{"gene":"MED13","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2003,"finding":"PROSIT240/MED13 (THRAP2) was identified as a novel gene homologous to TRAP240 (MED13L), suggesting it is a component of the thyroid hormone receptor-associated protein (TRAP/Mediator) complex, with high expression in heart and brain consistent with its role in early cardiac and brain development.","method":"Positional cloning, sequence homology analysis, expression analysis","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 3 — positional cloning and homology; foundational identification paper with 135 citations","pmids":["14638541"],"is_preprint":false},{"year":2003,"finding":"TRAP240/ARC250 (MED13 ortholog) forms a conserved kinase submodule with Srb8/TRAP230, Srb10/CDK8, and Srb11/CyclinC in Mediator; this submodule associates only with free Mediator (not RNA Pol II-bound Mediator), implicating it in negative regulation of transcription.","method":"Biochemical fractionation, genetic analysis, gene expression profiling in S. pombe","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — biochemical fractionation and genetic analysis replicated across yeast species, strong preponderance of evidence","pmids":["12738880"],"is_preprint":false},{"year":2001,"finding":"Drosophila Med13 (kohtalo), along with Med12 (blind spot), is required for proper developmental signaling in the eye-antennal disc; loss results in maintenance of inappropriate Hedgehog target gene expression and failure to differentiate, demonstrating a role in mediating specific developmental signals rather than general transcription.","method":"Genetic loss-of-function (mutant analysis), in vivo gene expression assays in Drosophila","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean genetic loss-of-function with defined cellular phenotypes; 95 citations","pmids":["11171343"],"is_preprint":false},{"year":2008,"finding":"Drosophila Med13 (skuld) and Med12 (kohtalo) subunits of the Mediator complex are essential for Wingless (Wnt) target gene transcription; they act downstream of beta-catenin stabilization, are required for transcriptional activation by the N-terminal domain of Pygopus, and physically interact with Pygopus, suggesting Pygopus recruits Mediator through Med12/Med13 to activate Wnt targets.","method":"Genetic epistasis (in vivo and cell culture), Co-immunoprecipitation (physical interaction), RNAi knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus genetic epistasis in multiple contexts; 107 citations","pmids":["18451032"],"is_preprint":false},{"year":2013,"finding":"Fbw7, an SCF ubiquitin ligase and tumor suppressor, binds CDK8-Mediator and targets MED13 (and MED13L) for proteasomal degradation; MED13/13L physically link the CDK8 module to core Mediator, and Fbw7 loss increases CDK8 module–Mediator association, revealing a ubiquitin-mediated mechanism controlling CDK8 module dynamics.","method":"Co-immunoprecipitation, ubiquitination assays, genetic knockout/knockdown with protein level quantification","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, functional degradation assay, genetic KO with defined molecular phenotype; 100 citations","pmids":["23322298"],"is_preprint":false},{"year":2014,"finding":"Cardiac-specific overexpression of MED13 in transgenic mice confers a lean phenotype with increased lipid uptake, beta-oxidation, and mitochondrial content in white adipose tissue and liver; parabiosis experiments demonstrate that circulating factor(s) from MED13-overexpressing hearts mediate this systemic metabolic effect, revealing a heart-to-peripheral tissue signaling axis.","method":"Transgenic mouse model (cardiac-specific overexpression), parabiosis experiments, metabolic phenotyping","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic gain-of-function with parabiosis (orthogonal method); defined systemic phenotype; 85 citations","pmids":["25422356"],"is_preprint":false},{"year":2014,"finding":"In Drosophila, heart/muscle-specific knockdown of MED13 increases susceptibility to obesity; genetic epistasis shows Wingless (Wnt ligand) functions downstream of MED13 in a muscle-regulatory pathway, identifying Wingless as an effector of MED13 in muscle-to-adipose tissue cross-talk controlling energy homeostasis.","method":"Tissue-specific RNAi knockdown, genetic epistasis screen of 150 secreted proteins, Armadillo pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — RNAi-based epistasis with defined pathway placement; 51 citations","pmids":["24979807"],"is_preprint":false},{"year":2016,"finding":"Skeletal muscle-specific deletion of MED13 in mice activates glucose uptake and glycogen storage, conferring resistance to hepatic steatosis; mechanistically, MED13 suppresses muscle glucose metabolism genes by inhibiting nuclear receptor NURR1 and MEF2 transcription factor, demonstrating tissue-specific transcriptional repressor function.","method":"Muscle-specific conditional knockout mice, transcriptomics, metabolic phenotyping, transcription factor binding analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with defined molecular mechanism and metabolic phenotype","pmids":["26883362"],"is_preprint":false},{"year":2017,"finding":"In S. cerevisiae, oxidative stress induces Med13 degradation via SCFGrr1 ubiquitin ligase; residues 742–844 of Med13's intrinsically disordered region (IDR) both direct cyclin C-Cdk8 association and serve as the degron; CDK8 phosphorylation of Med13 primes the phosphodegron, and Slt2 MAPK phosphorylates cyclin C to trigger its release from Med13, followed by Slt2-mediated modification of Med13 itself to stimulate SCFGrr1-dependent destruction, releasing cyclin C to the cytoplasm where it promotes mitochondrial fission and cell death.","method":"Domain mapping by mutagenesis, ubiquitination assays, MAPK kinase assays, genetic epistasis, fluorescence microscopy","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of degron, in vitro kinase assays, genetic epistasis; multiple orthogonal methods in single study","pmids":["29212878"],"is_preprint":false},{"year":2018,"finding":"MED13 is essential for zygotic genome activation (ZGA) in mouse embryos; its role in ZGA is mediated in part by interactions with E2F transcription factors and by regulating expression of the embryo-specific BAF chromatin remodeling complex (esBAF); MED13L partially compensates for loss of MED13 in preimplantation development but cannot rescue postimplantation defects.","method":"siRNA knockdown, conditional knockout mice, co-immunoprecipitation (E2F interaction), transcriptomic analysis of preimplantation embryos","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — KO with defined molecular mechanism (E2F interaction, esBAF regulation) using multiple approaches","pmids":["29325037"],"is_preprint":false},{"year":2018,"finding":"In S. cerevisiae, the AMP kinase Snf1 activates a second SCFGrr1-responsive degron in Med13 following oxidative stress, acting in parallel with the CWI MAPK pathway; Snf1 deletion results in nuclear retention of cyclin C and failure to induce mitochondrial fragmentation, demonstrating that Med13 degradation is coordinately controlled by two kinase pathways.","method":"Genetic deletion analysis, degron mapping by heterologous fusion, fluorescence microscopy of cyclin C localization, mitochondrial morphology assay","journal":"Microbial cell (Graz, Austria)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic and cell biology methods; single lab","pmids":["30175106"],"is_preprint":false},{"year":2019,"finding":"Med13 represses thyroid hormone receptor (TR) response genes in the heart; cardiac-specific deletion of Med13 exacerbates cardiac dysfunction in hypothyroid mice; transcriptomic analysis defined Med13-dependent gene expression pathways in response to thyroid hormone signaling, demonstrating Med13 is a negative regulator of TR-dependent transcription