.","method":"Conditional MEF2D knockout in Tregs, Co-immunoprecipitation (MEF2D–Foxp3), gene expression analysis, allograft survival model, syngeneic tumor model","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined immunological phenotypes, Co-IP demonstrating Foxp3 interaction, in vivo allograft and tumor models; multiple orthogonal methods","pmids":["32790649"],"is_preprint":false},{"year":2024,"finding":"In ILC2s and CD4 T cells, Mef2d promotes type-2 immunity by repressing Regnase-1 endonuclease expression to enhance IL-33 receptor (ST2) levels and IL-33 signaling, and acts downstream of calcium-mediated signaling to translocate NFAT1 to the nucleus to promote type-2 cytokine production. CRISPR screen in ILCs identified Mef2d as a regulator of GATA3-dependent type-2 lymphocyte differentiation.","method":"CRISPR screens in ILCs, Mef2d conditional deletion from ILC2s and T cells, allergen lung challenge model, Regnase-1/ST2 expression analysis, NFAT1 nuclear translocation assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus conditional KO in two cell types, allergen model, and multiple mechanistic readouts; rigorous study published in Science","pmids":["38935708"],"is_preprint":false},{"year":2023,"finding":"In CD4 T cells, Mef2d negatively regulates Sh2d1a (encoding SAP) expression via DNA binding-dependent transcriptional repression, inhibiting SAP-dependent B:T synapse formation and preventing differentiation of antigen-specific CD4 T cells into GC-TFH cells. Mef2d also directly represses the Il21 gene, reducing IL-21 production.","method":"Mef2d CD4 T cell-specific KO, SAP expression analysis, GC-TFH differentiation assays after protein immunization, luciferase reporter for Il21 and Sh2d1a, ChIP for MEF2D binding","journal":"Science Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — T cell-specific KO with defined immunological phenotype, reporter and ChIP confirming direct transcriptional repression; multiple orthogonal methods","pmids":["36961907"],"is_preprint":false},{"year":2023,"finding":"The alternatively spliced β-domain of Mef2D promotes formation of mobile nuclear condensates (liquid-liquid phase separation) and solid-like cytosolic aggregates in C2C12 cells. Aggregate formation correlates with higher transcriptional activity and enhanced MyoD/desmin expression. NMR and molecular dynamics simulations show the β-domain samples both ordered and disordered conformations, fine-tuning Mef2D higher-order assembly as a platform for myogenic regulatory factors during differentiation.","method":"NMR spectroscopy, molecular dynamics simulations, live-cell imaging of nuclear condensates, immunofluorescence for aggregates, transcriptional reporter assays, C2C12 myogenesis model","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural analysis, molecular dynamics, live imaging, and functional transcription assays; multiple rigorous methods in one study","pmids":["36898987"],"is_preprint":false},{"year":2023,"finding":"MEF2D transactivates Itgb1 (β1-integrin) and Itgb4 (β4-integrin) to facilitate disseminated cancer cell adhesion and colonization during intrahepatic metastasis. An integrin-FAK circuit promotes USP14-mediated deubiquitination of MEF2D at a phospho-Ser432-dependent switch, stabilizing MEF2D by preventing MDM2-mediated ubiquitin-proteasomal degradation.","method":"Motif enrichment analysis, ChIP (MEF2D at Itgb1/Itgb4 promoters), Co-IP (MEF2D–USP14, MEF2D–MDM2), ubiquitination assay, phospho-specific mutants, in vivo intrahepatic metastasis model","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, ubiquitination assays, and in vivo model; single lab, multiple methods but limited independent replication","pmids":["37828611"],"is_preprint":false},{"year":2016,"finding":"MEF2D rearrangements (e.g., MEF2D-BCL9, MEF2D-DAZAP1, MEF2D-HNRNPUL1, MEF2D-SS18) result in enhanced MEF2D transcriptional activity, lymphoid transformation, and activation of HDAC9 expression in B-ALL. MEF2D-rearranged ALL is sensitive to HDAC inhibitor treatment.","method":"RNA sequencing of 560 ALL cases, functional transformation assays, HDAC9 reporter/expression analysis, HDAC inhibitor sensitivity testing","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large RNA-seq cohort identifying fusions, functional transformation and HDAC9 expression assays; single consortium study","pmids":["27824051"],"is_preprint":false},{"year":2005,"finding":"The MEF2D/DAZAP1 fusion protein (from variant t(1;19) ALL translocation) binds DNA with the same specificity as wild-type MEF2D but is a substantially more potent transcriptional activator. The reciprocal DAZAP1/MEF2D fusion retains sequence-specific RNA-binding activity.","method":"EMSA (DNA binding), transient transfection reporter assays (transcriptional activation), RNA binding assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and reporter assays directly compare fusion vs. wild-type MEF2D activity; single lab, two orthogonal methods","pmids":["15744350"],"is_preprint":false},{"year":2007,"finding":"Both MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins transform NIH 3T3 cells (soft agar colony formation ~20-fold above vector), and co-expression of both is synergistic (~3-fold additional increase). Wild-type DAZAP1, MEF2D, and DAZAP1/MEF2D support proliferation under low serum and suppress apoptosis, while MEF2D/DAZAP1 does not.","method":"Retroviral gene transfer, soft agar colony formation assay, low-serum proliferation assay, apoptosis assays in NIH 3T3 cells","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cellular transformation assay comparing fusion proteins vs. wild-type; single lab, multiple readouts","pmids":["17898785"],"is_preprint":false},{"year":2008,"finding":"Muscle contraction per se rapidly increases MEF2D binding activity at the SLC2A4 (GLUT4) gene promoter in soleus muscle, contributing to GLUT4 mRNA and protein upregulation. This was confirmed by EMSA/supershift and ChIP showing ~4-fold increase in MEF2D occupancy at the promoter after electrical stimulation.","method":"EMSA, supershift assay, ChIP on native nucleosomes, electrically-induced contraction in vitro, qPCR and protein quantification","journal":"American Journal of Physiology—Endocrinology and Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA confirm direct MEF2D promoter binding upon contraction; single lab, two orthogonal methods","pmids":["18957617"],"is_preprint":false},{"year":2021,"finding":"In Treg cells, loss of Mef2c induces expression of HDAC9, which then converts Mef2d (the more abundant family member) into a transcriptional repressor at the Il10 and Icos loci, impairing Treg suppressive functions. This defines a Mef2c–HDAC9–Mef2d regulatory circuit controlling effector Treg gene expression.","method":"Mef2c conditional KO in Tregs, HDAC9 expression analysis, Mef2d ChIP at Il10/Icos loci, syngeneic tumor model","journal":"Frontiers in Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO epistasis and ChIP showing Mef2d conversion to repressor; single lab, mechanistic pathway defined","pmids":["34290714"],"is_preprint":false},{"year":2017,"finding":"KDM1A (LSD1) demethylase interacts with MEF2D and acts as a demethylase to reduce MEF2D methylation; demethylated MEF2D binds the PD-L1 (CD274) promoter and activates its expression in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation (KDM1A–MEF2D), methylation analysis, luciferase reporter assay, CRISPR-KO cells, ChIP","journal":"Journal of Immunology Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP demonstrate direct interaction and promoter binding; single lab, two orthogonal methods","pmids":["34307695"],"is_preprint":false},{"year":2017,"finding":"MEF2D haploinsufficiency reduces NRF2 transcription in photoreceptors. Reactive oxygen species cause aberrant redox modification of MEF2D in the retina, inhibiting its transcription of the downstream target NRF2, a master regulator of antioxidant gene expression. This contributes to accelerated photoreceptor death under light-induced oxidative stress.","method":"Mef2d+/- mouse retina, light-induced retinal degeneration model, MEF2D redox modification assay, NRF2 reporter and expression analysis, proelectrophilic drug rescue","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct MEF2D redox modification tied to NRF2 transcriptional output in haploinsufficient retina; single lab, multiple methods","pmids":["28461502"],"is_preprint":false},{"year":2019,"finding":"The lncRNA EPIC1 binds MEF2D protein directly (confirmed by RNA pull-down and RIP) and promotes MEF2D ubiquitylation, leading to MEF2D protein degradation and inhibition of osteosarcoma cell viability and invasion.","method":"RNA pull-down, RNA immunoprecipitation (RIP), ubiquitination assay, co-transfection rescue, xenograft tumor model","journal":"International Journal of Biological Macromolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA pull-down and RIP confirm