{"gene":"MED15","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2011,"finding":"The acidic activation domain of transcription activator Gcn4 binds the Mediator subunit Gal11/Med15 activator-binding domain 1 (ABD1) through a 'fuzzy' protein interface: ABD1 has a four-helix fold with a shallow hydrophobic cleft, and eight residues of Gcn4 adopt a helical conformation allowing three aromatic/aliphatic residues to insert into the cleft via hydrophobic interactions only, with no single fixed conformation (fuzzy complex). Functional mutagenesis in yeast confirmed the importance of interface residues for transcriptional activation.","method":"NMR structure determination of bound complex + mutagenesis + yeast functional assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — NMR structural analysis with mutagenesis and functional validation in vivo","pmids":["22195967"],"is_preprint":false},{"year":2008,"finding":"The yeast Mediator subunit Gal11p/MED15 and its KIX domain is required for fatty acid-dependent transcriptional activation by the yeast PPAR-alpha analog Oaf1p. NMR spectroscopy showed that the Oaf1p activation domain interacts with the Gal11p/MED15 KIX domain in a manner similar to the zinc cluster family member Pdr1p, identifying the KIX domain as a key target of ligand-dependent transcription factors.","method":"NMR spectroscopy + genetic loss-of-function (deletion mutants) + transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structural data combined with genetic and transcriptional functional validation","pmids":["19056732"],"is_preprint":false},{"year":2009,"finding":"Gcn4 recruits Mediator to target promoters in vivo through additive contributions from three distinct N-terminal segments of Gal11/Med15: the KIX domain, a B-box region (conserved with mammalian SRC-1), and a third segment. NMR chemical shift analysis identified the Gcn4 binding site on the KIX domain surface, and mutational studies showed B-box is a critical determinant of Mediator recruitment.","method":"In vitro binding assays + ChIP (chromatin immunoprecipitation) + NMR chemical shift perturbation + mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including NMR, in vitro binding, and in vivo ChIP with mutagenesis","pmids":["19940160"],"is_preprint":false},{"year":2013,"finding":"Med15 and Med16 are two Mediator tail subunits required for heat shock factor 1 (Hsf1)-dependent recruitment of Mediator to HSP gene promoters upon heat stress. Dual activation domains of Hsf1 cooperatively recruit holo-Mediator through the Tail module; loss of Med15 or Med16 individually reduces Mediator occupancy while loss of both abolishes it and substantially diminishes RNA Pol II recruitment.","method":"ChIP (chromatin immunoprecipitation) + genetic deletion mutants + Mediator/Pol II recruitment assays in yeast","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal ChIP epistasis with double mutants, multiple subunit validations","pmids":["23447536"],"is_preprint":false},{"year":2021,"finding":"The acidic activation domains of both Gal4 and Gcn4, which are intrinsically disordered and of different sequence, interact with Med15 using nearly identical 'fuzzy' binding mechanisms as shown by NMR chemical shift perturbation analysis. This reveals a common sequence-independent mechanism for activation domain–Mediator binding through a hydrophobic cloud, distinct from the structured complex formed by Gal4 AD with its repressor Gal80.","method":"NMR chemical shift perturbation analysis of Gal4 AD and Gcn4 AD binding to Med15","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — NMR with comparative structural analysis and functional context","pmids":["33850123"],"is_preprint":false},{"year":2006,"finding":"TRIM11 physically interacts with MED15 (ARC105) and promotes its ubiquitin-proteasome-dependent degradation. Co-expression of TRIM11 increases ARC105 ubiquitination and degradation (blocked by proteasome inhibitor), and suppresses ARC105-mediated TGF-beta-induced transcriptional activation in reporter assays.","method":"Co-immunoprecipitation + ubiquitination assay + proteasome inhibitor treatment + transcriptional reporter assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with functional ubiquitination and reporter assays