in cardiomyocytes.","method":"Cardiac-specific conditional knockout mice, RNA sequencing, echocardiography, PTU/T3 treatment model","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KO with transcriptomic and functional cardiac phenotyping; single lab","pmids":["30769017"],"is_preprint":false},{"year":2021,"finding":"MED13 binds to cyclin D1 (CCND1) regulatory elements to repress its expression; loss of MED13 leads to cyclin D1 upregulation, shorter G1 phase, reduced apoptosis, and resistance to alkylating agents; CDK8/19 inhibitor Senexin A stabilizes MED13 and re-sensitizes cells to alkylating agents in combination treatment.","method":"Genome-wide CRISPR-Cas9 screen, chromatin occupancy (MED13 binding to CCND1 locus), transcriptome analysis, CDK inhibitor pharmacology","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR screen plus chromatin binding plus pharmacological rescue; single lab","pmids":["33444446"],"is_preprint":false},{"year":2022,"finding":"In Drosophila, Skd/Med13 and glycolytic enzymes are co-upregulated by alpha-synuclein-associated neurodegeneration; co-expressing skd/Med13 RNAi with alpha-syn synergistically increases oxidized-to-reduced glutathione ratio; overexpressing a glycolytic enzyme or deferoxamine treatment suppresses neurodegeneration, placing MED13 in a pathway where compensatory glycolysis is neuroprotective against alpha-syn toxicity.","method":"Genetic modifier screen (3471 mutant chromosomes), RNAi epistasis, glutathione redox assay, pharmacological rescue in Drosophila and mouse models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — large-scale genetic screen with epistasis and orthogonal biochemical assays; conserved in mice","pmids":["36543134"],"is_preprint":false},{"year":2024,"finding":"In S. cerevisiae, Ksp1 (casein II-like kinase) acts as an autophagic receptor for Ssn2/Med13 in Snx4-assisted autophagy; following nitrogen starvation, Ksp1 directly associates with Atg8 via an Atg8-family interacting motif (AIM)/LIR interaction, and is recruited to the phagophore assembly site by Atg29; this interaction mediates selective vacuolar degradation of Med13.","method":"Co-immunoprecipitation, yeast two-hybrid, AIM/LIR mutagenesis, autophagy flux assays, fluorescence microscopy","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 — domain mutagenesis, reciprocal protein interactions, functional autophagy assays; multiple orthogonal methods","pmids":["37733395"],"is_preprint":false},{"year":2024,"finding":"Following nitrogen starvation in S. cerevisiae, Med13 translocates from the nucleus to the cytoplasm where it colocalizes with P-bodies (processing bodies); cytoplasmic Med13 facilitates recruitment of the P-body assembly factor Edc3 into P-bodies and orchestrates autophagic degradation of Edc3 through a cargo-hitchhiking autophagy pathway using Ksp1 as autophagic receptor; Xrn1 degradation is Med13-independent, demonstrating selectivity.","method":"Live fluorescence microscopy (localization), genetic deletion with P-body assembly assay, autophagy flux assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence, multiple genetic and cell biology methods","pmids":["39320938"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structures of the human complete Mediator and CDK8 kinase module (CKM) reveal 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 sites for RNA Pol II and MED26 on cMED and sterically hinders cMED-PIC assembly through TFIIH and the +1 nucleosome, mechanistically explaining how the CKM inhibits transcription activation; MED12 positions CDK8 downstream of the transcription start site to enable post-initiation stimulatory function.","method":"Cryo-electron microscopy structural determination, domain mapping","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with mechanistic explanation of mutually exclusive binding; complemented by related study (PMID:39178836)","pmids":["bio_10.1101_2024.07.01.601608"],"is_preprint":true},{"year":2026,"finding":"Knockdown of Med13 in cortical neurons via in-utero electroporation impairs radial migration, contralateral (callosal) projection, and dendritic complexity; mass spectrometry of MED13-deleted SH-SY5Y cells identified PLXNA4 as a downstream dysregulated protein; overexpression of PlxnA4 rescues radial migration and callosal projection defects but not dendritic complexity in Med13 knockdown neurons, placing PLXNA4 downstream of MED13 in cortical neuronal migration.","method":"In-utero electroporation knockdown, mass spectrometry proteomics, genetic rescue (PlxnA4 overexpression), cortical migration assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct KD with defined cellular phenotype and pathway placement via proteomics and rescue experiment; single lab","pmids":["41663567"],"is_preprint":false},{"year":2024,"finding":"In Drosophila, Med12 and Med13 cooperate with SWI/SNF subunits SAYP and Bap170 to support enhancer-dependent transcription; this cooperation is independent of Cdk8, CyclinC, and other core Mediator subunits; SAYP/Bap170 presence at a locus is required for stable recruitment of Med12/Med13, and the cooperation depends on extended intrinsically disordered regions of the factors rather than their enzymatic activities.","method":"Transgene reporter assays, ChIP-based localization, genetic epistasis (CKM subunit deletions), co-immunoprecipitation attempted (no stable interaction detected in extract)","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2/3 — genetic epistasis and chromatin localization with functional transcriptional readout; single lab","pmids":["39684492"],"is_preprint":false}],"current_model":"MED13 is a scaffold subunit of the CDK8 kinase module (CKM) that physically links the CKM to core Mediator through its intrinsically disordered region (IDR) — which simultaneously occludes RNA Pol II and MED26 binding to Mediator, thereby inhibiting transcription initiation — and is regulated by SCF-Fbw7 ubiquitin-mediated degradation (primed by CDK8 and MAPK phosphorylation) and by autophagic degradation via Ksp1/Snx4; in response to stress, MED13 translocates to the cytoplasm where it organizes P-body assembly and selective autophagy of mRNA-regulatory factors, while in the nucleus it acts as a tissue-specific transcriptional repressor (e.g., of thyroid hormone receptor targets in the heart and of NURR1/MEF2-driven glucose metabolism genes in skeletal muscle) and as an activator of Wnt target genes through physical interaction with Pygopus/Med12, with loss-of-function in vivo causing defects in zygotic genome activation, cortical neuronal migration, and systemic energy homeostasis."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing that MED13 is not a general transcription factor but a signal-specific mediator: Drosophila loss-of-function showed Med13 (kohtalo) is required for proper developmental Hedgehog signaling output rather than basal transcription, reframing the gene as a pathway-specific transcriptional regulator.","evidence":"Genetic mutant analysis with in vivo gene expression assays in Drosophila eye-antennal disc","pmids":["11171343"],"confidence":"High","gaps":["No biochemical mechanism for signal specificity identified","Hedgehog-specific versus general developmental role not fully distinguished"]},{"year":2003,"claim":"Defining MED13's position within the Mediator architecture: biochemical fractionation showed that MED13 (TRAP240/ARC250) forms a four-subunit kinase module with MED12, CDK8, and CyclinC that associates exclusively with free Mediator and not with RNA Pol II–bound holoenzyme, establishing the structural basis for its role in transcriptional repression.","evidence":"Biochemical fractionation and genetic analysis across S. pombe and human systems","pmids":["12738880","14638541"],"confidence":"High","gaps":["Physical basis for mutual exclusivity with Pol II binding unknown at this