binding, ubiquitination assay shows effect; single lab, limited mechanistic detail on E3 ligase identity","pmids":["30703420"],"is_preprint":false},{"year":2019,"finding":"Pokemon (ZBTB7A) transcription factor binds two recognition sites within the MEF2D promoter upstream region and enhances MEF2D transcription in hepatocellular carcinoma cells, thereby promoting HCC invasiveness.","method":"ChIP (Pokemon binding to MEF2D promoter), luciferase reporter assay, Pokemon knockdown, MEF2D rescue experiment, transwell invasion assay, in vivo metastasis model","journal":"Hepatology International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter confirm direct promoter binding, functional rescue confirms epistasis; single lab","pmids":["26797719"],"is_preprint":false},{"year":2019,"finding":"MEF2D directly binds the SORBS2 gene promoter and reduces SORBS2 expression in hepatocellular carcinoma, with MEF2D acting as an upstream repressor of SORBS2 which in turn inhibits HCC metastasis via the c-Abl/ERK signaling pathway.","method":"ChIP (MEF2D at SORBS2 promoter), luciferase reporter, MEF2D knockdown, in vivo metastasis model","journal":"American Journal of Cancer Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and reporter confirm promoter binding, but mechanism of repression not fully characterized; single lab","pmids":["31911856"],"is_preprint":false}],"current_model":"MEF2D is a broadly expressed MADS-box transcription factor that activates or represses tissue-specific gene programs by directly binding target promoters/enhancers, with its activity controlled by a multilayered post-translational regulatory network: GSK3β and CDK5 phosphorylate MEF2D to inhibit it; ATM phosphorylates and activates it after DNA damage; p300 acetylates it to enhance PD-L1 promoter binding; KDM1A demethylates it to activate transcription; oxidative modifications increase its Hsc70 affinity and accelerate chaperone-mediated autophagy (CMA)-dependent lysosomal degradation; and USP14-mediated deubiquitination stabilizes it against MDM2-dependent proteasomal degradation. MEF2D localizes both to the nucleus and to neuronal mitochondria (via an N-terminal motif and mtHsp70), where it directly activates ND6 transcription to support complex I activity and neuronal survival. Its transcriptional specificity is context-dependent—CRX recruits MEF2D to retina-specific enhancers, Foxp3 redirects it in Tregs, and 14-3-3τ displaces HDAC4 to relieve repression—while MEF2D fusions (e.g., MEF2D-HNRNPUL1, MEF2D-BCL9) gain enhanced DNA-binding and transactivation to drive B-cell acute lymphoblastic leukemia."},"narrative":{"mechanistic_narrative":"MEF2D is a MADS-box transcription factor that directs tissue-specific gene programs by binding MEF2 consensus elements at target promoters and enhancers, acting as either an activator or a repressor depending on its cofactor context [PMID:7760790, PMID:25801704]. In skeletal muscle it cooperates with myogenin to recruit the SWI/SNF ATPase Brg1 and open chromatin at late muscle genes, and is sufficient with myogenin to drive differentiation [PMID:16424906]; an alternatively spliced β-domain promotes higher-order assembly into nuclear condensates that serve as a platform for myogenic regulatory factors [PMID:36898987]. Its DNA-binding repertoire is steered by partner factors: CRX redirects MEF2D to retina-specific enhancers lacking canonical sites [PMID:25801704], Sp1 enables activation of promoters without MEF2 elements [PMID:12213324], and switching between repressive HDAC complexes and the p300 coactivator toggles MEF2D between repressor and activator states [PMID:20590529, PMID:31678303]. MEF2D activity is tuned by an extensive post-translational network: inhibitory phosphorylation by GSK3β and CDK5 [PMID:19801631, PMID:25417143], activating phosphorylation by ATM after DNA damage [PMID:24672010], acetylation by p300 (opposed by SIRT7 deacetylation) [PMID:31678303], and demethylation by KDM1A [PMID:34307695], while its abundance is controlled by oxidation-accelerated chaperone-mediated autophagy through Hsc70 [PMID:19119233, PMID:24219011] and by USP14-mediated deubiquitination that protects it from MDM2-dependent proteasomal degradation [PMID:37828611]. A pool of MEF2D localizes to neuronal mitochondria via an N-terminal motif and mtHsp70, where it activates ND6 transcription to sustain complex I activity and neuronal survival [PMID:21393861]. Through these activities MEF2D supports neuronal survival programs (Nur77, bcl-w) [PMID:23536182, PMID:19458239], drives pathological cardiac remodeling and represses PTEN in cardiomyocytes [PMID:18079970, PMID:26294766], and shapes adaptive and innate immunity by partnering with Foxp3 in Tregs and controlling type-2 lymphocyte and T-follicular-helper differentiation [PMID:32790649, PMID:38935708, PMID:36961907]. MEF2D is oncogenic in multiple contexts, activating PD-L1, ZEB1, and integrin programs in carcinoma [PMID:31678303, PMID:27364559, PMID:37828611] and acting through chromatin-binding fusion proteins (MEF2D-HNRNPUL1, MEF2D-DAZAP1, MEF2D-BCL9) with enhanced transactivation to drive B-cell acute lymphoblastic leukemia [PMID:35544603, PMID:15744350, PMID:27824051].","teleology":[{"year":1995,"claim":"Established MEF2D as a sequence-specific DNA-binding transcription factor that mediates inducible gene expression, defining its core molecular activity.","evidence":"EMSA, transfection reconstitution in NIH 3T3 cells, and domain-swap analysis at the c-jun promoter","pmids":["7760790"],"confidence":"High","gaps":["Did not identify cofactors mediating activation in vivo","Mechanism shared with SRF inferred, not directly tested"]},{"year":2006,"claim":"Showed how MEF2D drives muscle gene programs at the chromatin level by cooperating with myogenin to recruit the Brg1 chromatin remodeler.","evidence":"ChIP in cells and embryonic tissue, ectopic co-expression, and Brg1 dominant-negative/knockdown chromatin accessibility assays","pmids":["16424906"],"confidence":"High","gaps":["Direct MEF2D-Brg1 contact not biochemically resolved","Order of recruitment relative to MyoD not fully defined"]},{"year":2008,"claim":"Established a required, dosage-sensitive role for MEF2D in stress-dependent pathological cardiac remodeling, distinguishing it as a driver of the fetal gene program.","evidence":"Conditional MEF2D knockout, pressure-overload and adrenergic stimulation models, and transgenic overexpression in mouse heart","pmids":["18079970"],"confidence":"High","gaps":["Direct cardiac target genes not enumerated in this study","Cofactor dependency in cardiomyocytes not defined"]},{"year":2009,"claim":"Defined MEF2D protein turnover via chaperone-mediated autophagy and linked its dysregulation to Parkinson's disease through alpha-synuclein.","evidence":"Reciprocal Co-IP with Hsc70, CMA inhibition assays, alpha-synuclein transgenic mouse, and human PD brain analysis","pmids":["19119233"],"confidence":"High","gaps":["Signals triggering cytoplasmic shuttling not defined","Lysosomal translocation machinery for MEF2D not detailed"]},{"year":2009,"claim":"Identified GSK3β as a direct inhibitory kinase coupling neuronal activity withdrawal to MEF2D inactivation and neuronal death.","evidence":"In vitro kinase assay with site-directed mutagenesis and GSK3β-resistant mutant rescue in cerebellar granule neurons","pmids":["19801631"],"confidence":"High","gaps":["Phosphatase reversing these sites not identified","Phosphorylation effect on cofactor binding not resolved"]},{"year":2011,"claim":"Revealed an unexpected mitochondrial pool of MEF2D that directly drives ND6 transcription to support complex I activity and neuronal survival.","evidence":"ICC, immunoelectron microscopy, fractionation, ChIP on mtDNA, dominant-negative construct, MPTP mouse model, and PD brain tissue","pmids":["21393861"],"confidence":"High","gaps":["Import mechanism beyond N-terminal motif/mtHsp70 unresolved","Regulation of nuclear vs mitochondrial partitioning unknown"]},{"year":2013,"claim":"Mapped multiple post-translational and cofactor controls on MEF2D activity (CDK5 inhibitory phosphorylation, O-GlcNAc, Nur77 promoter binding) governing neuronal and myogenic outputs.","evidence":"CDK5 kinase/siRNA in ICH model, O-GlcNAc biochemistry and ChIP in C2C12, and MEF2D ChIP at the Nur77 promoter with in vivo Nur77 epistasis","pmids":["25417143","23523791","23536182"],"confidence":"High","gaps":["Cross-talk between distinct modifications not integrated","O-GlcNAc transferase specificity for MEF2D isoforms not resolved"]},{"year":2014,"claim":"Established opposing stress-responsive controls on MEF2D: ATM activates it to promote survival after DNA damage, while oxidative modification accelerates its CMA degradation.","evidence":"In vitro kinase assays, phosphomimetic/oxidation-resistant mutant rescue, Mef2d KO mice, and PD brain tissue (two studies)","pmids":["24672010","24219011"],"confidence":"High","gaps":["Integration of