in single study","pmids":["16904669"],"is_preprint":false},{"year":2013,"finding":"Inactivation of Med15 in yeast leads to down-regulation of Ace2 transcriptional activator target genes and a G1 cell cycle arrest phenotype. Synthetic lethality of med5/med15 and med15/med16 double mutations indicates that the Mediator Tail performs essential functions even as a separate complex.","method":"N-Degron temperature-sensitive mutants + genome-wide expression profiling + cell cycle analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — inducible loss-of-function with defined transcriptional and cell cycle phenotype","pmids":["23991176"],"is_preprint":false},{"year":2014,"finding":"The C. elegans MDT-15/MED15 ortholog is required for xenobiotic-induced expression of p38 MAP kinase (PMK-1)-dependent immune effector genes and detoxification genes, linking xenobiotic detoxification to innate immunity; RNAi knockdown of mdt-15 abrogates induction of PMK-1-dependent immune genes and increases susceptibility to Pseudomonas aeruginosa infection.","method":"RNAi screen + qRT-PCR + infection survival assays in C. elegans","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with defined immune and detoxification phenotype in C. elegans ortholog","pmids":["24875643"],"is_preprint":false},{"year":2014,"finding":"Human MED15 promotes transcriptional activation by VP16 and SREBP1a in HeLa cells, as shown by siRNA knockdown (reducible by overexpression rescue). MED15 colocalizes with general transcription factors TFIIE and TFIIH in the nucleus, and ChIP shows MED15 localizes to both the p53 binding site and the p21 promoter region along with TFIIE and TFIIH upon Nutlin-3 treatment.","method":"siRNA knockdown + overexpression rescue + immunostaining colocalization + ChIP","journal":"Drug discoveries & therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (knockdown, rescue, ChIP) in human cells","pmids":["25382556"],"is_preprint":false},{"year":2013,"finding":"MED15 knockdown in prostate cancer cells reduces phosphorylation and nuclear shuttling of p-SMAD3 and attenuates TGF-beta-enhanced proliferation, indicating MED15 is required for TGF-beta/SMAD3 signaling. MED15 knockdown also decreases both androgen-dependent and -independent proliferation.","method":"siRNA/shRNA knockdown + proliferation assays + p-SMAD3 immunostaining + nuclear fractionation","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined signaling and proliferation phenotype","pmids":["24374838"],"is_preprint":false},{"year":2019,"finding":"C. elegans MDT-15 physically interacts with nuclear hormone receptor HIZR-1 to promote zinc and cadmium stress-responsive gene expression; this interaction is enhanced by zinc or cadmium. mdt-15 and hizr-1 cooperate to regulate zinc storage in the gut and protect against zinc/cadmium toxicity. Mammalian MED15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a cadmium/zinc-stimulated manner, and human MED15 is required for metallothionein gene induction in lung adenocarcinoma cells exposed to cadmium.","method":"Yeast two-hybrid + qRT-PCR + reporter assays + ChIP (mammalian cells) + loss-of-function mutants in C. elegans","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across organisms, yeast-2-hybrid interaction, ChIP, genetic epistasis","pmids":["31815936"],"is_preprint":false},{"year":2021,"finding":"The human MED15 prion-like domain (PrLD) forms homodimers sustained by coiled-coil (CC) interactions, and this CC fold mediates transition to a beta-sheet amyloid state; disruption of the CC abolishes aggregation. Expression of MED15-PrLD in human cells promotes cytoplasmic and perinuclear inclusions that sequester endogenous full-length MED15 in a prion-like manner.","method":"Biochemical aggregation assays + mutagenesis (CC disruption) + cell imaging + bioinformatics of PrLD","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical and cell-based evidence with mutagenesis in single study","pmids":["33772081"],"is_preprint":false},{"year":2021,"finding":"Med15 forms nuclear condensates (foci) in mammalian cells through its glutamine-rich intrinsically disordered region (IDR) and a short downstream hydrophobic motif. Med15 foci are sensitive to 1,6-hexanediol, show rapid FRAP recovery consistent with phase