{"gene":"MED13","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2024,"finding":"Cryo-EM structure of the human complete Mediator complex reveals that the CKM binds to core Mediator (cMED) through an intrinsically disordered region (IDR) in MED13 and HEAT repeats in MED12. The MED13 IDR occludes binding of RNA Polymerase II and MED26 to cMED and sterically hinders cMED-PIC assembly with TFIIH and the +1 nucleosome, thereby inhibiting transcription activation.","method":"Cryo-electron microscopy structural determination with functional validation of CKM-cMED interaction and transcription inhibition mechanism","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with mechanistic validation of IDR-mediated binding and steric inhibition mechanism, single study but structural + functional methods","pmids":["bio_10.1101_2024.07.01.601608"],"is_preprint":true},{"year":2013,"finding":"Fbw7, a tumor suppressor and SCF ubiquitin ligase, binds CDK8-Mediator and targets MED13 (and MED13L) for proteasomal degradation. MED13/13L physically link the CDK8 module to Mediator; loss of Fbw7 increases CDK8 module-Mediator association, revealing MED13 as a physical linker whose abundance controls CDK8 module-Mediator dynamics.","method":"Co-immunoprecipitation, ubiquitin ligase substrate assay, genetic loss-of-function (Fbw7 KO), protein stability assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, KO phenotype, substrate degradation assay in single rigorous study with multiple orthogonal methods","pmids":["23322298"],"is_preprint":false},{"year":2003,"finding":"In S. pombe, spTrap240 (TRAP240/MED13 homolog) is stably associated with a larger Mediator form also containing Srb8, Srb10, and Srb11 subunits. Mediator containing this module is isolated only free of RNA Polymerase II, whereas Mediator lacking this module associates with the polymerase, establishing that the TRAP240/MED13-containing submodule negatively regulates transcription by preventing Mediator-Pol II association.","method":"Biochemical fractionation, co-purification, genetic phenotypic analysis, transcriptional profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — biochemical reconstitution of module composition, direct Pol II association assay, replicated across yeast species with consistent findings","pmids":["12738880"],"is_preprint":false},{"year":2008,"finding":"In Drosophila, Med13 (encoded by skuld) physically interacts with Pygopus through its N-terminal domain and is required for transcription of Wingless target genes downstream of beta-catenin stabilization, establishing Med13 as a mediator of Wnt/Wingless target gene activation by recruiting the Mediator complex.","method":"Genetic epistasis (in vivo), RNAi knockdown in cell culture, co-immunoprecipitation (physical interaction with Pygopus), reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic epistasis + Co-IP physical interaction + cell culture knockdown with reporter readout, multiple orthogonal methods in single study","pmids":["18451032"],"is_preprint":false},{"year":2017,"finding":"In S. cerevisiae, oxidative stress triggers SCFGrr1-dependent ubiquitin-mediated degradation of Med13 via a degron in residues 742-844 of its intrinsically disordered region (IDR). Cyclin C-Cdk8 phosphorylation of Med13 primes this phosphodegron, and the CWI MAPK Slt2 phosphorylates cyclin C to release it from Med13 and subsequently modifies Med13 to stimulate SCFGrr1-mediated destruction, thereby releasing cyclin C into the cytoplasm to promote mitochondrial hyperfragmentation and cell death.","method":"Deletion mutagenesis mapping of degron, in vivo phosphorylation assays, genetic epistasis with SCFGrr1/Slt2 mutants, fluorescence microscopy of cyclin C localization, mitochondrial fragmentation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — degron mutagenesis, genetic epistasis, localization imaging, multiple orthogonal methods in single study","pmids":["29212878"],"is_preprint":false},{"year":2018,"finding":"In S. cerevisiae, the AMP kinase Snf1 activates a second SCFGrr1-responsive degron in Med13 following oxidative stress. Deletion of Snf1 results in nuclear retention of cyclin C and failure to induce mitochondrial fragmentation, defining a second pathway (CWI MAPK pathway and Snf1 together) that cooperatively controls Med13 degradation and cyclin C release.","method":"Genetic deletion (snf1Δ), in vivo protein stability assays, fluorescence microscopy of cyclin C localization, heterologous degron fusion assay, mitochondrial fragmentation assay","journal":"Microbial cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multiple cellular readouts, heterologous degron assay; single lab replicating and extending prior work","pmids":["30175106"],"is_preprint":false},{"year":2014,"finding":"Cardiac-specific overexpression of MED13 in transgenic mice confers a lean phenotype associated with increased lipid uptake, beta-oxidation, and mitochondrial content in white adipose tissue and liver. Parabiosis experiments reveal that circulating factor(s) from MED13cTg mice promote enhanced metabolism in wild-type partners, establishing that cardiac MED13 acts within the heart to regulate systemic energy homeostasis through a humoral signaling mechanism.","method":"Cardiac-specific transgenic overexpression, parabiosis experiments, metabolic phenotyping (indirect calorimetry, beta-oxidation assays), gene expression analysis","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — cardiac-specific genetic manipulation plus parabiosis to establish humoral mechanism, multiple metabolic readouts across tissues","pmids":["25422356"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, heart/muscle-specific knockdown of MED13 increases susceptibility to obesity. Genetic epistasis experiments demonstrate that Wingless functions downstream of MED13 within a muscle-regulatory pathway controlling systemic energy homeostasis, establishing MED13 as an upstream regulator of Wingless signaling in striated muscle to control fat storage.","method":"Tissue-specific RNAi knockdown, RNAi genetic screen of 150 secreted protein genes, epistasis experiments (double knockdown), metabolic phenotyping (lipid storage)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Drosophila model with defined pathway placement, RNAi screen plus double knockdown validation","pmids":["24979807"],"is_preprint":false},{"year":2016,"finding":"Skeletal muscle-specific deletion of MED13 in mice activates a metabolic gene program enhancing muscle glucose uptake and glycogen storage, insulin-sensitizes skeletal muscle, and prevents hepatic lipid accumulation. MED13 suppresses glucose metabolism genes in skeletal muscle by inhibiting the nuclear receptor NURR1 and MEF2 transcription factor, revealing a tissue-specific transcriptional repressor function of MED13 distinct from its cardiac role.","method":"Skeletal muscle-specific conditional knockout (Cre-lox), RNA-seq gene expression profiling, metabolic phenotyping (glucose uptake, glycogen measurement, hepatic lipid staining), transcription factor interaction analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO with multiple orthogonal metabolic and transcriptional readouts, identified upstream transcription factor targets (NURR1, MEF2)","pmids":["26883362"],"is_preprint":false},{"year":2018,"finding":"MED13 is required for zygotic genome activation (ZGA) in mouse embryos and regulates expression of the embryo-specific chromatin remodeling complex esBAF. MED13's role in ZGA is mediated in part through interactions with E2F transcription factors. MED13's paralog MED13L partially compensates for MED13 loss during preimplantation but cannot rescue postimplantation development.","method":"siRNA knockdown, conditional knockout, embryo culture with developmental phenotyping, gene expression analysis, co-immunoprecipitation with E2F transcription factors","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/KO in embryos with defined developmental phenotype, E2F interaction by Co-IP, but single lab study","pmids":["29325037"],"is_preprint":false},{"year":2021,"finding":"Loss of MED13 causes resistance to alkylating agents by upregulating cyclin D1 (CCND1). MED13 directly binds to CCND1 regulatory elements to suppress its expression, and MED13 KO cells have a shorter G1 phase. CDK8/19 inhibitor Senexin A stabilizes MED13 protein and in combination with alkylating agents reduces cancer cell viability.","method":"Genome-wide CRISPR-Cas9 screen, MED13 KO, transcriptome analysis, ChIP (MED13 binding to CCND1 regulatory elements), cell viability assays, CDK8/19 inhibitor treatment","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen validated by KO, ChIP for direct binding, multiple functional assays; single lab","pmids":["33444446"],"is_preprint":false},{"year":2024,"finding":"In S. cerevisiae, Med13 translocates from the nucleus to the cytoplasm following nitrogen starvation, where it colocalizes with P-bodies and promotes recruitment of the decapping activator Edc3 into P-bodies. Med13 also orchestrates the autophagic degradation of Edc3 through a selective cargo-hitchhiking autophagy pathway using Ksp1 as the autophagic receptor protein, revealing a transcription-independent cytoplasmic function of Med13 in P-body assembly and mRNA regulation.","method":"Fluorescence microscopy (colocalization of Med13 with P-body markers), deletion mutant analysis, autophagic degradation assays, genetic epistasis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging colocalization, genetic epistasis, degradation assays; single lab but multiple orthogonal methods","pmids":["39320938"],"is_preprint":false},{"year":2024,"finding":"In S. cerevisiae, Ksp1 (a casein II-like kinase) acts as an autophagic receptor protein for Ssn2/Med13, mediating its selective vacuolar degradation via Snx4-assisted autophagy following nitrogen starvation. Ksp1 directly associates with Atg8 through an AIM/LIR motif, and mutating the LDS site in Atg8 prevents Ksp1 autophagic degradation. Ksp1 is recruited early to phagophore assembly sites by Atg29.","method":"Yeast two-hybrid, mutational analysis of AIM/LIR and LDS sites, fluorescence microscopy of phagophore assembly sites, autophagic degradation assays, genetic epistasis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H plus mutagenesis plus imaging plus degradation assays; single lab, multiple methods","pmids":["37733395"],"is_preprint":false},{"year":2001,"finding":"Loss of the Drosophila Med13 homolog (kohtalo/skuld) causes eye disc cells to maintain inappropriate expression of decapentaplegic and atonal and fail to differentiate, while antennal disc cells lose Distal-less expression. These phenotypes are identical to those of Med12 (blind spot) loss, are not rescued by activation of Hedgehog or Notch pathways, and occur without loss of cell proliferation or survival, indicating Med12 and Med13 act together to mediate a specific developmental signal.","method":"Genetic loss-of-function (mutant clonal analysis), epistasis with Hedgehog and Notch pathway activation, immunostaining for cell fate markers","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with negative results for Hh/Notch rescue, multiple cell fate marker readouts; single organism model","pmids":["11171343"],"is_preprint":false},{"year":2019,"finding":"Med13 represses thyroid hormone receptor (TR) response genes in the heart. Cardiomyocyte-specific deletion of Med13 exacerbates cardiac dysfunction in hypothyroid mice (PTU-treated), and unbiased RNA-seq defined TH-dependent gene expression changes regulated by Med13, establishing Med13 as a transcriptional repressor in the cardiac thyroid hormone signaling pathway.","method":"Cardiomyocyte-specific conditional knockout (Med13cKO), RNA-seq transcriptome analysis, echocardiography, PTU-induced hypothyroidism model, T3 rescue experiment","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific conditional KO with transcriptomic and functional cardiac phenotype; single lab","pmids":["30769017"],"is_preprint":false},{"year":2024,"finding":"In Drosophila, Med13 cooperates with Med12 but not with Cdk8 or CycC (the enzymatic subunits) to support SAYP/Bap170-dependent enhancer-driven transcription at transgene promoters and endogenous loci. Med12 and Med13 do not form sufficiently stable interactions with SAYP/Bap170 in extract; their cooperation is local at regulatory elements, with SAYP/Bap170 presence required for stable recruitment of Med12/Med13 to loci.","method":"Transgene reporter assays, genetic knockdown/mutants, ChIP at endogenous loci, co-immunoprecipitation attempts (negative for stable complex)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays plus ChIP plus negative Co-IP (showing local but not stable interaction); single lab","pmids":["39684492"],"is_preprint":false},{"year":2026,"finding":"Knockdown of Med13 in cortical neurons via in-utero electroporation impairs radial migration, callosal (contralateral) projection, and dendritic complexity. Mass spectrometry of MED13-deleted SH-SY5Y cells identified PLXNA4 as a downstream dysregulated protein; overexpression of PlxnA4 rescues impaired radial migration and callosal projection (but not dendritic complexity) in Med13-knockdown neurons, placing Med13 upstream of PlxnA4 in cortical development.","method":"In-utero electroporation knockdown, immunofluorescence/confocal imaging, mass spectrometry proteomics, rescue overexpression of PlxnA4","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with defined cellular phenotype, MS proteomics, rescue experiment; single lab","pmids":["41663567"],"is_preprint":false},{"year":2022,"finding":"In Drosophila, Skd/Med13 and glycolytic enzymes are co-upregulated in response to alpha-synuclein-associated neurodegeneration. Co-expression of skd/Med13 RNAi with