activating phosphorylation with degradation signals unclear","Sites of oxidative modification not fully mapped"]},{"year":2015,"claim":"Demonstrated context-dependent target selection (CRX-directed retinal enhancers) and a cardioprotective role via direct PTEN activation restraining PI3K/Akt and cell-cycle re-entry.","evidence":"ChIP-seq with MEF2D-CRX Co-IP in retina, and siRNA knockdown with RNA-seq and PTEN ChIP in neonatal cardiomyocytes","pmids":["25801704","26294766"],"confidence":"High","gaps":["Determinants of partner choice at noncanonical sites unclear","Cardiomyocyte vs retina cofactor differences not unified"]},{"year":2016,"claim":"Identified recurrent MEF2D rearrangements in B-ALL with enhanced transcriptional activity, HDAC9 activation, and HDAC-inhibitor sensitivity, establishing MEF2D fusions as leukemia drivers.","evidence":"RNA-seq of 560 ALL cases, transformation assays, and HDAC inhibitor sensitivity testing","pmids":["27824051"],"confidence":"Medium","gaps":["Mechanistic basis of enhanced activity not resolved in this study","Fusion partner contributions not dissected"]},{"year":2019,"claim":"Defined MEF2D as a direct activator of the PD-L1 (CD274) gene under acetylation control, linking it to tumor immune evasion.","evidence":"ChIP, reciprocal Co-IP with p300/SIRT7, luciferase reporter, KO cells, and immune-competent allograft tumor models","pmids":["31678303"],"confidence":"High","gaps":["Generality of PD-L1 regulation beyond HCC not established","Relationship between acetylation and methylation control unclear"]},{"year":2020,"claim":"Showed that Foxp3 redirects MEF2D away from canonical HDAC complexes to acquire Treg-specific effector functions, embedding MEF2D in immune tolerance.","evidence":"Conditional MEF2D KO in Tregs, MEF2D-Foxp3 Co-IP, and allograft/tumor models","pmids":["32790649"],"confidence":"High","gaps":["Direct Treg target genes bound by MEF2D not enumerated","Structural basis of Foxp3-induced cofactor switch unknown"]},{"year":2022,"claim":"Provided atomic-resolution insight into how the MEF2D-HNRNPUL1 fusion gains chromatin binding and dimerization to drive B-ALL, and validated DNA-binding disruption as therapeutic.","evidence":"X-ray crystallography of MEF2D-MRE complex, ChIP-seq, knock-in mouse, mutagenesis, and in vivo leukemia model","pmids":["35544603"],"confidence":"High","gaps":["Whether mechanism generalizes to other MEF2D fusions untested here","Full cofactor complex recruited by the HNRNPUL1 moiety not defined"]},{"year":2024,"claim":"Established MEF2D as a regulator of innate and adaptive type-2 immunity, repressing Regnase-1 to amplify IL-33 signaling and controlling NFAT1 nuclear translocation.","evidence":"CRISPR screen in ILCs, conditional Mef2d deletion in ILC2s and T cells, allergen lung challenge, and mechanistic readouts","pmids":["38935708"],"confidence":"High","gaps":["Direct vs indirect repression of Regnase-1 not fully separated","Mechanism of MEF2D-NFAT1 functional coupling unresolved"]},{"year":null,"claim":"How the many post-translational modifications, isoform/condensate states, and cell-type-specific cofactors are integrated to produce a single MEF2D activity output in a given tissue remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking modification state to cofactor choice","Quantitative rules governing activator vs repressor switching not defined","Mitochondrial vs nuclear partitioning control not mechanistically established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,8,7,12,16,20,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,8,21,35,37]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,8,32]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,8,12,16,20,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,26,10,32]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[29,30,31,23,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[21,34,18,33,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16,13,19]}],"complexes":[],"partners":["HNRNPUL1","DAZAP1","CRX","FOXP3","HDAC4","SP1","MEF2A","USP14"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14814","full_name":"Myocyte-specific enhancer factor 2D","aliases":[],"length_aa":521,"mass_kda":55.9,"function":"Transcriptional activator which binds specifically to the MEF2 element, 5'-YTA[AT](4)TAR-3', found in numerous muscle-specific, growth factor- and stress-induced genes. Mediates cellular functions not only in skeletal and cardiac muscle development, but also in neuronal differentiation and survival. Plays diverse roles in the control of cell growth, survival and apoptosis via p38 MAPK signaling in muscle-specific and/or growth factor-related transcription. Plays a critical role in the regulation of neuronal apoptosis (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14814/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MEF2D","classification":"Not Classified","n_dependent_lines":26,"n_total_lines":1208,"dependency_fraction":0.02152317880794702},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MEF2D","total_profiled":1310},"omim":[{"mim_id":"609493","title":"SLC2A4 REGULATOR; SLC2A4RG","url":"https://www.omim.org/entry/609493"},{"mim_id":"606543","title":"HISTONE DEACETYLASE 9; HDAC9","url":"https://www.omim.org/entry/606543"},{"mim_id":"606542","title":"HISTONE DEACETYLASE 7A; HDAC7A","url":"https://www.omim.org/entry/606542"},{"mim_id":"606229","title":"ARGONAUTE RISC COMPONENT 2; AGO2","url":"https://www.omim.org/entry/606229"},{"mim_id":"605315","title":"HISTONE DEACETYLASE 5; HDAC5","url":"https://www.omim.org/entry/605315"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":157.9}],"url":"https://www.proteinatlas.org/search/MEF2D"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q14814","domains":[{"cath_id":"3.40.1810.10","chopping":"13-91","consensus_level":"medium","plddt":96.9061,"start":13,"end":91}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14814","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14814-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14814-F1-predicted_aligned_error_v6.png","plddt_mean":53.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MEF2D","jax_strain_url":"https://www.jax.org/strain/search?query=MEF2D"},"sequence":{"accession":"Q14814","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14814.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14814/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14814"}},"corpus_meta":[{"pmid":"19119233","id":"PMC_19119233","title":"Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy.","date":"2009","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19119233","citation_count":258,"is_preprint":false},{"pmid":"27824051","id":"PMC_27824051","title":"Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27824051","citation_count":235,"is_preprint":false},{"pmid":"18079970","id":"PMC_18079970","title":"The MEF2D transcription factor mediates stress-dependent cardiac remodeling in mice.","date":"2008","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/18079970","citation_count":209,"is_preprint":false},{"pmid":"7760790","id":"PMC_7760790","title":"Regulatory role of MEF2D in serum induction of the c-jun promoter.","date":"1995","source":"Molecular and cellular 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25400071","citation_count":68,"is_preprint":false},{"pmid":"25801704","id":"PMC_25801704","title":"MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers.","date":"2015","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/25801704","citation_count":68,"is_preprint":false},{"pmid":"27364559","id":"PMC_27364559","title":"MEF2D Transduces Microenvironment Stimuli to ZEB1 to Promote Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27364559","citation_count":65,"is_preprint":false},{"pmid":"19458239","id":"PMC_19458239","title":"A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w.","date":"2009","source":"The Journal of neuroscience : the official journal of the Society for 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Inhibition of CMA causes accumulation of inactive MEF2D in the cytoplasm. Alpha-synuclein (wild-type and PD-associated mutant) disrupts MEF2D–Hsc70 binding, blocking CMA-mediated degradation and leading to neuronal death.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, CMA inhibition assays, neuronal cell line experiments, alpha-synuclein transgenic mouse model\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional CMA inhibition, in vivo transgenic model, and human PD brain confirmation; replicated across multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"19119233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A portion of MEF2D localizes to neuronal mitochondria via an N-terminal targeting motif and the chaperone mtHsp70, where it binds a MEF2 consensus site in the mitochondrial DNA region containing the ND6 gene (encoding a complex I subunit) and activates ND6 transcription. Blocking mitochondrial MEF2D function decreases complex I activity, increases H2O2, reduces ATP, and sensitizes neurons to stress-induced death.