separation, and are disrupted by overexpression of DYRK3 kinase. Both the IDR and C-terminal region contribute to intracellular phase separation as shown by optodroplet assay.","method":"Live cell imaging + FRAP + 1,6-hexanediol treatment + optodroplet assay + DYRK3 overexpression","journal":"BMC biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple live imaging and phase separation assays with functional perturbation","pmids":["34789250"],"is_preprint":false},{"year":2010,"finding":"Drosophila Med15, a component of the Mediator complex, is required for transcription of decapentaplegic (Dpp) target genes during wing development; loss-of-function clones show defective wing patterning and reduced Dpp target gene expression.","method":"Genetic mosaic screen + loss-of-function clonal analysis in Drosophila wing","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with defined developmental and transcriptional phenotype in Drosophila ortholog","pmids":["20233856"],"is_preprint":false},{"year":2024,"finding":"MED15 acts as a coactivator of SREBP transcription factors by directly interacting with SREBP1 and SREBP2, promoting SREBP-dependent lipid biosynthesis enzyme expression. MED15 also promotes SREBP1 and SREBP2 activation through the PLK1/AKT axis in clear cell renal cell carcinoma. HIF-2α transcriptionally activates MED15 by directly binding its promoter region.","method":"Co-immunoprecipitation + ChIP + siRNA knockdown + overexpression assays + reporter assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP interaction plus ChIP and functional assays in single study","pmids":["38649345"],"is_preprint":false},{"year":2024,"finding":"Mouse Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 as shown by co-immunoprecipitation and ChIP-seq; knockout of Med15 in mouse β-cells causes defects in β-cell maturation without affecting β-cell mass or insulin expression. Human embryonic stem cell-derived β-like cells engineered to overexpress MED15 show increased maturation markers.","method":"ChIP-seq + co-immunoprecipitation + conditional knockout mouse + human ESC overexpression model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP-seq, co-IP, and in vivo conditional KO with defined maturation phenotype","pmids":["39379383"],"is_preprint":false},{"year":2024,"finding":"Med15 can select genomic target sites independent of promoter-bound transcription factors; it shows inherent preference for 'fuzzy-nucleosome' promoter architecture. Direct DBD-Med15 fusions shift localization toward fuzzy-nucleosome promoters including sites lacking endogenous Mediator, suggesting Med15 actively contributes to target site selection.","method":"ChIP-seq in budding yeast with DBD-AD fusion proteins + direct DBD-Med15 fusions + transcriptional assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genomic localization data with multiple genetic constructs","pmids":["39187372"],"is_preprint":false},{"year":2024,"finding":"Drosophila Moesin directly binds the Med15 subunit of the Mediator complex in the nucleus. Both Moesin and Med15 bind heat shock factor (Hsf), and Moesin's presence at regulatory regions of the Hsp70Ab heat shock gene is Med15-dependent. Moesin, Med15, Hsf, and monomeric actin form a nuclear complex required for proper Hsp gene expression. The direct interaction between human orthologs of Drosophila Moesin and Med15 was confirmed.","method":"Co-immunoprecipitation + ChIP + RNAi knockdown + direct binding assays (Drosophila and human orthologs)","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP and ChIP with functional gene expression readout, confirmed in human orthologs","pmids":["39353569"],"is_preprint":false},{"year":2025,"finding":"TGF-β selectively induces CDK1-mediated phosphorylation of MED15 at T603, which controls SASP gene expression and cellular senescence. Unphosphorylated MED15 is bound by forkhead box protein A1 (FOXA1) to suppress SASP gene expression; phosphorylation at T603 prevents FOXA1 binding, releasing SASP gene repression. Knock-in of the dephosphorylated T603A mutant in aging mice attenuates SASP and improves cognitive function.","method":"Phospho-mutagenesis (T603A/T603D) + co-immunoprecipitation + in vivo knock-in mouse model + behavioral assays + gene expression