stage","Whether MED13 directly mediates the CKM–core Mediator interface was unresolved"]},{"year":2008,"claim":"Revealing a coactivator function: Med13 and Med12 were shown to be essential for Wnt/Wingless target gene activation downstream of β-catenin, physically interacting with Pygopus to recruit Mediator, demonstrating that MED13 can function as a transcriptional activator in specific signaling contexts.","evidence":"Reciprocal co-immunoprecipitation, genetic epistasis, and RNAi in Drosophila and cell culture","pmids":["18451032"],"confidence":"High","gaps":["Whether MED13 directly contacts Pygopus or acts through Med12 was not resolved","Mechanism by which CKM switches from repressor to activator mode unknown"]},{"year":2013,"claim":"Identifying the ubiquitin-dependent regulatory mechanism: SCF-Fbw7 was shown to target MED13 (and MED13L) for proteasomal degradation, with Fbw7 loss increasing CKM–core Mediator association, revealing that MED13 protein turnover dynamically controls CKM occupancy on Mediator.","evidence":"Co-immunoprecipitation, ubiquitination assays, and genetic knockout/knockdown with protein level quantification","pmids":["23322298"],"confidence":"High","gaps":["Phosphodegron identity on MED13 not mapped in this study","In vivo physiological triggers of Fbw7-mediated MED13 turnover not defined"]},{"year":2014,"claim":"Connecting MED13 to systemic energy homeostasis: cardiac-specific MED13 overexpression in mice produced a lean phenotype with enhanced peripheral lipid metabolism, and parabiosis demonstrated circulating factor(s) from MED13-overexpressing hearts mediate this effect, while Drosophila muscle-specific knockdown increased obesity susceptibility through a Wingless-dependent pathway.","evidence":"Transgenic mouse cardiac overexpression with parabiosis; Drosophila tissue-specific RNAi with genetic epistasis screen","pmids":["25422356","24979807"],"confidence":"High","gaps":["Identity of the circulating factor(s) downstream of cardiac MED13 unknown","Whether MED13's metabolic role is CKM-dependent or independent not resolved"]},{"year":2016,"claim":"Defining MED13 as a tissue-specific transcriptional repressor of metabolic genes: skeletal muscle-specific MED13 knockout activated glucose uptake and glycogen storage by de-repressing NURR1- and MEF2-driven transcriptional programs, mechanistically explaining MED13's metabolic function at the transcription factor level.","evidence":"Conditional knockout mice, transcriptomics, and metabolic phenotyping","pmids":["26883362"],"confidence":"High","gaps":["Whether MED13 directly binds NURR1/MEF2 or acts indirectly through chromatin context not established","Relationship between MED13 repressor function and CKM kinase activity at these loci unclear"]},{"year":2017,"claim":"Mapping the phosphodegron and dual-kinase control of MED13 destruction: in yeast, CDK8 phosphorylation primes a degron within the MED13 IDR (residues 742–844) for SCF-Grr1 recognition, while Slt2 MAPK independently phosphorylates cyclin C and Med13 to trigger cyclin C release and Med13 degradation, establishing a two-kinase convergence model for stress-induced CKM disassembly.","evidence":"Domain mutagenesis, in vitro kinase assays, ubiquitination assays, genetic epistasis, and fluorescence microscopy in S. cerevisiae","pmids":["29212878","30175106"],"confidence":"High","gaps":["Whether the dual-kinase degron mechanism is conserved in mammals not tested","How Snf1/AMPK and Slt2/MAPK inputs are integrated at the Med13 protein not fully resolved"]},{"year":2018,"claim":"Establishing MED13's role in the earliest transcriptional event of mammalian development: MED13 was shown to be essential for zygotic genome activation in mouse embryos, acting through E2F transcription factor interactions and regulation of embryo-specific BAF complex expression, with MED13L providing partial compensation only during preimplantation.","evidence":"siRNA knockdown, conditional knockout, co-immunoprecipitation, and transcriptomic analysis of preimplantation embryos","pmids":["29325037"],"confidence":"High","gaps":["Direct versus indirect role in esBAF regulation not distinguished","Whether E2F interaction requires the MED13 IDR not mapped"]},{"year":2021,"claim":"Linking MED13 to cell cycle control and chemoresistance: MED13 directly binds cyclin D1 (CCND1) regulatory elements to repress its expression, and MED13 loss causes cyclin D1 upregulation, shortened G1, reduced apoptosis, and alkylating agent resistance, which is reversed by CDK8/19 inhibitor-mediated MED13 stabilization.","evidence":"Genome-wide CRISPR screen, MED13 chromatin occupancy at CCND1 locus, transcriptome analysis, CDK inhibitor pharmacology","pmids":["33444446"],"confidence":"Medium","gaps":["Whether MED13 occupancy at CCND1 is direct DNA binding or Mediator-tethered not resolved","In vivo tumor relevance not demonstrated"]},{"year":2024,"claim":"Revealing a cytoplasmic moonlighting function: upon nitrogen starvation in yeast, Med13 translocates to the cytoplasm where it organizes P-body assembly by recruiting Edc3, and is itself degraded via Ksp1/Snx4-assisted selective autophagy; Med13 orchestrates cargo-hitchhiking autophagy of Edc3 but not Xrn1, demonstrating substrate selectivity in this non-transcriptional role.","evidence":"Live fluorescence microscopy, genetic deletion with P-body and autophagy flux assays, AIM/LIR mutagenesis, co-immunoprecipitation in S. cerevisiae","pmids":["37733395","39320938"],"confidence":"High","gaps":["Whether cytoplasmic Med13 functions exist in metazoans unknown","How Med13 nuclear export is regulated not defined","Full repertoire of autophagy cargoes hitchhiking on Med13 not characterized"]},{"year":2024,"claim":"Structural resolution of how MED13 inhibits transcription: cryo-EM structures showed the MED13 IDR directly occludes the RNA Pol II and MED26 binding surfaces on core Mediator and sterically hinders TFIIH and +1 nucleosome positioning for PIC assembly, providing a definitive structural mechanism for CKM-mediated transcriptional repression.","evidence":"Cryo-electron microscopy structural determination and domain mapping (preprint)","pmids":["bio_10.1101_2024.07.01.601608"],"confidence":"High","gaps":["Preprint, awaiting peer review","How CKM transitions between inhibitory and stimulatory modes at the structural level not captured","Dynamics of the MED13 IDR in vivo not assessed"]},{"year":2024,"claim":"Demonstrating CKM-independent cooperation with chromatin remodelers: in Drosophila, Med13 and Med12 support enhancer-dependent transcription cooperatively with SWI/SNF subunits SAYP/Bap170, independently of CDK8, CyclinC, and other core Mediator subunits, through IDR-mediated interactions rather than enzymatic activities.","evidence":"Transgene reporter assays, ChIP-based localization, genetic epistasis with CKM subunit deletions in Drosophila","pmids":["39684492"],"confidence":"Medium","gaps":["No stable physical interaction detected by co-IP; mechanism of cooperation is indirect or transient","Whether this IDR-dependent cooperation occurs at endogenous loci genome-wide unknown"]},{"year":2026,"claim":"Placing MED13 in a cortical neuronal migration pathway: Med13 knockdown impaired radial migration, callosal projection, and dendritic complexity, with PLXNA4 identified as a downstream effector that rescues migration and projection but not dendritic defects, dissecting the developmental functions of MED13 in the brain.","evidence":"In-utero electroporation knockdown, mass spectrometry proteomics, PlxnA4 overexpression rescue in mouse cortical neurons","pmids":["41663567"],"confidence":"Medium","gaps":["Whether MED13 directly regulates PLXNA4 transcription not shown","Dendritic complexity pathway downstream of MED13 remains unidentified","Single lab, not independently replicated"]},{"year":null,"claim":"Major open questions include: the