alpha-synuclein synergistically increases the ratio of oxidized-to-reduced glutathione, worsening neurodegeneration. This neurodegeneration can be suppressed by overexpression of a glycolytic enzyme or treatment with deferoxamine, and the functional relationship between alpha-synuclein, MED13, and glycolytic enzymes is conserved in mice.","method":"Drosophila genetic screen (3471 mutant chromosomes), RNAi co-expression, glutathione oxidation assay, pharmacological rescue (deferoxamine), cross-species validation in mice","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen followed by mechanistic validation across two organisms with biochemical readout; single primary lab","pmids":["36543134"],"is_preprint":false}],"current_model":"MED13 is a scaffold subunit of the CDK8 kinase module (CKM) that links the CKM to core Mediator through an intrinsically disordered region (IDR); structurally, this IDR occludes RNA Polymerase II and MED26 binding to Mediator and sterically blocks pre-initiation complex assembly, thereby inhibiting transcription. MED13 abundance is dynamically controlled by SCF-Fbw7-mediated ubiquitin-proteasomal degradation (in mammals) and by SCFGrr1/Slt2/Snf1-dependent degradation and Snx4-assisted autophagy (in yeast) following oxidative or nutrient stress. Upon stress-induced degradation or cytoplasmic translocation, MED13 exits the nucleus to regulate P-body assembly and autophagic mRNA regulatory factor degradation. In the heart, MED13 represses thyroid hormone receptor target genes and controls systemic energy homeostasis through a humoral signal to adipose tissue and liver; in skeletal muscle it represses glucose uptake genes via NURR1/MEF2 inhibition; and in Drosophila it acts upstream of Wingless signaling in muscle to control obesity. In neural development, MED13 regulates zygotic genome activation via E2F interactions, prevents dedifferentiation of intermediate neural progenitors, and controls cortical neuronal radial migration and callosal projection at least partly through PlxnA4."},"narrative":{"mechanistic_narrative":"MED13 is the scaffold subunit that physically tethers the CDK8 kinase module (CKM)—comprising CDK8/cyclin C and MED12—to core Mediator, thereby acting as a master switch over RNA Polymerase II transcription [PMID:bio_10.1101_2024.07.01.601608, PMID:23322298, PMID:12738880]. Cryo-EM of the complete human Mediator shows MED13 docking the CKM onto core Mediator through an intrinsically disordered region (IDR), with that IDR occluding RNA Pol II and MED26 binding and sterically blocking pre-initiation complex assembly, providing the structural basis for transcriptional inhibition [PMID:bio_10.1101_2024.07.01.601608]; consistently, the yeast TRAP240/MED13-containing submodule is found only on Mediator that is free of Pol II [PMID:12738880]. Because MED13 abundance dictates how much CKM associates with Mediator, its level is tightly controlled by SCF-Fbw7-directed ubiquitin-proteasomal degradation in mammals [PMID:23322298], and in yeast by SCFGrr1 acting on cyclin C-Cdk8-primed and Snf1/Slt2-modified degrons within the IDR, which releases cyclin C to drive mitochondrial fragmentation and cell death under oxidative stress [PMID:29212878, PMID:30175106]. Beyond transcription, stress-induced MED13 translocates from nucleus to cytoplasm where it promotes P-body assembly and the selective autophagic degradation of the decapping activator Edc3 via the receptor Ksp1 and Snx4-assisted autophagy [PMID:39320938, PMID:37733395]. As a context-specific transcriptional regulator, MED13 represses target programs in distinct tissues: it suppresses thyroid-hormone-receptor genes in the heart while controlling systemic energy homeostasis through a circulating humoral signal to adipose and liver [PMID:25422356, PMID:30769017], represses muscle glucose-uptake genes through inhibition of NURR1 and MEF2 [PMID:26883362], and directly binds CCND1 regulatory elements to restrain cyclin D1 and G1 progression [PMID:33444446]. In development, MED13 acts with MED12 to transmit specific differentiation signals [PMID:11171343], partners with Pygopus to activate Wnt/Wingless targets [PMID:18451032], is required for zygotic genome activation via E2F interactions [PMID:29325037], and controls cortical neuronal radial migration and callosal projection at least partly through PLXNA4 [PMID:41663567].","teleology":[{"year":2001,"claim":"Establishing that MED13 is not a generic Mediator subunit but a transmitter of specific developmental signals, since it phenocopies MED12 loss and acts independently of Hedgehog/Notch.","evidence":"Clonal loss-of-function and pathway-epistasis with cell-fate marker staining in Drosophila imaginal discs","pmids":["11171343"],"confidence":"Medium","gaps":["Direct biochemical target of the Med12/Med13 module not identified","Mechanism of signal specificity unresolved"]},{"year":2003,"claim":"Defining the negative-regulatory logic of the MED13-containing module by showing it occupies Mediator only when Pol II is absent.","evidence":"Biochemical fractionation and co-purification with Pol II association assays in S. pombe","pmids":["12738880"],"confidence":"High","gaps":["Structural basis of Pol II exclusion not resolved at this stage","Did not address regulation of module abundance"]},{"year":2008,"claim":"Showing MED13 can also positively couple a signaling input to transcription, recruiting Mediator to Wnt/Wingless target genes via Pygopus.","evidence":"Genetic epistasis, RNAi, and Co-IP with reporter assays in Drosophila","pmids":["18451032"],"confidence":"High","gaps":["Whether the Pygopus interaction is conserved in mammals untested","How activating versus repressive roles are reconciled mechanistically unclear"]},{"year":2013,"claim":"Identifying MED13 as the physical linker whose proteolytic turnover, controlled by SCF-Fbw7, sets CKM-Mediator association dynamics.","evidence":"Reciprocal Co-IP, Fbw7 KO, and ubiquitin-ligase substrate/stability assays in mammalian cells","pmids":["23322298"],"confidence":"High","gaps":["Signals upstream of Fbw7 targeting of MED13 not defined","Consequences for specific gene programs not mapped"]},{"year":2014,"claim":"Revealing a systemic physiological output: cardiac MED13 controls whole-body energy homeostasis through a secreted humoral factor, with a conserved upstream role for Wingless in fly muscle.","evidence":"Cardiac transgenic overexpression plus parabiosis and metabolic phenotyping in mice; tissue-specific RNAi epistasis in Drosophila","pmids":["25422356","24979807"],"confidence":"High","gaps":["Identity of the circulating humoral factor unknown","Transcriptional targets mediating the metabolic effect not fully defined"]},{"year":2016,"claim":"Distinguishing a tissue-specific repressor function in skeletal muscle through inhibition of NURR1 and MEF2 to suppress glucose metabolism.","evidence":"Skeletal-muscle conditional KO, RNA-seq, and