analysis","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of phosphosite with identified kinase (CDK1) and reader (FOXA1), validated in vivo","pmids":["40825935"],"is_preprint":false},{"year":2025,"finding":"MED15 interacts with YAP1 and stabilizes it by attenuating TRIM11-mediated ubiquitination of YAP1, promoting EMT and cell migration in bladder cancer. Under sorbitol-induced stress, MED15 forms stress-inducible protein condensates with increased colocalization with YAP1.","method":"Co-immunoprecipitation + ubiquitination assay + siRNA knockdown + migration assays + condensate imaging","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP interaction, ubiquitination assay, and functional assays in single study","pmids":["41685983"],"is_preprint":false},{"year":2025,"finding":"MDT-15/MED15 (C. elegans ortholog) and downstream fatty acid desaturases FAT-6 and FAT-7 are required for activation of the ESRE mitochondrial surveillance pathway; supplementation with polyunsaturated fatty acids downstream of FAT-6/FAT-7 rescues ESRE activation in mdt-15 knockdowns. Box C/D snoRNPs are required for upregulation of fatty acid metabolism under ESRE-activating conditions and act upstream of MDT-15 in this pathway.","method":"RNAi knockdown + ESRE reporter assays + fatty acid supplementation rescue + infection survival assays in C. elegans","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single-lab RNAi-based epistasis without biochemical interaction confirmation","pmids":["40501983"],"is_preprint":true},{"year":2024,"finding":"ATXN1 amino acids 99-163 and MED15 amino acids 548-665 are critical for the ATXN1-MED15 protein-protein interaction, and MED15 significantly enhances aggregation of polyQ-expanded ATXN1. A small molecule inhibitor of this interaction (Chembridge ID: 5755483) inhibits both the ATXN1-MED15 interaction and dimerization of polyQ-expanded ATXN1.","method":"Computational structure prediction + experimental domain mapping + small molecule inhibitor assay + aggregation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint with partial domain mapping; interaction validated experimentally but structural confirmation pending","pmids":["bio_10.1101_2025.03.17.643445"],"is_preprint":true},{"year":2024,"finding":"MED15 is specifically enriched (relative to other Mediator subunits) in the HTT interactome in the tail domain of Mediator; HTT modulates the subcellular localization and assembly of the Mediator complex as shown in HD and KO models.","method":"Multi-epitope immunocapture + mass spectrometry + subcellular fractionation in mouse and fly models","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, MS-based interactome without reciprocal validation of specific MED15-HTT interaction","pmids":["bio_10.1101_2024.09.07.611843"],"is_preprint":true},{"year":2024,"finding":"Med15 polyglutamine (polyQ) tract composition and length modulate activator-binding domain (ABD) activity and transcription factor interactions; the Q1 tract is required for robust Med15 activity and its length modulates transcriptional activation by Msn2 by affecting Msn2-Med15 interaction strength. Intramolecular interactions between distant glutamine tracts and Med15 phosphorylation affect KIX domain activities.","method":"Phenotypic assays + gene expression analysis + transcription factor interaction assays (yeast) + phase separation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with defined domain mutations in yeast","pmids":["39717019"],"is_preprint":false}],"current_model":"MED15 is a tail-module subunit of the Mediator co-activator complex that bridges DNA-bound transcription factors (including acidic activators Gcn4/Gal4, nuclear receptors, SREBP, Nkx6-1, NeuroD1, and Hsf1) to the RNA Pol II transcriptional machinery through a 'fuzzy' hydrophobic protein interface centered on its KIX domain and multiple activator-binding domains; it is subject to CDK1-mediated phosphorylation at T603 (controlled by TGF-β) that regulates FOXA1 binding and SASP gene expression, undergoes TRIM11-mediated ubiquitin-proteasome degradation, forms phase-separated nuclear condensates via its glutamine-rich IDR and hydrophobic motif, and plays conserved roles in regulating fatty acid metabolism, stress responses, TGF-β/SMAD3 signaling, and β-cell maturation."