\",\n      \"method\": \"Immunocytochemistry, immunoelectron microscopy, biochemical fractionation, chromatin immunoprecipitation (ChIP) on mtDNA, luciferase reporter, dominant-negative mitochondrial MEF2D construct, mouse PD model (MPTP), postmortem PD brain analysis\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ICC, IEM, fractionation, ChIP, functional knockdown, in vivo model, human tissue) in one study\",\n      \"pmids\": [\"21393861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GSK3β directly phosphorylates MEF2D at three specific residues in its transactivation domain, inhibiting MEF2D transcriptional activity. In cerebellar granule neurons, withdrawal of neuronal activity activates nuclear GSK3β, leading to GSK3β-dependent inhibition of MEF2 function and contributing to neuronal death. Expression of a GSK3β-resistant MEF2D mutant protects neurons from GSK3β activation- or activity deprivation-induced toxicity.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, cerebellar granule neuron culture, transactivation reporter assays, overexpression of GSK3β-resistant MEF2D mutant\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation with mutagenesis of specific residues, functional rescue in primary neurons\",\n      \"pmids\": [\"19801631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Oxidative stress (6-OHDA) causes direct oxidative modifications of MEF2D, which increases its binding affinity for Hsc70 and accelerates its CMA-mediated degradation via upregulation of LAMP2A. An oxidation-resistant MEF2D mutant protects dopaminergic neurons from 6-OHDA-induced death. Oxidized MEF2D is elevated in postmortem PD brains.\",\n      \"method\": \"Biochemical oxidation assays, Co-IP (MEF2D–Hsc70 binding), LAMP2A quantification, MEF2D oxidation-resistant mutant expression, mouse substantia nigra analysis, postmortem PD brain samples\",\n      \"journal\": \"Antioxidants & Redox Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical modification assay, mutant rescue, in vivo model, and human tissue confirmation across multiple methods\",\n      \"pmids\": [\"24219011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATM kinase phosphorylates MEF2D at four ATM consensus sites following DNA damage, activating MEF2D and promoting neuronal survival. ATM associates with MEF2D after DNA damage; a phosphomimetic MEF2D mutant protects cerebellar granule cells from etoposide-induced death, whereas a non-phosphorylatable mutant does not. Mef2d knockout mice show increased cerebellar susceptibility to DNA damage.\",\n      \"method\": \"In vitro kinase assay, Co-immunoprecipitation (ATM–MEF2D), shRNA knockdown, phosphomimetic/non-phosphorylatable mutant rescue, Mef2d knockout mouse cerebellar damage model\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct kinase assay, mutagenesis, reciprocal Co-IP, and in vivo KO phenotype with multiple orthogonal methods\",\n      \"pmids\": [\"24672010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MEF2D is required for stress-dependent pathological cardiac remodeling in vivo. MEF2D-null mice are resistant to cardiac hypertrophy, fetal gene activation, and fibrosis in response to pressure overload and beta-adrenergic stimulation. Conversely, transgenic overexpression of MEF2D is sufficient to drive the fetal gene program and pathological cardiac remodeling.\",\n      \"method\": \"Conditional MEF2D knockout mouse, pressure overload model, chronic adrenergic stimulation, MEF2D transgenic overexpression mouse\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo KO and gain-of-function transgenic models with defined cardiac phenotypes\",\n      \"pmids\": [\"18079970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"MEF2D is the predominant HeLa cell protein binding the MEF2 site in the c-jun promoter and is required for serum-inducible c-jun expression. Transfection of MEF2D into low-MEF2-activity NIH 3T3 cells reconstitutes serum induction. The MEF2D DNA-binding domain fused to a heterologous activation domain is sufficient for serum induction, suggesting a shared mechanism with SRF-mediated c-fos serum response.\",\n      \"method\": \"DNA-binding assays (EMSA), transfection reconstitution in NIH 3T3 cells, deletion analysis/domain swap\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — EMSA, functional reconstitution, and domain deletion analysis with multiple orthogonal approaches\",\n      \"pmids\": [\"7760790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"At the onset of skeletal muscle specification, MEF2D appears at late muscle gene loci concomitant with the SWI/SNF ATPase Brg1 and chromatin opening. Ectopic co-expression of myogenin and MEF2D (without MyoD) is sufficient to induce muscle differentiation in a manner entirely dependent on Brg1, showing that MEF2D cooperates with myogenin to recruit Brg1 for chromatin remodeling at muscle-specific genes.\",\n      \"method\": \"ChIP in cultured cells and embryonic tissue, ectopic co-expression, Brg1 dominant-negative and knockdown, chromatin accessibility assays\",\n      \"journal\": \"EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP in cells and embryonic tissue, functional co-expression rescue, and Brg1 dependency demonstrated by multiple methods\",\n      \"pmids\": [\"16424906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In the retina, MEF2D binds retina-specific enhancers by cooperating with the tissue-specific factor CRX, which recruits MEF2D away from canonical MEF2-binding sites and redirects it to retina-specific enhancers lacking the consensus MEF2 sequence. MEF2D and CRX then co-activate photoreceptor-specific genes critical for retinal function.\",\n      \"method\": \"ChIP-seq, genome-wide MEF2D binding analysis, MEF2D and CRX co-immunoprecipitation, retinal gene expression analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq with genome-wide scope, Co-IP of MEF2D–CRX interaction, functional co-activation demonstrated\",\n      \"pmids\": [\"25801704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"14-3-3tau physically interacts with MEF2D (identified by yeast two-hybrid and confirmed by co-precipitation in vivo) and specifically enhances MEF2 transactivational activity by competitively inhibiting HDAC4 from binding to MEF2D, thereby promoting muscle cell differentiation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, transient transfection reporter assay, HDAC4 competition experiment\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP in vivo, functional transactivation assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"11433030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rbfox2 RNA-binding protein regulates alternative splicing of Mef2d. Restoration of Rbfox2-dependent Mef2d splicing isoforms rescues myoblast fusion in Rbfox2-depleted cultures, demonstrating that Mef2d isoform switching downstream of Rbfox2 is functionally required for myoblast fusion during myogenesis.\",\n      \"method\": \"RNA-seq, Rbfox2 iCLIP, shRNA depletion, splicing isoform rescue experiments in myoblast fusion assays\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — iCLIP defines direct splicing targets, RNA-seq quantifies transitions, rescue of fusion phenotype by specific isoforms; multiple orthogonal methods\",\n      \"pmids\": [\"25087874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MEF2D is required for normal myogenesis; its loss in rhabdomyosarcoma cells prevents muscle differentiation. Re-expression of MEF2D in RMS cells activates muscle-specific gene expression (including myosin heavy chain), upregulates p21, inhibits proliferation and motility, and abolishes tumorigenicity in xenograft models.\",\n      \"method\": \"Stable transfection, ChIP (showing absence of MEF2D at muscle gene promoters in RMS), luciferase reporter, proliferation assay, scratch assay, soft agar assay, xenograft tumor model\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, functional rescue in cell lines and in vivo xenograft; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24279793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MEF2D binds the CD274 (PD-L1) gene promoter and activates its transcription in hepatocellular carcinoma cells. Upon IFN-γ stimulation, p300 acetyltransferase acetylates MEF2D and promotes its binding (with acetylated histones) to the CD274 promoter. SIRT7 forms a complex with MEF2D under basal conditions and deacetylates it to attenuate PD-L1 expression; IFN-γ disrupts MEF2D–SIRT7 interaction by inducing p300 binding to MEF2D.