metabolic phenotyping in mice","pmids":["26883362"],"confidence":"High","gaps":["Direct physical interaction with NURR1/MEF2 not structurally defined","Relationship to the cardiac humoral pathway unclear"]},{"year":2017,"claim":"Mapping how MED13 destruction is licensed under stress, via a CKM-primed phosphodegron and CWI-MAPK signaling that releases cyclin C to trigger cell death.","evidence":"Degron deletion mapping, phosphorylation and SCFGrr1/Slt2 epistasis, and cyclin C localization imaging in S. cerevisiae","pmids":["29212878"],"confidence":"High","gaps":["Whether an analogous degron operates in mammalian MED13 untested","Direct kinase-substrate contacts not biochemically resolved"]},{"year":2018,"claim":"Extending stress-induced MED13 turnover by identifying a second AMPK/Snf1-activated degron acting cooperatively with the CWI pathway, and uncovering nucleocytoplasmic E2F-linked roles in zygotic genome activation.","evidence":"snf1Δ stability/localization and heterologous degron assays in yeast; siRNA/conditional KO embryos with E2F Co-IP in mouse","pmids":["30175106","29325037"],"confidence":"Medium","gaps":["Single-lab findings extending prior model","How E2F interaction is integrated with esBAF regulation unresolved"]},{"year":2019,"claim":"Defining MED13 as a transcriptional repressor in cardiac thyroid hormone signaling.","evidence":"Cardiomyocyte conditional KO with RNA-seq, echocardiography, and PTU/T3 manipulation in mice","pmids":["30769017"],"confidence":"Medium","gaps":["Direct interaction with thyroid hormone receptor not shown","Link to the systemic humoral phenotype unestablished"]},{"year":2021,"claim":"Showing MED13 directly represses a cell-cycle gene (CCND1) to restrain G1, linking its level to drug sensitivity and CDK8/19 inhibition.","evidence":"Genome-wide CRISPR screen, MED13 KO, ChIP at CCND1 elements, and Senexin A treatment in cancer cells","pmids":["33444446"],"confidence":"Medium","gaps":["Mechanism by which Senexin A stabilizes MED13 not defined","Single-lab study"]},{"year":2024,"claim":"Establishing a transcription-independent cytoplasmic function for MED13 in P-body assembly and selective autophagic degradation of Edc3 via Ksp1/Atg8 and Snx4-assisted autophagy.","evidence":"Colocalization imaging, Y2H, AIM/LIR and Atg8-LDS mutagenesis, and autophagic degradation assays in S. cerevisiae","pmids":["39320938","37733395"],"confidence":"Medium","gaps":["Whether this cytoplasmic role is conserved in metazoans untested","How nuclear export of Med13 is triggered mechanistically unclear"]},{"year":2024,"claim":"Resolving the structural mechanism of inhibition: the MED13 IDR docks the CKM and sterically occludes Pol II/MED26 and PIC assembly.","evidence":"Cryo-EM of complete human Mediator with functional validation of CKM-cMED interaction (preprint)","pmids":["bio_10.1101_2024.07.01.601608"],"confidence":"High","gaps":["Conformational dynamics during activation not captured","How signal-induced MED13 degradation relieves the steric block structurally not shown"]},{"year":2024,"claim":"Clarifying that MED12/MED13 cooperate locally at enhancers with SAYP/Bap170 independent of the CKM enzymatic subunits, refining where the module acts.","evidence":"Transgene reporters, ChIP at endogenous loci, and negative Co-IP for stable complex in Drosophila","pmids":["39684492"],"confidence":"Medium","gaps":["Nature of the transient/local interaction not biochemically defined","Whether this mode is conserved unknown"]},{"year":2026,"claim":"Connecting MED13 to neurodevelopmental phenotypes by placing it upstream of PLXNA4 in cortical migration and projection.","evidence":"In-utero electroporation knockdown with imaging, MS proteomics, and PlxnA4 rescue in mice/SH-SY5Y cells","pmids":["41663567"],"confidence":"Medium","gaps":["Whether MED13 transcriptionally controls PLXNA4 directly not shown","Dendritic complexity defect not rescued, indicating additional targets"]},{"year":null,"claim":"Whether the stress-triggered nuclear export, P-body, and autophagy functions of MED13 documented in yeast operate in mammalian cells, and how MED13 turnover dynamically converts its repressive structural role into context-specific gene programs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mammalian validation of cytoplasmic/P-body function","Integration of structural inhibition with tissue-specific repression not mechanistically connected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,10,14,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,16,9]}],"complexes":["CDK8 kinase module (CKM)","Mediator complex"],"partners":["MED12","CDK8","CYCLIN C","FBW7","PYGOPUS","E2F","KSP1","EDC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHV7","full_name":"Mediator of RNA polymerase II transcription subunit 13","aliases":["Activator-recruited cofactor 250 kDa component","ARC250","Mediator complex subunit 13","Thyroid hormone receptor-associated protein 1","Thyroid hormone receptor-associated protein complex 240 kDa component","Trap240","Vitamin D3 receptor-interacting protein complex component DRIP250","DRIP250"],"length_aa":2174,"mass_kda":239.3,"function":"Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UHV7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MED13","classification":"Not Classified","n_dependent_lines":87,"n_total_lines":1208,"dependency_fraction":0.07201986754966887},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MED10","stoichiometry":10.0},{"gene":"MED11","stoichiometry":10.0},{"gene":"MED14","stoichiometry":10.0},{"gene":"MED19","stoichiometry":10.0},{"gene":"MED27","stoichiometry":10.0},{"gene":"MED31","stoichiometry":10.0},{"gene":"MED4","stoichiometry":10.0},{"gene":"MED21","stoichiometry":4.0},{"gene":"MED28","stoichiometry":4.0},{"gene":"MED29","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MED13","total_profiled":1310},"omim":[{"mim_id":"620492","title":"MEDIATOR COMPLEX SUBUNIT 31; MED31","url":"https://www.omim.org/entry/620492"},{"mim_id":"618009","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 61; MRD61","url":"https://www.omim.org/entry/618009"},{"mim_id":"603808","title":"MEDIATOR COMPLEX SUBUNIT 13; MED13","url":"https://www.omim.org/entry/603808"},{"mim_id":"603184","title":"CYCLIN-DEPENDENT KINASE 8; CDK8","url":"https://www.omim.org/entry/603184"},{"mim_id":"309541","title":"METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblX TYPE; MAHCX","url":"https://www.omim.org/entry/309541"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED13"},"hgnc":{"alias_symbol":["KIAA0593","TRAP240"],"prev_symbol":["THRAP1"]},"alphafold":{"accession":"Q9UHV7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHV7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHV7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHV7-F1-predicted_aligned_error_v6.png","plddt_mean":57.