identity of the circulating metabolic factor(s) released downstream of cardiac MED13 overexpression; the structural basis for how MED13 switches between repressive and activating modes at specific loci; whether the cytoplasmic P-body/autophagy functions of Med13 are conserved in mammals; and the full spectrum of MED13 transcriptional targets governing cortical neurodevelopment.","evidence":"","pmids":[],"confidence":"Low","gaps":["Circulating factor identity unknown","Structural basis for context-dependent activation versus repression unresolved","Mammalian conservation of cytoplasmic functions untested","Complete neurodevelopmental target gene network undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,3,7,11,12]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,16]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,8,9,12,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,3,7,9,11,12,16,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,6,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14,15]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,8,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12]}],"complexes":["CDK8 kinase module (CKM)","Mediator complex"],"partners":["CDK8","CCNC","MED12","FBXW7","PYGO2","MED26","PLXNA4","KSP1"],"other_free_text":[]},"mechanistic_narrative":"MED13 is a scaffold subunit of the CDK8 kinase module (CKM) of the Mediator complex that functions as both a transcriptional repressor and a regulated signaling node linking nuclear gene expression to systemic metabolism and stress responses. Structurally, the MED13 intrinsically disordered region (IDR) physically bridges the CKM to core Mediator while simultaneously occluding RNA Pol II and MED26 binding sites, thereby inhibiting pre-initiation complex assembly and transcription activation [PMID:12738880, PMID:bio_10.1101_2024.07.01.601608]. MED13 acts as a tissue-specific transcriptional repressor—suppressing thyroid hormone receptor targets in the heart, NURR1/MEF2-driven glucose metabolism genes in skeletal muscle, and cyclin D1 expression to enforce G1 checkpoint control—while also serving as a coactivator of Wnt target genes through physical interaction with Pygopus and Med12 [PMID:30769017, PMID:26883362, PMID:33444446, PMID:18451032]. MED13 turnover is regulated by SCF-Fbw7 ubiquitin ligase–mediated proteasomal degradation primed by CDK8 and MAPK phosphorylation, and by Ksp1/Snx4-directed selective autophagy during nutrient stress, during which MED13 translocates to the cytoplasm to organize P-body assembly and autophagic degradation of mRNA-regulatory factors [PMID:23322298, PMID:29212878, PMID:37733395, PMID:39320938]."},"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 the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12738880","citation_count":96,"is_preprint":false},{"pmid":"11171343","id":"PMC_11171343","title":"Drosophila homologues of the transcriptional coactivation complex subunits TRAP240 and TRAP230 are required for identical processes in eye-antennal disc development.","date":"2001","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11171343","citation_count":95,"is_preprint":false},{"pmid":"25422356","id":"PMC_25422356","title":"MED13-dependent signaling from the heart confers leanness by enhancing metabolism in adipose tissue and liver.","date":"2014","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25422356","citation_count":85,"is_preprint":false},{"pmid":"29740699","id":"PMC_29740699","title":"De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder.","date":"2018","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29740699","citation_count":64,"is_preprint":false},{"pmid":"24979807","id":"PMC_24979807","title":"Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24979807","citation_count":51,"is_preprint":false},{"pmid":"25377553","id":"PMC_25377553","title":"The Arabidopsis Mediator CDK8 module genes CCT (MED12) and GCT (MED13) are global regulators of developmental phase transitions.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25377553","citation_count":48,"is_preprint":false},{"pmid":"26883362","id":"PMC_26883362","title":"A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism.","date":"2016","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/26883362","citation_count":40,"is_preprint":false},{"pmid":"28780645","id":"PMC_28780645","title":"The MEDIATOR genes MED12 and MED13 control Arabidopsis root system configuration influencing sugar and auxin responses.","date":"2017","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28780645","citation_count":34,"is_preprint":false},{"pmid":"29212878","id":"PMC_29212878","title":"A complex molecular switch directs stress-induced cyclin C nuclear release through SCFGrr1-mediated degradation of Med13.","date":"2017","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/29212878","citation_count":34,"is_preprint":false},{"pmid":"30419283","id":"PMC_30419283","title":"MicroRNA-499-5p regulates skeletal myofiber specification via NFATc1/MEF2C pathway and Thrap1/MEF2C axis.","date":"2018","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30419283","citation_count":33,"is_preprint":false},{"pmid":"29325037","id":"PMC_29325037","title":"Mediator complex component MED13 regulates zygotic genome activation and is required for postimplantation development in the mouse.","date":"2018","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/29325037","citation_count":30,"is_preprint":false},{"pmid":"22162340","id":"PMC_22162340","title":"An 800  kb deletion at 17q23.2 including the MED13 (THRAP1) gene, revealed by aCGH in a patient with a SMC 17p.","date":"2011","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/22162340","citation_count":21,"is_preprint":false},{"pmid":"30175106","id":"PMC_30175106","title":"Snf1 cooperates with the CWI MAPK pathway to mediate the degradation of Med13 following oxidative stress.","date":"2018","source":"Microbial cell (Graz, Austria)","url":"https://pubmed.ncbi.nlm.nih.gov/30175106","citation_count":18,"is_preprint":false},{"pmid":"36087421","id":"PMC_36087421","title":"MED13 mutation: A novel cause of developmental and epileptic encephalopathy with infantile spasms.","date":"2022","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/36087421","citation_count":17,"is_preprint":false},{"pmid":"32070878","id":"PMC_32070878","title":"Dexmedetomidine protects H9C2 against hypoxia/reoxygenation injury through miR-208b-3p/Med13/Wnt signaling pathway axis.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32070878","citation_count":17,"is_preprint":false},{"pmid":"36543134","id":"PMC_36543134","title":"MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36543134","citation_count":15,"is_preprint":false},{"pmid":"27129500","id":"PMC_27129500","title":"Frameshift Mutations of HSPA4 and MED13 in Gastric and Colorectal Cancers.","date":"2016","source":"Pathology oncology research : POR","url":"https://pubmed.ncbi.nlm.nih.gov/27129500","citation_count":14,"is_preprint":false},{"pmid":"29746886","id":"PMC_29746886","title":"Exercise training prevents obesity-associated disorders: Role of miRNA-208a and MED13.","date":"2018","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29746886","citation_count":14,"is_preprint":false},{"pmid":"33258286","id":"PMC_33258286","title":"Could the MED13 mutations manifest as a Kabuki-like syndrome?","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33258286","citation_count":10,"is_preprint":false},{"pmid":"30769017","id":"PMC_30769017","title":"Regulation of cardiac transcription by thyroid hormone and Med13.","date":"2019","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/30769017","citation_count":10,"is_preprint":false},{"pmid":"33444446","id":"PMC_33444446","title":"Loss of Mediator complex subunit 13 (MED13) promotes resistance to alkylation through cyclin D1 upregulation.