\",\n      \"method\": \"ChIP, co-immunoprecipitation, pull-down assays, dual luciferase reporter, MEF2D/SIRT7 knockout cells, allograft tumor models in immune-competent and immune-deficient mice\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, reciprocal Co-IP, pull-down, luciferase reporter, KO models with in vivo immune-competent tumor models; multiple orthogonal methods in one study\",\n      \"pmids\": [\"31678303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MEF2D regulates expression of the anti-apoptotic bcl-w gene in dorsal root ganglia sensory neurons downstream of a target-derived neurotrophin–Trk–ERK5/MEF2 pathway, constituting a retrograde survival signaling program. ERK5 activation by distal-axon neurotrophin stimulation induces MEF2D-dependent mef2d and bcl-w expression to promote sensory neuron survival.\",\n      \"method\": \"Neurotrophin compartmentalized axon stimulation, MEF2D expression analysis, ERK5 pathway inhibition, bcl-w reporter and expression assays, sensory neuron survival assays\",\n      \"journal\": \"Journal of Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pathway analysis in primary neurons with pathway inhibitor and distal-axon stimulation; single lab, multiple methods\",\n      \"pmids\": [\"19458239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MEF2D is activated by the calcineurin/NFATc1 pathway in muscle cells during calcium-ionophore treatment. MEF2D, NFATc1, and MyoD co-activate the beta-MyHC promoter in a calcineurin-dependent manner; MEF2D binds to the MyoD complex at the promoter and is recruited with p300. This was shown by EMSA, ChIP, and nuclear complex co-immunoprecipitation.\",\n      \"method\": \"EMSA, ChIP, nuclear complex co-immunoprecipitation (NCcoIP), transient transfection reporter assay, calcineurin inhibitor experiments\",\n      \"journal\": \"Journal of Cellular Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP confirm binding at promoter; multiple methods, single lab\",\n      \"pmids\": [\"17111365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDK5 phosphorylation of MEF2D at Ser444 contributes to MEF2D inactivation and neuronal apoptosis following intracerebral hemorrhage. Knockdown of CDK5 suppresses neuronal apoptosis with concurrent reduction in MEF2D phosphorylation at Ser444.\",\n      \"method\": \"CDK5 kinase activity assay, phospho-specific immunostaining, CDK5 siRNA knockdown, rat intracerebral hemorrhage model, primary cortical neuron culture\",\n      \"journal\": \"Journal of Molecular Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific phosphorylation evidence with KD phenotype in primary neurons and in vivo model; single lab\",\n      \"pmids\": [\"25417143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MEF2D constitutively binds the Nur77 (NR4A1) promoter in neurons under basal conditions; this binding is lost following MPP+ treatment. MEF2D loss leads to decreased Nur77 expression, sensitizing dopaminergic neurons to MPTP-induced death. Ectopic Nur77 expression in nigrostriatal neurons rescues dopaminergic loss in Nur77-deficient MPTP-treated mice, placing Nur77 downstream of MEF2D in a neuronal survival pathway.\",\n      \"method\": \"ChIP (MEF2D binding to Nur77 promoter), in vivo MPTP mouse model, Nur77 knockout mice, lentiviral Nur77 rescue, striatal dopamine/DOPAC measurement\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrates direct promoter binding, in vivo epistasis via Nur77 KO and rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"23536182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In hippocampal neurons, cAMP inhibits Ca2+-activated MEF2D-mediated gene expression by antagonizing HDAC5 nuclear export (blocking MEF2D derepression) and inhibiting nuclear import of the MEF2 co-activator NFAT3/c4. Unlike CREB, MEF2D is not directly activated by cAMP.\",\n      \"method\": \"Neuronal transfection reporter assays, nuclear/cytoplasmic fractionation, pharmacological cAMP elevation, Ca2+ manipulation in hippocampal neurons\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic steps tested in primary neurons; single lab, two orthogonal methods\",\n      \"pmids\": [\"16870618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MEF2D directly regulates transcription of ZEB1 (an EMT driver gene) and facilitates histone acetylation at the ZEB1 promoter in colorectal cancer cells. MEF2D acts as a central integrator of multiple tumor microenvironment signals to activate ZEB1, promoting cancer cell invasion and EMT.\",\n      \"method\": \"ChIP (MEF2D binding to ZEB1 promoter), luciferase reporter, MEF2D knockdown/overexpression, invasion assay, in vivo metastasis model\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct ZEB1 promoter binding, functional phenotype in cells and in vivo; single lab\",\n      \"pmids\": [\"27364559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MEF2D loss in neonatal cardiomyocytes triggers cell cycle re-entry and programmed cell death. Genome-wide transcriptome analysis showed that MEF2D depletion upregulates positive cell cycle regulators. PTEN, the primary negative regulator of PI3K/Akt, is a direct MEF2D target gene; MEF2D-deficient cardiomyocytes show reduced PTEN and activated PI3K/Akt signaling.\",\n      \"method\": \"siRNA knockdown of MEF2D in neonatal cardiomyocytes, RNA-seq/transcriptome profiling, ChIP (PTEN as direct target), cell cycle analysis, apoptosis assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms PTEN as direct target, RNA-seq provides genome-wide transcriptome data, KD with defined cell cycle/death phenotype; single lab\",\n      \"pmids\": [\"26294766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In MLL-rearranged AML, MEF2D binds to and suppresses chromatin accessibility of CEBPE cis-regulatory regions, thereby blocking a CEBPE-centered myeloid differentiation program. Knockout of MEF2D activates CEBPE expression, induces myeloid differentiation, and impairs leukemia growth. CEBPE depletion partially rescues cell growth defects caused by MEF2D loss, placing MEF2D upstream of CEBPE in a leukemia self-renewal circuit.\",\n      \"method\": \"MEF2D knockout (CRISPR), RNA-seq, ATAC-seq/chromatin profiling (ChIP), CEBPE depletion rescue, in vivo leukemia progression model\",\n      \"journal\": \"Blood Advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chromatin profiling, KO and rescue epistasis, in vivo leukemia model; multiple orthogonal methods in one study\",\n      \"pmids\": [\"34597364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The MEF2D-HNRNPUL1 (MH) fusion protein acquires increased chromatin-binding ability at MEF2D-responsive element (MRE) motifs. X-ray crystallography of the MEF2D-MRE complex revealed atomic-resolution structure. Disrupting MH–DNA interaction alleviated aberrant target gene expression and B-cell differentiation arrest. The HNRNPUL1 C-terminal moiety contributes to trans-regulatory activity, cofactor recruitment, and homodimerization of the fusion protein.\",\n      \"method\": \"Knock-in mouse model, RNA-seq, ChIP-seq, X-ray crystallography, MH–DNA interaction mutagenesis, HDAC inhibitor treatment, xenograft/in vivo leukemia model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — X-ray crystal structure with functional mutagenesis, ChIP-seq, knock-in mouse, and in vivo therapeutic validation; multiple rigorous orthogonal methods\",\n      \"pmids\": [\"35544603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"O-GlcNAc glycosylation of MEF2D (specifically the Mef2D1a splice variant, in both its DNA-binding and transactivation domains) negatively regulates MEF2D recruitment to the myogenin promoter. Decreased O-GlcNAc glycosylation upon myogenic stimulus is required for MEF2D binding to the myogenin promoter and subsequent myogenin expression.\",\n      \"method\": \"O-GlcNAc glycosylation assays, deletion mutant analysis, O-GlcNAc transferase/hydrolase inhibitors, ChIP (MEF2D at myogenin promoter), C2C12 differentiation model\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct glycosylation biochemistry, domain mapping, ChIP confirming promoter recruitment change; single lab\",\n      \"pmids\": [\"23523791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MEF2D forms a protein complex with Sp1 in U937 promyeloid cells. Co-expression of MEF2D and Sp1 synergistically activates the CD14 promoter during monocytic differentiation, providing a mechanism for MEF2D to regulate gene expression at promoters lacking canonical MEF2-binding sites.\",\n      \"method\": \"Co-immunoprecipitation (MEF2D–Sp1 complex), transient transfection reporter assay, CD14 promoter activation analysis\",\n      \"journal\": \"Molecular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP and functional reporter assay confirm complex and synergistic activation; single lab, two methods\",\n      \"pmids\": [\"12213324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MEF2D forms high-level MEF2A–MEF2D heterodimers in macrophage-differentiated HL60 cells. MEF2A/D dimers strongly interact with HDAC1 (and to a lesser extent HDAC7) in macrophages, and only in differentiated macrophages does endogenous p300 associate with MEF2A—suggesting that MEF2A/D can act as either repressors (via HDAC1/7) or activators (via p300) of target genes including c-Jun.