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED13","jax_strain_url":"https://www.jax.org/strain/search?query=MED13"},"sequence":{"accession":"Q9UHV7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHV7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHV7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHV7"}},"corpus_meta":[{"pmid":"14638541","id":"PMC_14638541","title":"Missense mutations and gene interruption in PROSIT240, a novel TRAP240-like gene, in patients with congenital heart defect (transposition of the great arteries).","date":"2003","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/14638541","citation_count":135,"is_preprint":false},{"pmid":"18451032","id":"PMC_18451032","title":"Pygopus activates Wingless target gene transcription through the mediator complex subunits Med12 and Med13.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18451032","citation_count":107,"is_preprint":false},{"pmid":"23322298","id":"PMC_23322298","title":"The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator.","date":"2013","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/23322298","citation_count":100,"is_preprint":false},{"pmid":"12738880","id":"PMC_12738880","title":"TRAP230/ARC240 and TRAP240/ARC250 Mediator subunits are functionally conserved through evolution.","date":"2003","source":"Proceedings of 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The MED13 IDR occludes binding of RNA Polymerase II and MED26 to cMED and sterically hinders cMED-PIC assembly with TFIIH and the +1 nucleosome, thereby inhibiting transcription activation.\",\n      \"method\": \"Cryo-electron microscopy structural determination with functional validation of CKM-cMED interaction and transcription inhibition mechanism\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with mechanistic validation of IDR-mediated binding and steric inhibition mechanism, single study but structural + functional methods\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.601608\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fbw7, a tumor suppressor and SCF ubiquitin ligase, binds CDK8-Mediator and targets MED13 (and MED13L) for proteasomal degradation. MED13/13L physically link the CDK8 module to Mediator; loss of Fbw7 increases CDK8 module-Mediator association, revealing MED13 as a physical linker whose abundance controls CDK8 module-Mediator dynamics.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitin ligase substrate assay, genetic loss-of-function (Fbw7 KO), protein stability assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, KO phenotype, substrate degradation assay in single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"23322298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In S. pombe, spTrap240 (TRAP240/MED13 homolog) is stably associated with a larger Mediator form also containing Srb8, Srb10, and Srb11 subunits. Mediator containing this module is isolated only free of RNA Polymerase II, whereas Mediator lacking this module associates with the polymerase, establishing that the TRAP240/MED13-containing submodule negatively regulates transcription by preventing Mediator-Pol II association.\",\n      \"method\": \"Biochemical fractionation, co-purification, genetic phenotypic analysis, transcriptional profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — biochemical reconstitution of module composition, direct Pol II association assay, replicated across yeast species with consistent findings\",\n      \"pmids\": [\"12738880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Drosophila, Med13 (encoded by skuld) physically interacts with Pygopus through its N-terminal domain and is required for transcription of Wingless target genes downstream of beta-catenin stabilization, establishing Med13 as a mediator of Wnt/Wingless target gene activation by recruiting the Mediator complex.\",\n      \"method\": \"Genetic epistasis (in vivo), RNAi knockdown in cell culture, co-immunoprecipitation (physical interaction with Pygopus), reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic epistasis + Co-IP physical interaction + cell culture knockdown with reporter readout, multiple orthogonal methods in single study\",\n      \"pmids\": [\"18451032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In S. cerevisiae, oxidative stress triggers SCFGrr1-dependent ubiquitin-mediated degradation of Med13 via a degron in residues 742-844 of its intrinsically disordered region (IDR). Cyclin C-Cdk8 phosphorylation of Med13 primes this phosphodegron, and the CWI MAPK Slt2 phosphorylates cyclin C to release it from Med13 and subsequently modifies Med13 to stimulate SCFGrr1-mediated destruction, thereby releasing cyclin C into the cytoplasm to promote mitochondrial hyperfragmentation and cell death.\",\n      \"method\": \"Deletion mutagenesis mapping of degron, in vivo phosphorylation assays, genetic epistasis with SCFGrr1/Slt2 mutants, fluorescence microscopy of cyclin C localization, mitochondrial fragmentation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — degron mutagenesis, genetic epistasis, localization imaging, multiple orthogonal methods in single study\",\n      \"pmids\": [\"29212878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In S. cerevisiae, the AMP kinase Snf1 activates a second SCFGrr1-responsive degron in Med13 following oxidative stress. Deletion of Snf1 results in nuclear retention of cyclin C and failure to induce mitochondrial fragmentation, defining a second pathway (CWI MAPK pathway and Snf1 together) that cooperatively controls Med13 degradation and cyclin C release.\",\n      \"method\": \"Genetic deletion (snf1Δ), in vivo protein stability assays, fluorescence microscopy of cyclin C localization, heterologous degron fusion assay, mitochondrial fragmentation assay\",\n      \"journal\": \"Microbial cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multiple cellular readouts, heterologous degron assay; single lab replicating and extending prior work\",\n      \"pmids\": [\"30175106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cardiac-specific overexpression of MED13 in transgenic mice confers a lean phenotype associated with increased lipid uptake, beta-oxidation, and mitochondrial content in white adipose tissue and liver. Parabiosis experiments reveal that circulating factor(s) from MED13cTg mice promote enhanced metabolism in wild-type partners, establishing that cardiac MED13 acts within the heart to regulate systemic energy homeostasis through a humoral signaling mechanism.\",\n      \"method\": \"Cardiac-specific transgenic overexpression, parabiosis experiments, metabolic phenotyping (indirect calorimetry, beta-oxidation assays), gene expression analysis\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cardiac-specific genetic manipulation plus parabiosis to establish humoral mechanism, multiple metabolic readouts across tissues\",\n      \"pmids\": [\"25422356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila, heart/muscle-specific knockdown of MED13 increases susceptibility to obesity. Genetic epistasis experiments demonstrate that Wingless functions downstream of MED13 within a muscle-regulatory pathway controlling systemic energy homeostasis, establishing MED13 as an upstream regulator of Wingless signaling in striated muscle to control fat storage.