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/33444446","citation_count":6,"is_preprint":false},{"pmid":"38745205","id":"PMC_38745205","title":"Expanding phenotype of MED13-associated syndrome presenting novel de novo missense variant in a patient with multiple congenital anomalies.","date":"2024","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/38745205","citation_count":6,"is_preprint":false},{"pmid":"37733395","id":"PMC_37733395","title":"Ksp1 is an autophagic receptor protein for the Snx4-assisted autophagy of Ssn2/Med13.","date":"2024","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37733395","citation_count":5,"is_preprint":false},{"pmid":"39320938","id":"PMC_39320938","title":"Med13 is required for efficient P-body recruitment and autophagic degradation of Edc3 following nitrogen starvation.","date":"2024","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/39320938","citation_count":5,"is_preprint":false},{"pmid":"38854223","id":"PMC_38854223","title":"MED13 Gene Mutation Related to Autism Spectrum Disorder: A Case Report.","date":"2024","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/38854223","citation_count":5,"is_preprint":false},{"pmid":"26231682","id":"PMC_26231682","title":"Deletion of the MED13 and CDK8 subunits of the Mediator improves the phenotype of a long-lived respiratory deficient mutant of Podospora anserina.","date":"2015","source":"Fungal genetics and biology : FG & B","url":"https://pubmed.ncbi.nlm.nih.gov/26231682","citation_count":4,"is_preprint":false},{"pmid":"38528425","id":"PMC_38528425","title":"A de novo frameshift variant in MED13 gene in a patient with autism spectrum disorder and magnetic resonance imaging abnormalities mimicking tuberous sclerosis.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38528425","citation_count":2,"is_preprint":false},{"pmid":"39178836","id":"PMC_39178836","title":"An intrinsically disordered region in MED13 turns Mediator on/off on cue.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/39178836","citation_count":1,"is_preprint":false},{"pmid":"41195223","id":"PMC_41195223","title":"A novel frameshift variant in the MED13 gene causing intellectual developmental disorder-61 in a Chinese family.","date":"2025","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/41195223","citation_count":1,"is_preprint":false},{"pmid":"39684492","id":"PMC_39684492","title":"Subunits Med12 and Med13 of Mediator Cooperate with Subunits SAYP and Bap170 of SWI/SNF in Active Transcription in Drosophila.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39684492","citation_count":0,"is_preprint":false},{"pmid":"41959135","id":"PMC_41959135","title":"Med12 and Med13 prevent tumorigenic dedifferentiation of intermediate neural progenitors and premature loss of neural stem cells.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41959135","citation_count":0,"is_preprint":false},{"pmid":"41663567","id":"PMC_41663567","title":"Med13 is involved in the radial migration and contralateral projection of cortical neurons via PlxnA4.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41663567","citation_count":0,"is_preprint":false},{"pmid":"40358161","id":"PMC_40358161","title":"Quitting Your Day Job in Response to Stress: Cell Survival and Cell Death Require Secondary Cytoplasmic Roles of Cyclin C and Med13.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/40358161","citation_count":0,"is_preprint":false},{"pmid":"41593703","id":"PMC_41593703","title":"miR-4326 predicts adverse outcomes of triple-negative breast cancer and regulates cell growth and motility through modulating MED13.","date":"2026","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41593703","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.10.617571","title":"Structural and evolutionary determinants of Argonaute function","date":"2024-10-13","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.10.617571","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.01.601608","title":"Structural basis of the human transcriptional Mediator complex modulated by its dissociable Kinase module","date":"2024-07-03","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.01.601608","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18876,"output_tokens":4889,"usd":0.064981},"stage2":{"model":"claude-opus-4-6","input_tokens":8375,"output_tokens":3922,"usd":0.209888},"total_usd":0.274869,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"PROSIT240/MED13 (THRAP2) was identified as a novel gene homologous to TRAP240 (MED13L), suggesting it is a component of the thyroid hormone receptor-associated protein (TRAP/Mediator) complex, with high expression in heart and brain consistent with its role in early cardiac and brain development.\",\n      \"method\": \"Positional cloning, sequence homology analysis, expression analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — positional cloning and homology; foundational identification paper with 135 citations\",\n      \"pmids\": [\"14638541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TRAP240/ARC250 (MED13 ortholog) forms a conserved kinase submodule with Srb8/TRAP230, Srb10/CDK8, and Srb11/CyclinC in Mediator; this submodule associates only with free Mediator (not RNA Pol II-bound Mediator), implicating it in negative regulation of transcription.\",\n      \"method\": \"Biochemical fractionation, genetic analysis, gene expression profiling in S. pombe\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation and genetic analysis replicated across yeast species, strong preponderance of evidence\",\n      \"pmids\": [\"12738880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila Med13 (kohtalo), along with Med12 (blind spot), is required for proper developmental signaling in the eye-antennal disc; loss results in maintenance of inappropriate Hedgehog target gene expression and failure to differentiate, demonstrating a role in mediating specific developmental signals rather than general transcription.\",\n      \"method\": \"Genetic loss-of-function (mutant analysis), in vivo gene expression assays in Drosophila\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic loss-of-function with defined cellular phenotypes; 95 citations\",\n      \"pmids\": [\"11171343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Drosophila Med13 (skuld) and Med12 (kohtalo) subunits of the Mediator complex are essential for Wingless (Wnt) target gene transcription; they act downstream of beta-catenin stabilization, are required for transcriptional activation by the N-terminal domain of Pygopus, and physically interact with Pygopus, suggesting Pygopus recruits Mediator through Med12/Med13 to activate Wnt targets.\",\n      \"method\": \"Genetic epistasis (in vivo and cell culture), Co-immunoprecipitation (physical interaction), RNAi knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus genetic epistasis in multiple contexts; 107 citations\",\n      \"pmids\": [\"18451032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fbw7, an SCF ubiquitin ligase and tumor suppressor, binds CDK8-Mediator and targets MED13 (and MED13L) for proteasomal degradation; MED13/13L physically link the CDK8 module to core Mediator, and Fbw7 loss increases CDK8 module–Mediator association, revealing a ubiquitin-mediated mechanism controlling CDK8 module dynamics.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, genetic knockout/knockdown with protein level quantification\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional degradation assay, genetic KO with defined molecular phenotype; 100 citations\",\n      \"pmids\": [\"23322298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cardiac-specific overexpression of MED13 in transgenic mice confers a lean phenotype with increased lipid uptake, beta-oxidation, and mitochondrial content in white adipose tissue and liver; parabiosis experiments demonstrate that circulating factor(s) from MED13-overexpressing hearts mediate this systemic metabolic effect, revealing a heart-to-peripheral tissue signaling axis.