\",\n      \"method\": \"Co-immunoprecipitation, ChIP (MEF2A on c-Jun promoter), HDAC inhibitor experiments, differentiation assays\",\n      \"journal\": \"Biochemical Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP in primary cells and differentiated lines; single lab, multiple methods\",\n      \"pmids\": [\"20590529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MEF2D is required for monocyte/macrophage differentiation: expression of a dominant-negative MEF2D (lacking transactivation domain) in HL60 cells significantly decreases CD14 surface expression and NBT reduction ability upon VitD3-induced differentiation.\",\n      \"method\": \"Dominant-negative MEF2D stable expression, flow cytometry (CD14), NBT reduction assay, HL60 differentiation model\",\n      \"journal\": \"Molecular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative loss-of-function with defined differentiation phenotype; single lab, two orthogonal readouts\",\n      \"pmids\": [\"10684960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Xenopus, Mef2d acts upstream of MyoD to transactivate Myod expression in lateral presomitic cells required for lateral myogenesis, and also cooperates with Paraxis (Tcf15) to directly activate Meox2 expression upstream of Pax3 in dermomyotome formation progenitors. Gain- and loss-of-function experiments establish Mef2d as an upstream regulator coupling lateral myogenesis to dermomyotome formation.\",\n      \"method\": \"Gain-of-function (mRNA injection) and loss-of-function (morpholino) in Xenopus, cell tracing, in situ hybridization, promoter reporter assays for Myod and Meox2\",\n      \"journal\": \"PLOS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by gain and loss of function in Xenopus embryo with reporter assays and cell tracing; single lab\",\n      \"pmids\": [\"23300648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MEF2D activates transcription of NR4A1 (Nur77) and the reticulophagy receptor FAM134B2 gene under amino acid deficiency, as part of a MEF2D–NR4A1–FAM134B2-mediated reticulophagy pathway that contributes to amino acid homeostasis.\",\n      \"method\": \"Luciferase reporter assays, MEF2D ChIP, amino acid deprivation experiments, reticulophagy flux assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — abstract provides limited mechanistic detail; pathway assignment based on reporter and ChIP but only briefly described\",\n      \"pmids\": [\"34517786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In hepatocellular carcinoma, MEF2D in complex with HDAC4 directly binds the SPRY4 promoter and suppresses SPRY4 transcription, thereby relieving SPRY4-mediated inhibition of the MAPK/ERK pathway and contributing to sorafenib resistance.\",\n      \"method\": \"ChIP (MEF2D and HDAC4 binding to SPRY4 promoter), Co-immunoprecipitation (MEF2D–HDAC4 complex), HDAC4 inhibitor experiments, sorafenib resistance assays, in vivo tumor model\",\n      \"journal\": \"Cancer Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP confirm direct promoter binding of MEF2D–HDAC4 complex; single lab, two orthogonal methods\",\n      \"pmids\": [\"34339801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In CD4+Foxp3+ Treg cells, MEF2D interacts with Foxp3 and is released from canonical HDAC partners, gaining new functions. MEF2D is required for expression of IL-10, CTLA4, and Icos and for effector Treg phenotype acquisition, acting downstream of Blimp1. Conditional MEF2D deletion in Tregs impairs long-term allograft survival and enhances anti-tumor immunity.\",\n      \"method\": \"Conditional MEF2D knockout in Tregs, Co-immunoprecipitation (MEF2D–Foxp3), gene expression analysis, allograft survival model, syngeneic tumor model\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined immunological phenotypes, Co-IP demonstrating Foxp3 interaction, in vivo allograft and tumor models; multiple orthogonal methods\",\n      \"pmids\": [\"32790649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In ILC2s and CD4 T cells, Mef2d promotes type-2 immunity by repressing Regnase-1 endonuclease expression to enhance IL-33 receptor (ST2) levels and IL-33 signaling, and acts downstream of calcium-mediated signaling to translocate NFAT1 to the nucleus to promote type-2 cytokine production. CRISPR screen in ILCs identified Mef2d as a regulator of GATA3-dependent type-2 lymphocyte differentiation.\",\n      \"method\": \"CRISPR screens in ILCs, Mef2d conditional deletion from ILC2s and T cells, allergen lung challenge model, Regnase-1/ST2 expression analysis, NFAT1 nuclear translocation assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus conditional KO in two cell types, allergen model, and multiple mechanistic readouts; rigorous study published in Science\",\n      \"pmids\": [\"38935708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In CD4 T cells, Mef2d negatively regulates Sh2d1a (encoding SAP) expression via DNA binding-dependent transcriptional repression, inhibiting SAP-dependent B:T synapse formation and preventing differentiation of antigen-specific CD4 T cells into GC-TFH cells. Mef2d also directly represses the Il21 gene, reducing IL-21 production.\",\n      \"method\": \"Mef2d CD4 T cell-specific KO, SAP expression analysis, GC-TFH differentiation assays after protein immunization, luciferase reporter for Il21 and Sh2d1a, ChIP for MEF2D binding\",\n      \"journal\": \"Science Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — T cell-specific KO with defined immunological phenotype, reporter and ChIP confirming direct transcriptional repression; multiple orthogonal methods\",\n      \"pmids\": [\"36961907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The alternatively spliced β-domain of Mef2D promotes formation of mobile nuclear condensates (liquid-liquid phase separation) and solid-like cytosolic aggregates in C2C12 cells. Aggregate formation correlates with higher transcriptional activity and enhanced MyoD/desmin expression. NMR and molecular dynamics simulations show the β-domain samples both ordered and disordered conformations, fine-tuning Mef2D higher-order assembly as a platform for myogenic regulatory factors during differentiation.\",\n      \"method\": \"NMR spectroscopy, molecular dynamics simulations, live-cell imaging of nuclear condensates, immunofluorescence for aggregates, transcriptional reporter assays, C2C12 myogenesis model\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural analysis, molecular dynamics, live imaging, and functional transcription assays; multiple rigorous methods in one study\",\n      \"pmids\": [\"36898987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MEF2D transactivates Itgb1 (β1-integrin) and Itgb4 (β4-integrin) to facilitate disseminated cancer cell adhesion and colonization during intrahepatic metastasis. An integrin-FAK circuit promotes USP14-mediated deubiquitination of MEF2D at a phospho-Ser432-dependent switch, stabilizing MEF2D by preventing MDM2-mediated ubiquitin-proteasomal degradation.\",\n      \"method\": \"Motif enrichment analysis, ChIP (MEF2D at Itgb1/Itgb4 promoters), Co-IP (MEF2D–USP14, MEF2D–MDM2), ubiquitination assay, phospho-specific mutants, in vivo intrahepatic metastasis model\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, ubiquitination assays, and in vivo model; single lab, multiple methods but limited independent replication\",\n      \"pmids\": [\"37828611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MEF2D rearrangements (e.g., MEF2D-BCL9, MEF2D-DAZAP1, MEF2D-HNRNPUL1, MEF2D-SS18) result in enhanced MEF2D transcriptional activity, lymphoid transformation, and activation of HDAC9 expression in B-ALL. MEF2D-rearranged ALL is sensitive to HDAC inhibitor treatment.\",\n      \"method\": \"RNA sequencing of 560 ALL cases, functional transformation assays, HDAC9 reporter/expression analysis, HDAC inhibitor sensitivity testing\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large RNA-seq cohort identifying fusions, functional transformation and HDAC9 expression assays; single consortium study\",\n      \"pmids\": [\"27824051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The MEF2D/DAZAP1 fusion protein (from variant t(1;19) ALL translocation) binds DNA with the same specificity as wild-type MEF2D but is a substantially more potent transcriptional activator. The reciprocal DAZAP1/MEF2D fusion retains sequence-specific RNA-binding activity.\",\n      \"method\": \"EMSA (DNA binding), transient transfection reporter assays (transcriptional activation), RNA binding assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and reporter assays directly compare fusion vs. wild-type MEF2D activity; single lab, two orthogonal methods\",\n      \"pmids\": [\"15744350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Both MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins transform NIH 3T3 cells (soft agar colony formation ~20-fold above vector), and co-expression of both is synergistic (~3-fold additional increase). Wild-type DAZAP1, MEF2D, and DAZAP1/MEF2D support proliferation under low serum and suppress apoptosis, while MEF2D/DAZAP1 does not.