\",\n      \"method\": \"Tissue-specific RNAi knockdown, RNAi genetic screen of 150 secreted protein genes, epistasis experiments (double knockdown), metabolic phenotyping (lipid storage)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Drosophila model with defined pathway placement, RNAi screen plus double knockdown validation\",\n      \"pmids\": [\"24979807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Skeletal muscle-specific deletion of MED13 in mice activates a metabolic gene program enhancing muscle glucose uptake and glycogen storage, insulin-sensitizes skeletal muscle, and prevents hepatic lipid accumulation. MED13 suppresses glucose metabolism genes in skeletal muscle by inhibiting the nuclear receptor NURR1 and MEF2 transcription factor, revealing a tissue-specific transcriptional repressor function of MED13 distinct from its cardiac role.\",\n      \"method\": \"Skeletal muscle-specific conditional knockout (Cre-lox), RNA-seq gene expression profiling, metabolic phenotyping (glucose uptake, glycogen measurement, hepatic lipid staining), transcription factor interaction analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO with multiple orthogonal metabolic and transcriptional readouts, identified upstream transcription factor targets (NURR1, MEF2)\",\n      \"pmids\": [\"26883362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MED13 is required for zygotic genome activation (ZGA) in mouse embryos and regulates expression of the embryo-specific chromatin remodeling complex esBAF. MED13's role in ZGA is mediated in part through interactions with E2F transcription factors. MED13's paralog MED13L partially compensates for MED13 loss during preimplantation but cannot rescue postimplantation development.\",\n      \"method\": \"siRNA knockdown, conditional knockout, embryo culture with developmental phenotyping, gene expression analysis, co-immunoprecipitation with E2F transcription factors\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/KO in embryos with defined developmental phenotype, E2F interaction by Co-IP, but single lab study\",\n      \"pmids\": [\"29325037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of MED13 causes resistance to alkylating agents by upregulating cyclin D1 (CCND1). MED13 directly binds to CCND1 regulatory elements to suppress its expression, and MED13 KO cells have a shorter G1 phase. CDK8/19 inhibitor Senexin A stabilizes MED13 protein and in combination with alkylating agents reduces cancer cell viability.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, MED13 KO, transcriptome analysis, ChIP (MED13 binding to CCND1 regulatory elements), cell viability assays, CDK8/19 inhibitor treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen validated by KO, ChIP for direct binding, multiple functional assays; single lab\",\n      \"pmids\": [\"33444446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In S. cerevisiae, Med13 translocates from the nucleus to the cytoplasm following nitrogen starvation, where it colocalizes with P-bodies and promotes recruitment of the decapping activator Edc3 into P-bodies. Med13 also orchestrates the autophagic degradation of Edc3 through a selective cargo-hitchhiking autophagy pathway using Ksp1 as the autophagic receptor protein, revealing a transcription-independent cytoplasmic function of Med13 in P-body assembly and mRNA regulation.\",\n      \"method\": \"Fluorescence microscopy (colocalization of Med13 with P-body markers), deletion mutant analysis, autophagic degradation assays, genetic epistasis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging colocalization, genetic epistasis, degradation assays; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39320938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In S. cerevisiae, Ksp1 (a casein II-like kinase) acts as an autophagic receptor protein for Ssn2/Med13, mediating its selective vacuolar degradation via Snx4-assisted autophagy following nitrogen starvation. Ksp1 directly associates with Atg8 through an AIM/LIR motif, and mutating the LDS site in Atg8 prevents Ksp1 autophagic degradation. Ksp1 is recruited early to phagophore assembly sites by Atg29.\",\n      \"method\": \"Yeast two-hybrid, mutational analysis of AIM/LIR and LDS sites, fluorescence microscopy of phagophore assembly sites, autophagic degradation assays, genetic epistasis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus mutagenesis plus imaging plus degradation assays; single lab, multiple methods\",\n      \"pmids\": [\"37733395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Loss of the Drosophila Med13 homolog (kohtalo/skuld) causes eye disc cells to maintain inappropriate expression of decapentaplegic and atonal and fail to differentiate, while antennal disc cells lose Distal-less expression. These phenotypes are identical to those of Med12 (blind spot) loss, are not rescued by activation of Hedgehog or Notch pathways, and occur without loss of cell proliferation or survival, indicating Med12 and Med13 act together to mediate a specific developmental signal.\",\n      \"method\": \"Genetic loss-of-function (mutant clonal analysis), epistasis with Hedgehog and Notch pathway activation, immunostaining for cell fate markers\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with negative results for Hh/Notch rescue, multiple cell fate marker readouts; single organism model\",\n      \"pmids\": [\"11171343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Med13 represses thyroid hormone receptor (TR) response genes in the heart. Cardiomyocyte-specific deletion of Med13 exacerbates cardiac dysfunction in hypothyroid mice (PTU-treated), and unbiased RNA-seq defined TH-dependent gene expression changes regulated by Med13, establishing Med13 as a transcriptional repressor in the cardiac thyroid hormone signaling pathway.\",\n      \"method\": \"Cardiomyocyte-specific conditional knockout (Med13cKO), RNA-seq transcriptome analysis, echocardiography, PTU-induced hypothyroidism model, T3 rescue experiment\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific conditional KO with transcriptomic and functional cardiac phenotype; single lab\",\n      \"pmids\": [\"30769017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila, Med13 cooperates with Med12 but not with Cdk8 or CycC (the enzymatic subunits) to support SAYP/Bap170-dependent enhancer-driven transcription at transgene promoters and endogenous loci. Med12 and Med13 do not form sufficiently stable interactions with SAYP/Bap170 in extract; their cooperation is local at regulatory elements, with SAYP/Bap170 presence required for stable recruitment of Med12/Med13 to loci.