\",\n      \"method\": \"Transgenic mouse model (cardiac-specific overexpression), parabiosis experiments, metabolic phenotyping\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain-of-function with parabiosis (orthogonal method); defined systemic phenotype; 85 citations\",\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 shows Wingless (Wnt ligand) functions downstream of MED13 in a muscle-regulatory pathway, identifying Wingless as an effector of MED13 in muscle-to-adipose tissue cross-talk controlling energy homeostasis.\",\n      \"method\": \"Tissue-specific RNAi knockdown, genetic epistasis screen of 150 secreted proteins, Armadillo pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi-based epistasis with defined pathway placement; 51 citations\",\n      \"pmids\": [\"24979807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Skeletal muscle-specific deletion of MED13 in mice activates glucose uptake and glycogen storage, conferring resistance to hepatic steatosis; mechanistically, MED13 suppresses muscle glucose metabolism genes by inhibiting nuclear receptor NURR1 and MEF2 transcription factor, demonstrating tissue-specific transcriptional repressor function.\",\n      \"method\": \"Muscle-specific conditional knockout mice, transcriptomics, metabolic phenotyping, transcription factor binding analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with defined molecular mechanism and metabolic phenotype\",\n      \"pmids\": [\"26883362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In S. cerevisiae, oxidative stress induces Med13 degradation via SCFGrr1 ubiquitin ligase; residues 742–844 of Med13's intrinsically disordered region (IDR) both direct cyclin C-Cdk8 association and serve as the degron; CDK8 phosphorylation of Med13 primes the phosphodegron, and Slt2 MAPK phosphorylates cyclin C to trigger its release from Med13, followed by Slt2-mediated modification of Med13 itself to stimulate SCFGrr1-dependent destruction, releasing cyclin C to the cytoplasm where it promotes mitochondrial fission and cell death.\",\n      \"method\": \"Domain mapping by mutagenesis, ubiquitination assays, MAPK kinase assays, genetic epistasis, fluorescence microscopy\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of degron, in vitro kinase assays, genetic epistasis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"29212878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MED13 is essential for zygotic genome activation (ZGA) in mouse embryos; its role in ZGA is mediated in part by interactions with E2F transcription factors and by regulating expression of the embryo-specific BAF chromatin remodeling complex (esBAF); MED13L partially compensates for loss of MED13 in preimplantation development but cannot rescue postimplantation defects.\",\n      \"method\": \"siRNA knockdown, conditional knockout mice, co-immunoprecipitation (E2F interaction), transcriptomic analysis of preimplantation embryos\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined molecular mechanism (E2F interaction, esBAF regulation) using multiple approaches\",\n      \"pmids\": [\"29325037\"],\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, acting in parallel with the CWI MAPK pathway; Snf1 deletion results in nuclear retention of cyclin C and failure to induce mitochondrial fragmentation, demonstrating that Med13 degradation is coordinately controlled by two kinase pathways.\",\n      \"method\": \"Genetic deletion analysis, degron mapping by heterologous fusion, fluorescence microscopy of cyclin C localization, mitochondrial morphology assay\",\n      \"journal\": \"Microbial cell (Graz, Austria)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and cell biology methods; single lab\",\n      \"pmids\": [\"30175106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Med13 represses thyroid hormone receptor (TR) response genes in the heart; cardiac-specific deletion of Med13 exacerbates cardiac dysfunction in hypothyroid mice; transcriptomic analysis defined Med13-dependent gene expression pathways in response to thyroid hormone signaling, demonstrating Med13 is a negative regulator of TR-dependent transcription in cardiomyocytes.\",\n      \"method\": \"Cardiac-specific conditional knockout mice, RNA sequencing, echocardiography, PTU/T3 treatment model\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with transcriptomic and functional cardiac phenotyping; single lab\",\n      \"pmids\": [\"30769017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MED13 binds to cyclin D1 (CCND1) regulatory elements to repress its expression; loss of MED13 leads to cyclin D1 upregulation, shorter G1 phase, reduced apoptosis, and resistance to alkylating agents; CDK8/19 inhibitor Senexin A stabilizes MED13 and re-sensitizes cells to alkylating agents in combination treatment.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen, chromatin occupancy (MED13 binding to CCND1 locus), transcriptome analysis, CDK inhibitor pharmacology\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen plus chromatin binding plus pharmacological rescue; single lab\",\n      \"pmids\": [\"33444446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila, Skd/Med13 and glycolytic enzymes are co-upregulated by alpha-synuclein-associated neurodegeneration; co-expressing skd/Med13 RNAi with alpha-syn synergistically increases oxidized-to-reduced glutathione ratio; overexpressing a glycolytic enzyme or deferoxamine treatment suppresses neurodegeneration, placing MED13 in a pathway where compensatory glycolysis is neuroprotective against alpha-syn toxicity.\",\n      \"method\": \"Genetic modifier screen (3471 mutant chromosomes), RNAi epistasis, glutathione redox assay, pharmacological rescue in Drosophila and mouse models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large-scale genetic screen with epistasis and orthogonal biochemical assays; conserved in mice\",\n      \"pmids\": [\"36543134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In S. cerevisiae, Ksp1 (casein II-like kinase) acts as an autophagic receptor for Ssn2/Med13 in Snx4-assisted autophagy; following nitrogen starvation, Ksp1 directly associates with Atg8 via an Atg8-family interacting motif (AIM)/LIR interaction, and is recruited to the phagophore assembly site by Atg29; this interaction mediates selective vacuolar degradation of Med13.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, AIM/LIR mutagenesis, autophagy flux assays, fluorescence microscopy\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain mutagenesis, reciprocal protein interactions, functional autophagy assays; multiple orthogonal methods\",\n      \"pmids\": [\"37733395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Following nitrogen starvation in S. cerevisiae, Med13 translocates from the nucleus to the cytoplasm where it colocalizes with P-bodies (processing bodies); cytoplasmic Med13 facilitates recruitment of the P-body assembly factor Edc3 into P-bodies and orchestrates autophagic degradation of Edc3 through a cargo-hitchhiking autophagy pathway using Ksp1 as autophagic receptor; Xrn1 degradation is Med13-independent, demonstrating selectivity.\",\n      \"method\": \"Live fluorescence microscopy (localization), genetic deletion with P-body assembly assay, autophagy flux assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence, multiple genetic and cell biology methods\",\n      \"pmids\": [\"39320938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structures of the human complete Mediator and CDK8 kinase module (CKM) reveal 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 sites for RNA Pol II and MED26 on cMED and sterically hinders cMED-PIC assembly through TFIIH and the +1 nucleosome, mechanistically explaining how the CKM inhibits transcription activation; MED12 positions CDK8 downstream of the transcription start site to enable post-initiation stimulatory function.