\",\n      \"method\": \"Retroviral gene transfer, soft agar colony formation assay, low-serum proliferation assay, apoptosis assays in NIH 3T3 cells\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cellular transformation assay comparing fusion proteins vs. wild-type; single lab, multiple readouts\",\n      \"pmids\": [\"17898785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Muscle contraction per se rapidly increases MEF2D binding activity at the SLC2A4 (GLUT4) gene promoter in soleus muscle, contributing to GLUT4 mRNA and protein upregulation. This was confirmed by EMSA/supershift and ChIP showing ~4-fold increase in MEF2D occupancy at the promoter after electrical stimulation.\",\n      \"method\": \"EMSA, supershift assay, ChIP on native nucleosomes, electrically-induced contraction in vitro, qPCR and protein quantification\",\n      \"journal\": \"American Journal of Physiology—Endocrinology and Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA confirm direct MEF2D promoter binding upon contraction; single lab, two orthogonal methods\",\n      \"pmids\": [\"18957617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Treg cells, loss of Mef2c induces expression of HDAC9, which then converts Mef2d (the more abundant family member) into a transcriptional repressor at the Il10 and Icos loci, impairing Treg suppressive functions. This defines a Mef2c–HDAC9–Mef2d regulatory circuit controlling effector Treg gene expression.\",\n      \"method\": \"Mef2c conditional KO in Tregs, HDAC9 expression analysis, Mef2d ChIP at Il10/Icos loci, syngeneic tumor model\",\n      \"journal\": \"Frontiers in Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO epistasis and ChIP showing Mef2d conversion to repressor; single lab, mechanistic pathway defined\",\n      \"pmids\": [\"34290714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM1A (LSD1) demethylase interacts with MEF2D and acts as a demethylase to reduce MEF2D methylation; demethylated MEF2D binds the PD-L1 (CD274) promoter and activates its expression in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (KDM1A–MEF2D), methylation analysis, luciferase reporter assay, CRISPR-KO cells, ChIP\",\n      \"journal\": \"Journal of Immunology Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP demonstrate direct interaction and promoter binding; single lab, two orthogonal methods\",\n      \"pmids\": [\"34307695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MEF2D haploinsufficiency reduces NRF2 transcription in photoreceptors. Reactive oxygen species cause aberrant redox modification of MEF2D in the retina, inhibiting its transcription of the downstream target NRF2, a master regulator of antioxidant gene expression. This contributes to accelerated photoreceptor death under light-induced oxidative stress.\",\n      \"method\": \"Mef2d+/- mouse retina, light-induced retinal degeneration model, MEF2D redox modification assay, NRF2 reporter and expression analysis, proelectrophilic drug rescue\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct MEF2D redox modification tied to NRF2 transcriptional output in haploinsufficient retina; single lab, multiple methods\",\n      \"pmids\": [\"28461502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The lncRNA EPIC1 binds MEF2D protein directly (confirmed by RNA pull-down and RIP) and promotes MEF2D ubiquitylation, leading to MEF2D protein degradation and inhibition of osteosarcoma cell viability and invasion.\",\n      \"method\": \"RNA pull-down, RNA immunoprecipitation (RIP), ubiquitination assay, co-transfection rescue, xenograft tumor model\",\n      \"journal\": \"International Journal of Biological Macromolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA pull-down and RIP confirm binding, ubiquitination assay shows effect; single lab, limited mechanistic detail on E3 ligase identity\",\n      \"pmids\": [\"30703420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Pokemon (ZBTB7A) transcription factor binds two recognition sites within the MEF2D promoter upstream region and enhances MEF2D transcription in hepatocellular carcinoma cells, thereby promoting HCC invasiveness.\",\n      \"method\": \"ChIP (Pokemon binding to MEF2D promoter), luciferase reporter assay, Pokemon knockdown, MEF2D rescue experiment, transwell invasion assay, in vivo metastasis model\",\n      \"journal\": \"Hepatology International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter confirm direct promoter binding, functional rescue confirms epistasis; single lab\",\n      \"pmids\": [\"26797719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MEF2D directly binds the SORBS2 gene promoter and reduces SORBS2 expression in hepatocellular carcinoma, with MEF2D acting as an upstream repressor of SORBS2 which in turn inhibits HCC metastasis via the c-Abl/ERK signaling pathway.\",\n      \"method\": \"ChIP (MEF2D at SORBS2 promoter), luciferase reporter, MEF2D knockdown, in vivo metastasis model\",\n      \"journal\": \"American Journal of Cancer Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and reporter confirm promoter binding, but mechanism of repression not fully characterized; single lab\",\n      \"pmids\": [\"31911856\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MEF2D is a broadly expressed MADS-box transcription factor that activates or represses tissue-specific gene programs by directly binding target promoters/enhancers, with its activity controlled by a multilayered post-translational regulatory network: GSK3β and CDK5 phosphorylate MEF2D to inhibit it; ATM phosphorylates and activates it after DNA damage; p300 acetylates it to enhance PD-L1 promoter binding; KDM1A demethylates it to activate transcription; oxidative modifications increase its Hsc70 affinity and accelerate chaperone-mediated autophagy (CMA)-dependent lysosomal degradation; and USP14-mediated deubiquitination stabilizes it against MDM2-dependent proteasomal degradation. MEF2D localizes both to the nucleus and to neuronal mitochondria (via an N-terminal motif and mtHsp70), where it directly activates ND6 transcription to support complex I activity and neuronal survival. Its transcriptional specificity is context-dependent—CRX recruits MEF2D to retina-specific enhancers, Foxp3 redirects it in Tregs, and 14-3-3τ displaces HDAC4 to relieve repression—while MEF2D fusions (e.g., MEF2D-HNRNPUL1, MEF2D-BCL9) gain enhanced DNA-binding and transactivation to drive B-cell acute lymphoblastic leukemia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MEF2D is a MADS-box transcription factor that directs tissue-specific gene programs by binding MEF2 consensus elements at target promoters and enhancers, acting as either an activator or a repressor depending on its cofactor context [#6, #8]. In skeletal muscle it cooperates with myogenin to recruit the SWI/SNF ATPase Brg1 and open chromatin at late muscle genes, and is sufficient with myogenin to drive differentiation [#7]; an alternatively spliced \\u03b2-domain promotes higher-order assembly into nuclear condensates that serve as a platform for myogenic regulatory factors [#32]. Its DNA-binding repertoire is steered by partner factors: CRX redirects MEF2D to retina-specific enhancers lacking canonical sites [#8], Sp1 enables activation of promoters without MEF2 elements [#23], and switching between repressive HDAC complexes and the p300 coactivator toggles MEF2D between repressor and activator states [#24, #12]. MEF2D activity is tuned by an extensive post-translational network: inhibitory phosphorylation by GSK3\\u03b2 and CDK5 [#2, #15], activating phosphorylation by ATM after DNA damage [#4], acetylation by p300 (opposed by SIRT7 deacetylation) [#12], and demethylation by KDM1A [#39], while its abundance is controlled by oxidation-accelerated chaperone-mediated autophagy through Hsc70 [#0, #3] and by USP14-mediated deubiquitination that protects it from MDM2-dependent proteasomal degradation [#33]. A pool of MEF2D localizes to neuronal mitochondria via an N-terminal motif and mtHsp70, where it activates ND6 transcription to sustain complex I activity and neuronal survival [#1]. Through these activities MEF2D supports neuronal survival programs (Nur77, bcl-w) [#16, #13], drives pathological cardiac remodeling and represses PTEN in cardiomyocytes [#5, #19], and shapes adaptive and innate immunity by partnering with Foxp3 in Tregs and controlling type-2 lymphocyte and T-follicular-helper differentiation [#29, #30, #31]. MEF2D is oncogenic in multiple contexts, activating PD-L1, ZEB1, and integrin programs in carcinoma [#12, #18, #33] and acting through chromatin-binding fusion proteins (MEF2D-HNRNPUL1, MEF2D-DAZAP1, MEF2D-BCL9) with enhanced transactivation to drive B-cell acute lymphoblastic leukemia [#21, #35, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established MEF2D as a sequence-specific DNA-binding transcription factor that mediates inducible gene expression, defining its core molecular activity.