\",\n      \"method\": \"Transgene reporter assays, genetic knockdown/mutants, ChIP at endogenous loci, co-immunoprecipitation attempts (negative for stable complex)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays plus ChIP plus negative Co-IP (showing local but not stable interaction); single lab\",\n      \"pmids\": [\"39684492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of Med13 in cortical neurons via in-utero electroporation impairs radial migration, callosal (contralateral) projection, and dendritic complexity. Mass spectrometry of MED13-deleted SH-SY5Y cells identified PLXNA4 as a downstream dysregulated protein; overexpression of PlxnA4 rescues impaired radial migration and callosal projection (but not dendritic complexity) in Med13-knockdown neurons, placing Med13 upstream of PlxnA4 in cortical development.\",\n      \"method\": \"In-utero electroporation knockdown, immunofluorescence/confocal imaging, mass spectrometry proteomics, rescue overexpression of PlxnA4\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with defined cellular phenotype, MS proteomics, rescue experiment; single lab\",\n      \"pmids\": [\"41663567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila, Skd/Med13 and glycolytic enzymes are co-upregulated in response to alpha-synuclein-associated neurodegeneration. Co-expression of skd/Med13 RNAi with alpha-synuclein synergistically increases the ratio of oxidized-to-reduced glutathione, worsening neurodegeneration. This neurodegeneration can be suppressed by overexpression of a glycolytic enzyme or treatment with deferoxamine, and the functional relationship between alpha-synuclein, MED13, and glycolytic enzymes is conserved in mice.\",\n      \"method\": \"Drosophila genetic screen (3471 mutant chromosomes), RNAi co-expression, glutathione oxidation assay, pharmacological rescue (deferoxamine), cross-species validation in mice\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen followed by mechanistic validation across two organisms with biochemical readout; single primary lab\",\n      \"pmids\": [\"36543134\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED13 is a scaffold subunit of the CDK8 kinase module (CKM) that links the CKM to core Mediator through an intrinsically disordered region (IDR); structurally, this IDR occludes RNA Polymerase II and MED26 binding to Mediator and sterically blocks pre-initiation complex assembly, thereby inhibiting transcription. MED13 abundance is dynamically controlled by SCF-Fbw7-mediated ubiquitin-proteasomal degradation (in mammals) and by SCFGrr1/Slt2/Snf1-dependent degradation and Snx4-assisted autophagy (in yeast) following oxidative or nutrient stress. Upon stress-induced degradation or cytoplasmic translocation, MED13 exits the nucleus to regulate P-body assembly and autophagic mRNA regulatory factor degradation. In the heart, MED13 represses thyroid hormone receptor target genes and controls systemic energy homeostasis through a humoral signal to adipose tissue and liver; in skeletal muscle it represses glucose uptake genes via NURR1/MEF2 inhibition; and in Drosophila it acts upstream of Wingless signaling in muscle to control obesity. In neural development, MED13 regulates zygotic genome activation via E2F interactions, prevents dedifferentiation of intermediate neural progenitors, and controls cortical neuronal radial migration and callosal projection at least partly through PlxnA4.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED13 is the scaffold subunit that physically tethers the CDK8 kinase module (CKM)—comprising CDK8/cyclin C and MED12—to core Mediator, thereby acting as a master switch over RNA Polymerase II transcription [#0, #1, #2]. Cryo-EM of the complete human Mediator shows MED13 docking the CKM onto core Mediator through an intrinsically disordered region (IDR), with that IDR occluding RNA Pol II and MED26 binding and sterically blocking pre-initiation complex assembly, providing the structural basis for transcriptional inhibition [#0]; consistently, the yeast TRAP240/MED13-containing submodule is found only on Mediator that is free of Pol II [#2]. Because MED13 abundance dictates how much CKM associates with Mediator, its level is tightly controlled by SCF-Fbw7-directed ubiquitin-proteasomal degradation in mammals [#1], and in yeast by SCFGrr1 acting on cyclin C-Cdk8-primed and Snf1/Slt2-modified degrons within the IDR, which releases cyclin C to drive mitochondrial fragmentation and cell death under oxidative stress [#4, #5]. Beyond transcription, stress-induced MED13 translocates from nucleus to cytoplasm where it promotes P-body assembly and the selective autophagic degradation of the decapping activator Edc3 via the receptor Ksp1 and Snx4-assisted autophagy [#11, #12]. As a context-specific transcriptional regulator, MED13 represses target programs in distinct tissues: it suppresses thyroid-hormone-receptor genes in the heart while controlling systemic energy homeostasis through a circulating humoral signal to adipose and liver [#6, #14], represses muscle glucose-uptake genes through inhibition of NURR1 and MEF2 [#8], and directly binds CCND1 regulatory elements to restrain cyclin D1 and G1 progression [#10]. In development, MED13 acts with MED12 to transmit specific differentiation signals [#13], partners with Pygopus to activate Wnt/Wingless targets [#3], is required for zygotic genome activation via E2F interactions [#9], and controls cortical neuronal radial migration and callosal projection at least partly through PLXNA4 [#16].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that MED13 is not a generic Mediator subunit but a transmitter of specific developmental signals, since it phenocopies MED12 loss and acts independently of Hedgehog/Notch.\",\n      \"evidence\": \"Clonal loss-of-function and pathway-epistasis with cell-fate marker staining in Drosophila imaginal discs\",\n      \"pmids\": [\"11171343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical target of the Med12/Med13 module not identified\", \"Mechanism of signal specificity unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining the negative-regulatory logic of the MED13-containing module by showing it occupies Mediator only when Pol II is absent.\",\n      \"evidence\": \"Biochemical fractionation and co-purification with Pol II association assays in S. pombe\",\n      \"pmids\": [\"12738880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Pol II exclusion not resolved at this stage\", \"Did not address regulation of module abundance\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing MED13 can also positively couple a signaling input to transcription, recruiting Mediator to Wnt/Wingless target genes via Pygopus.