\",\n      \"method\": \"Cryo-electron microscopy structural determination, domain mapping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with mechanistic explanation of mutually exclusive binding; complemented by related study (PMID:39178836)\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.601608\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of Med13 in cortical neurons via in-utero electroporation impairs radial migration, contralateral (callosal) projection, and dendritic complexity; mass spectrometry of MED13-deleted SH-SY5Y cells identified PLXNA4 as a downstream dysregulated protein; overexpression of PlxnA4 rescues radial migration and callosal projection defects but not dendritic complexity in Med13 knockdown neurons, placing PLXNA4 downstream of MED13 in cortical neuronal migration.\",\n      \"method\": \"In-utero electroporation knockdown, mass spectrometry proteomics, genetic rescue (PlxnA4 overexpression), cortical migration assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct KD with defined cellular phenotype and pathway placement via proteomics and rescue experiment; single lab\",\n      \"pmids\": [\"41663567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Drosophila, Med12 and Med13 cooperate with SWI/SNF subunits SAYP and Bap170 to support enhancer-dependent transcription; this cooperation is independent of Cdk8, CyclinC, and other core Mediator subunits; SAYP/Bap170 presence at a locus is required for stable recruitment of Med12/Med13, and the cooperation depends on extended intrinsically disordered regions of the factors rather than their enzymatic activities.\",\n      \"method\": \"Transgene reporter assays, ChIP-based localization, genetic epistasis (CKM subunit deletions), co-immunoprecipitation attempted (no stable interaction detected in extract)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — genetic epistasis and chromatin localization with functional transcriptional readout; single lab\",\n      \"pmids\": [\"39684492\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED13 is a scaffold subunit of the CDK8 kinase module (CKM) that physically links the CKM to core Mediator through its intrinsically disordered region (IDR) — which simultaneously occludes RNA Pol II and MED26 binding to Mediator, thereby inhibiting transcription initiation — and is regulated by SCF-Fbw7 ubiquitin-mediated degradation (primed by CDK8 and MAPK phosphorylation) and by autophagic degradation via Ksp1/Snx4; in response to stress, MED13 translocates to the cytoplasm where it organizes P-body assembly and selective autophagy of mRNA-regulatory factors, while in the nucleus it acts as a tissue-specific transcriptional repressor (e.g., of thyroid hormone receptor targets in the heart and of NURR1/MEF2-driven glucose metabolism genes in skeletal muscle) and as an activator of Wnt target genes through physical interaction with Pygopus/Med12, with loss-of-function in vivo causing defects in zygotic genome activation, cortical neuronal migration, and systemic energy homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MED13 is a scaffold subunit of the CDK8 kinase module (CKM) of the Mediator complex that functions as both a transcriptional repressor and a regulated signaling node linking nuclear gene expression to systemic metabolism and stress responses. Structurally, the MED13 intrinsically disordered region (IDR) physically bridges the CKM to core Mediator while simultaneously occluding RNA Pol II and MED26 binding sites, thereby inhibiting pre-initiation complex assembly and transcription activation [PMID:12738880, PMID:bio_10.1101_2024.07.01.601608]. MED13 acts as a tissue-specific transcriptional repressor—suppressing thyroid hormone receptor targets in the heart, NURR1/MEF2-driven glucose metabolism genes in skeletal muscle, and cyclin D1 expression to enforce G1 checkpoint control—while also serving as a coactivator of Wnt target genes through physical interaction with Pygopus and Med12 [PMID:30769017, PMID:26883362, PMID:33444446, PMID:18451032]. MED13 turnover is regulated by SCF-Fbw7 ubiquitin ligase–mediated proteasomal degradation primed by CDK8 and MAPK phosphorylation, and by Ksp1/Snx4-directed selective autophagy during nutrient stress, during which MED13 translocates to the cytoplasm to organize P-body assembly and autophagic degradation of mRNA-regulatory factors [PMID:23322298, PMID:29212878, PMID:37733395, PMID:39320938].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing that MED13 is not a general transcription factor but a signal-specific mediator: Drosophila loss-of-function showed Med13 (kohtalo) is required for proper developmental Hedgehog signaling output rather than basal transcription, reframing the gene as a pathway-specific transcriptional regulator.\",\n      \"evidence\": \"Genetic mutant analysis with in vivo gene expression assays in Drosophila eye-antennal disc\",\n      \"pmids\": [\"11171343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No biochemical mechanism for signal specificity identified\", \"Hedgehog-specific versus general developmental role not fully distinguished\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defining MED13's position within the Mediator architecture: biochemical fractionation showed that MED13 (TRAP240/ARC250) forms a four-subunit kinase module with MED12, CDK8, and CyclinC that associates exclusively with free Mediator and not with RNA Pol II–bound holoenzyme, establishing the structural basis for its role in transcriptional repression.\",\n      \"evidence\": \"Biochemical fractionation and genetic analysis across S. pombe and human systems\",\n      \"pmids\": [\"12738880\", \"14638541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical basis for mutual exclusivity with Pol II binding unknown at this stage\", \"Whether MED13 directly mediates the CKM–core Mediator interface was unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealing a coactivator function: Med13 and Med12 were shown to be essential for Wnt/Wingless target gene activation downstream of β-catenin, physically interacting with Pygopus to recruit Mediator, demonstrating that MED13 can function as a transcriptional activator in specific signaling contexts.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, genetic epistasis, and RNAi in Drosophila and cell culture\",\n      \"pmids\": [\"18451032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MED13 directly contacts Pygopus or acts through Med12 was not resolved\", \"Mechanism by which CKM switches from repressor to activator mode unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying the ubiquitin-dependent regulatory mechanism: SCF-Fbw7 was shown to target MED13 (and MED13L) for proteasomal degradation, with Fbw7 loss increasing CKM–core Mediator association, revealing that MED13 protein turnover dynamically controls CKM occupancy on Mediator.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, and genetic knockout/knockdown with protein level quantification\",\n      \"pmids\": [\"23322298\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphodegron identity on MED13 not mapped in this study\", \"In vivo physiological triggers of Fbw7-mediated MED13 turnover not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connecting MED13 to systemic energy homeostasis: cardiac-specific MED13 overexpression in mice produced a lean phenotype with enhanced peripheral lipid metabolism, and parabiosis demonstrated circulating factor(s) from MED13-overexpressing hearts mediate this effect, while Drosophila muscle-specific knockdown increased obesity susceptibility through a Wingless-dependent pathway.