\",\n      \"evidence\": \"EMSA, transfection reconstitution in NIH 3T3 cells, and domain-swap analysis at the c-jun promoter\",\n      \"pmids\": [\"7760790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify cofactors mediating activation in vivo\", \"Mechanism shared with SRF inferred, not directly tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed how MEF2D drives muscle gene programs at the chromatin level by cooperating with myogenin to recruit the Brg1 chromatin remodeler.\",\n      \"evidence\": \"ChIP in cells and embryonic tissue, ectopic co-expression, and Brg1 dominant-negative/knockdown chromatin accessibility assays\",\n      \"pmids\": [\"16424906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MEF2D-Brg1 contact not biochemically resolved\", \"Order of recruitment relative to MyoD not fully defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established a required, dosage-sensitive role for MEF2D in stress-dependent pathological cardiac remodeling, distinguishing it as a driver of the fetal gene program.\",\n      \"evidence\": \"Conditional MEF2D knockout, pressure-overload and adrenergic stimulation models, and transgenic overexpression in mouse heart\",\n      \"pmids\": [\"18079970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cardiac target genes not enumerated in this study\", \"Cofactor dependency in cardiomyocytes not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined MEF2D protein turnover via chaperone-mediated autophagy and linked its dysregulation to Parkinson's disease through alpha-synuclein.\",\n      \"evidence\": \"Reciprocal Co-IP with Hsc70, CMA inhibition assays, alpha-synuclein transgenic mouse, and human PD brain analysis\",\n      \"pmids\": [\"19119233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering cytoplasmic shuttling not defined\", \"Lysosomal translocation machinery for MEF2D not detailed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified GSK3\\u03b2 as a direct inhibitory kinase coupling neuronal activity withdrawal to MEF2D inactivation and neuronal death.\",\n      \"evidence\": \"In vitro kinase assay with site-directed mutagenesis and GSK3\\u03b2-resistant mutant rescue in cerebellar granule neurons\",\n      \"pmids\": [\"19801631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase reversing these sites not identified\", \"Phosphorylation effect on cofactor binding not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed an unexpected mitochondrial pool of MEF2D that directly drives ND6 transcription to support complex I activity and neuronal survival.\",\n      \"evidence\": \"ICC, immunoelectron microscopy, fractionation, ChIP on mtDNA, dominant-negative construct, MPTP mouse model, and PD brain tissue\",\n      \"pmids\": [\"21393861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Import mechanism beyond N-terminal motif/mtHsp70 unresolved\", \"Regulation of nuclear vs mitochondrial partitioning unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped multiple post-translational and cofactor controls on MEF2D activity (CDK5 inhibitory phosphorylation, O-GlcNAc, Nur77 promoter binding) governing neuronal and myogenic outputs.\",\n      \"evidence\": \"CDK5 kinase/siRNA in ICH model, O-GlcNAc biochemistry and ChIP in C2C12, and MEF2D ChIP at the Nur77 promoter with in vivo Nur77 epistasis\",\n      \"pmids\": [\"25417143\", \"23523791\", \"23536182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cross-talk between distinct modifications not integrated\", \"O-GlcNAc transferase specificity for MEF2D isoforms not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established opposing stress-responsive controls on MEF2D: ATM activates it to promote survival after DNA damage, while oxidative modification accelerates its CMA degradation.\",\n      \"evidence\": \"In vitro kinase assays, phosphomimetic/oxidation-resistant mutant rescue, Mef2d KO mice, and PD brain tissue (two studies)\",\n      \"pmids\": [\"24672010\", \"24219011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of activating phosphorylation with degradation signals unclear\", \"Sites of oxidative modification not fully mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated context-dependent target selection (CRX-directed retinal enhancers) and a cardioprotective role via direct PTEN activation restraining PI3K/Akt and cell-cycle re-entry.\",\n      \"evidence\": \"ChIP-seq with MEF2D-CRX Co-IP in retina, and siRNA knockdown with RNA-seq and PTEN ChIP in neonatal cardiomyocytes\",\n      \"pmids\": [\"25801704\", \"26294766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of partner choice at noncanonical sites unclear\", \"Cardiomyocyte vs retina cofactor differences not unified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified recurrent MEF2D rearrangements in B-ALL with enhanced transcriptional activity, HDAC9 activation, and HDAC-inhibitor sensitivity, establishing MEF2D fusions as leukemia drivers.\",\n      \"evidence\": \"RNA-seq of 560 ALL cases, transformation assays, and HDAC inhibitor sensitivity testing\",\n      \"pmids\": [\"27824051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of enhanced activity not resolved in this study\", \"Fusion partner contributions not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined MEF2D as a direct activator of the PD-L1 (CD274) gene under acetylation control, linking it to tumor immune evasion.\",\n      \"evidence\": \"ChIP, reciprocal Co-IP with p300/SIRT7, luciferase reporter, KO cells, and immune-competent allograft tumor models\",\n      \"pmids\": [\"31678303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of PD-L1 regulation beyond HCC not established\", \"Relationship between acetylation and methylation control unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that Foxp3 redirects MEF2D away from canonical HDAC complexes to acquire Treg-specific effector functions, embedding MEF2D in immune tolerance.\",\n      \"evidence\": \"Conditional MEF2D KO in Tregs, MEF2D-Foxp3 Co-IP, and allograft/tumor models\",\n      \"pmids\": [\"32790649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Treg target genes bound by MEF2D not enumerated\", \"Structural basis of Foxp3-induced cofactor switch unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided atomic-resolution insight into how the MEF2D-HNRNPUL1 fusion gains chromatin binding and dimerization to drive B-ALL, and validated DNA-binding disruption as therapeutic.\",\n      \"evidence\": \"X-ray crystallography of MEF2D-MRE complex, ChIP-seq, knock-in mouse, mutagenesis, and in vivo leukemia model\",\n      \"pmids\": [\"35544603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mechanism generalizes to other MEF2D fusions untested here\", \"Full cofactor complex recruited by the HNRNPUL1 moiety not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established MEF2D as a regulator of innate and adaptive type-2 immunity, repressing Regnase-1 to amplify IL-33 signaling and controlling NFAT1 nuclear translocation.\",\n      \"evidence\": \"CRISPR screen in ILCs, conditional Mef2d deletion in ILC2s and T cells, allergen lung challenge, and mechanistic readouts\",\n      \"pmids\": [\"38935708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect repression of Regnase-1 not fully separated\", \"Mechanism of MEF2D-NFAT1 functional coupling unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many post-translational modifications, isoform/condensate states, and cell-type-specific cofactors are integrated to produce a single MEF2D activity output in a given tissue remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking modification state to cofactor choice\", \"Quantitative rules governing activator vs repressor switching not defined\", \"Mitochondrial vs nuclear partitioning control not mechanistically established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 8, 7, 12, 16, 20, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 8, 21, 35, 37]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 8, 32]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 8, 12, 16, 20, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 26, 10, 32]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [29, 30, 31, 23, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [21, 34, 18, 33, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16, 13, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HNRNPUL1\", \"DAZAP1\", \"CRX\", \"FOXP3\", \"HDAC4\", \"SP1\", \"MEF2A\", \"USP14\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}