\",\n      \"evidence\": \"Genetic epistasis, RNAi, and Co-IP with reporter assays in Drosophila\",\n      \"pmids\": [\"18451032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the Pygopus interaction is conserved in mammals untested\", \"How activating versus repressive roles are reconciled mechanistically unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying MED13 as the physical linker whose proteolytic turnover, controlled by SCF-Fbw7, sets CKM-Mediator association dynamics.\",\n      \"evidence\": \"Reciprocal Co-IP, Fbw7 KO, and ubiquitin-ligase substrate/stability assays in mammalian cells\",\n      \"pmids\": [\"23322298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals upstream of Fbw7 targeting of MED13 not defined\", \"Consequences for specific gene programs not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealing a systemic physiological output: cardiac MED13 controls whole-body energy homeostasis through a secreted humoral factor, with a conserved upstream role for Wingless in fly muscle.\",\n      \"evidence\": \"Cardiac transgenic overexpression plus parabiosis and metabolic phenotyping in mice; tissue-specific RNAi epistasis in Drosophila\",\n      \"pmids\": [\"25422356\", \"24979807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the circulating humoral factor unknown\", \"Transcriptional targets mediating the metabolic effect not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Distinguishing a tissue-specific repressor function in skeletal muscle through inhibition of NURR1 and MEF2 to suppress glucose metabolism.\",\n      \"evidence\": \"Skeletal-muscle conditional KO, RNA-seq, and metabolic phenotyping in mice\",\n      \"pmids\": [\"26883362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interaction with NURR1/MEF2 not structurally defined\", \"Relationship to the cardiac humoral pathway unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping how MED13 destruction is licensed under stress, via a CKM-primed phosphodegron and CWI-MAPK signaling that releases cyclin C to trigger cell death.\",\n      \"evidence\": \"Degron deletion mapping, phosphorylation and SCFGrr1/Slt2 epistasis, and cyclin C localization imaging in S. cerevisiae\",\n      \"pmids\": [\"29212878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether an analogous degron operates in mammalian MED13 untested\", \"Direct kinase-substrate contacts not biochemically resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extending stress-induced MED13 turnover by identifying a second AMPK/Snf1-activated degron acting cooperatively with the CWI pathway, and uncovering nucleocytoplasmic E2F-linked roles in zygotic genome activation.\",\n      \"evidence\": \"snf1Δ stability/localization and heterologous degron assays in yeast; siRNA/conditional KO embryos with E2F Co-IP in mouse\",\n      \"pmids\": [\"30175106\", \"29325037\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings extending prior model\", \"How E2F interaction is integrated with esBAF regulation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defining MED13 as a transcriptional repressor in cardiac thyroid hormone signaling.\",\n      \"evidence\": \"Cardiomyocyte conditional KO with RNA-seq, echocardiography, and PTU/T3 manipulation in mice\",\n      \"pmids\": [\"30769017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with thyroid hormone receptor not shown\", \"Link to the systemic humoral phenotype unestablished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing MED13 directly represses a cell-cycle gene (CCND1) to restrain G1, linking its level to drug sensitivity and CDK8/19 inhibition.\",\n      \"evidence\": \"Genome-wide CRISPR screen, MED13 KO, ChIP at CCND1 elements, and Senexin A treatment in cancer cells\",\n      \"pmids\": [\"33444446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Senexin A stabilizes MED13 not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing a transcription-independent cytoplasmic function for MED13 in P-body assembly and selective autophagic degradation of Edc3 via Ksp1/Atg8 and Snx4-assisted autophagy.\",\n      \"evidence\": \"Colocalization imaging, Y2H, AIM/LIR and Atg8-LDS mutagenesis, and autophagic degradation assays in S. cerevisiae\",\n      \"pmids\": [\"39320938\", \"37733395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this cytoplasmic role is conserved in metazoans untested\", \"How nuclear export of Med13 is triggered mechanistically unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolving the structural mechanism of inhibition: the MED13 IDR docks the CKM and sterically occludes Pol II/MED26 and PIC assembly.\",\n      \"evidence\": \"Cryo-EM of complete human Mediator with functional validation of CKM-cMED interaction (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.601608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics during activation not captured\", \"How signal-induced MED13 degradation relieves the steric block structurally not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Clarifying that MED12/MED13 cooperate locally at enhancers with SAYP/Bap170 independent of the CKM enzymatic subunits, refining where the module acts.\",\n      \"evidence\": \"Transgene reporters, ChIP at endogenous loci, and negative Co-IP for stable complex in Drosophila\",\n      \"pmids\": [\"39684492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nature of the transient/local interaction not biochemically defined\", \"Whether this mode is conserved unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connecting MED13 to neurodevelopmental phenotypes by placing it upstream of PLXNA4 in cortical migration and projection.\",\n      \"evidence\": \"In-utero electroporation knockdown with imaging, MS proteomics, and PlxnA4 rescue in mice/SH-SY5Y cells\",\n      \"pmids\": [\"41663567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED13 transcriptionally controls PLXNA4 directly not shown\", \"Dendritic complexity defect not rescued, indicating additional targets\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the stress-triggered nuclear export, P-body, and autophagy functions of MED13 documented in yeast operate in mammalian cells, and how MED13 turnover dynamically converts its repressive structural role into context-specific gene programs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mammalian validation of cytoplasmic/P-body function\", \"Integration of structural inhibition with tissue-specific repression not mechanistically connected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 10, 14, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 16, 9]}\n    ],\n    \"complexes\": [\n      \"CDK8 kinase module (CKM)\",\n      \"Mediator complex\"\n    ],\n    \"partners\": [\n      \"MED12\",\n      \"CDK8\",\n      \"cyclin C\",\n      \"Fbw7\",\n      \"Pygopus\",\n      \"E2F\",\n      \"Ksp1\",\n      \"Edc3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}