\",\n      \"evidence\": \"Transgenic mouse cardiac overexpression with parabiosis; Drosophila tissue-specific RNAi with genetic epistasis screen\",\n      \"pmids\": [\"25422356\", \"24979807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the circulating factor(s) downstream of cardiac MED13 unknown\", \"Whether MED13's metabolic role is CKM-dependent or independent not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining MED13 as a tissue-specific transcriptional repressor of metabolic genes: skeletal muscle-specific MED13 knockout activated glucose uptake and glycogen storage by de-repressing NURR1- and MEF2-driven transcriptional programs, mechanistically explaining MED13's metabolic function at the transcription factor level.\",\n      \"evidence\": \"Conditional knockout mice, transcriptomics, and metabolic phenotyping\",\n      \"pmids\": [\"26883362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MED13 directly binds NURR1/MEF2 or acts indirectly through chromatin context not established\", \"Relationship between MED13 repressor function and CKM kinase activity at these loci unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping the phosphodegron and dual-kinase control of MED13 destruction: in yeast, CDK8 phosphorylation primes a degron within the MED13 IDR (residues 742–844) for SCF-Grr1 recognition, while Slt2 MAPK independently phosphorylates cyclin C and Med13 to trigger cyclin C release and Med13 degradation, establishing a two-kinase convergence model for stress-induced CKM disassembly.\",\n      \"evidence\": \"Domain mutagenesis, in vitro kinase assays, ubiquitination assays, genetic epistasis, and fluorescence microscopy in S. cerevisiae\",\n      \"pmids\": [\"29212878\", \"30175106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the dual-kinase degron mechanism is conserved in mammals not tested\", \"How Snf1/AMPK and Slt2/MAPK inputs are integrated at the Med13 protein not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing MED13's role in the earliest transcriptional event of mammalian development: MED13 was shown to be essential for zygotic genome activation in mouse embryos, acting through E2F transcription factor interactions and regulation of embryo-specific BAF complex expression, with MED13L providing partial compensation only during preimplantation.\",\n      \"evidence\": \"siRNA knockdown, conditional knockout, co-immunoprecipitation, and transcriptomic analysis of preimplantation embryos\",\n      \"pmids\": [\"29325037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect role in esBAF regulation not distinguished\", \"Whether E2F interaction requires the MED13 IDR not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking MED13 to cell cycle control and chemoresistance: MED13 directly binds cyclin D1 (CCND1) regulatory elements to repress its expression, and MED13 loss causes cyclin D1 upregulation, shortened G1, reduced apoptosis, and alkylating agent resistance, which is reversed by CDK8/19 inhibitor-mediated MED13 stabilization.\",\n      \"evidence\": \"Genome-wide CRISPR screen, MED13 chromatin occupancy at CCND1 locus, transcriptome analysis, CDK inhibitor pharmacology\",\n      \"pmids\": [\"33444446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED13 occupancy at CCND1 is direct DNA binding or Mediator-tethered not resolved\", \"In vivo tumor relevance not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing a cytoplasmic moonlighting function: upon nitrogen starvation in yeast, Med13 translocates to the cytoplasm where it organizes P-body assembly by recruiting Edc3, and is itself degraded via Ksp1/Snx4-assisted selective autophagy; Med13 orchestrates cargo-hitchhiking autophagy of Edc3 but not Xrn1, demonstrating substrate selectivity in this non-transcriptional role.\",\n      \"evidence\": \"Live fluorescence microscopy, genetic deletion with P-body and autophagy flux assays, AIM/LIR mutagenesis, co-immunoprecipitation in S. cerevisiae\",\n      \"pmids\": [\"37733395\", \"39320938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cytoplasmic Med13 functions exist in metazoans unknown\", \"How Med13 nuclear export is regulated not defined\", \"Full repertoire of autophagy cargoes hitchhiking on Med13 not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Structural resolution of how MED13 inhibits transcription: cryo-EM structures showed the MED13 IDR directly occludes the RNA Pol II and MED26 binding surfaces on core Mediator and sterically hinders TFIIH and +1 nucleosome positioning for PIC assembly, providing a definitive structural mechanism for CKM-mediated transcriptional repression.\",\n      \"evidence\": \"Cryo-electron microscopy structural determination and domain mapping (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.01.601608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, awaiting peer review\", \"How CKM transitions between inhibitory and stimulatory modes at the structural level not captured\", \"Dynamics of the MED13 IDR in vivo not assessed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating CKM-independent cooperation with chromatin remodelers: in Drosophila, Med13 and Med12 support enhancer-dependent transcription cooperatively with SWI/SNF subunits SAYP/Bap170, independently of CDK8, CyclinC, and other core Mediator subunits, through IDR-mediated interactions rather than enzymatic activities.\",\n      \"evidence\": \"Transgene reporter assays, ChIP-based localization, genetic epistasis with CKM subunit deletions in Drosophila\",\n      \"pmids\": [\"39684492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No stable physical interaction detected by co-IP; mechanism of cooperation is indirect or transient\", \"Whether this IDR-dependent cooperation occurs at endogenous loci genome-wide unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placing MED13 in a cortical neuronal migration pathway: Med13 knockdown impaired radial migration, callosal projection, and dendritic complexity, with PLXNA4 identified as a downstream effector that rescues migration and projection but not dendritic defects, dissecting the developmental functions of MED13 in the brain.\",\n      \"evidence\": \"In-utero electroporation knockdown, mass spectrometry proteomics, PlxnA4 overexpression rescue in mouse cortical neurons\",\n      \"pmids\": [\"41663567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED13 directly regulates PLXNA4 transcription not shown\", \"Dendritic complexity pathway downstream of MED13 remains unidentified\", \"Single lab, not independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include: the identity of the circulating metabolic factor(s) released downstream of cardiac MED13 overexpression; the structural basis for how MED13 switches between repressive and activating modes at specific loci; whether the cytoplasmic P-body/autophagy functions of Med13 are conserved in mammals; and the full spectrum of MED13 transcriptional targets governing cortical neurodevelopment.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Circulating factor identity unknown\", \"Structural basis for context-dependent activation versus repression unresolved\", \"Mammalian conservation of cytoplasmic functions untested\", \"Complete neurodevelopmental target gene network undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 3, 7, 11, 12]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 8, 9, 12, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 3, 7, 9, 11, 12, 16, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 8, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"CDK8 kinase module (CKM)\",\n      \"Mediator complex\"\n    ],\n    \"partners\": [\n      \"CDK8\",\n      \"CCNC\",\n      \"MED12\",\n      \"FBXW7\",\n      \"PYGO2\",\n      \"MED26\",\n      \"PLXNA4\",\n      \"KSP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}