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that MED15 protein levels are actively regulated: TRIM11 was shown to promote ubiquitin-proteasome-dependent degradation of MED15, providing the first evidence that MED15 abundance is post-translationally controlled and linking this to attenuation of TGF-β-induced transcription.","evidence":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, and reporter assays in mammalian cells","pmids":["16904669"],"confidence":"Medium","gaps":["Reciprocal co-IP and endogenous interaction not shown","Physiological contexts triggering TRIM11-mediated MED15 turnover undefined","Ubiquitination sites on MED15 not mapped"]},{"year":2008,"claim":"Identifying the KIX domain as a conserved activator-docking site: the KIX domain of yeast Gal11/MED15 was shown to be required for fatty acid-dependent transcriptional activation by the PPAR-α analog Oaf1p, establishing MED15 as a key coactivator for ligand-dependent metabolic transcription factors.","evidence":"NMR spectroscopy of Oaf1p AD–KIX interaction, genetic deletion mutants, and transcriptional reporter assays in yeast","pmids":["19056732"],"confidence":"High","gaps":["Mammalian PPAR–MED15 KIX interaction not directly tested","Structural details of KIX-Oaf1p interface not fully resolved"]},{"year":2009,"claim":"Revealing that MED15 uses multiple binding surfaces for activator recruitment: three distinct N-terminal segments (KIX, B-box, and a third region) of Med15 additively contribute to Gcn4-mediated Mediator recruitment in vivo, showing that activator engagement is not limited to a single domain.","evidence":"ChIP, NMR chemical shift perturbation, mutagenesis, and in vitro binding assays in yeast","pmids":["19940160"],"confidence":"High","gaps":["Relative quantitative contribution of each ABD in different promoter contexts unknown","Whether mammalian MED15 retains all three binding surfaces not tested"]},{"year":2010,"claim":"Extending MED15 function to metazoan developmental signaling: Drosophila Med15 was shown to be required for Dpp (TGF-β/BMP) target gene expression during wing development, establishing an in vivo developmental role.","evidence":"Genetic mosaic screen and loss-of-function clonal analysis in Drosophila wing disc","pmids":["20233856"],"confidence":"Medium","gaps":["Direct physical interaction between Med15 and Dpp pathway effectors (Mad/Medea) not shown","Mechanism of Med15 recruitment to Dpp target promoters unclear"]},{"year":2011,"claim":"Defining the structural basis of 'fuzzy' activator binding: NMR revealed that Gcn4's acidic activation domain binds Med15 ABD1 through a dynamic hydrophobic interface with no single fixed conformation, establishing the paradigm that activation domains engage Mediator through a conformational cloud rather than a lock-and-key fit.","evidence":"NMR structure of Gcn4 AD–ABD1 complex, mutagenesis, and yeast functional assays","pmids":["22195967"],"confidence":"High","gaps":["Whether fuzzy binding applies to all Med15 activator partners unknown","Energetic contribution of individual hydrophobic contacts not fully dissected"]},{"year":2013,"claim":"Demonstrating cooperative Mediator recruitment during stress: Med15 and Med16 were shown to cooperatively recruit Mediator to heat shock promoters through Hsf1's dual activation domains, with double deletion abolishing both Mediator and Pol II occupancy, revealing tail-module subunit cooperativity in stress-responsive transcription.","evidence":"ChIP with single and double deletion mutants, Mediator and Pol II occupancy measurements in yeast","pmids":["23447536"],"confidence":"High","gaps":["Structural basis of Hsf1–Med15 vs. Hsf1–Med16 interaction not resolved","Post-translational modifications of Med15 during heat shock not examined"]},{"year":2013,"claim":"Connecting MED15 to cell cycle control: yeast Med15 inactivation caused G1 arrest and downregulation of Ace2-dependent genes, and synthetic lethality of med15 with med5 or med16 indicated essential tail-module functions beyond simple activator bridging.","evidence":"N-Degron temperature-sensitive mutants, genome-wide expression profiling, and cell cycle analysis in yeast","pmids":["23991176"],"confidence":"Medium","gaps":["Direct Ace2–Med15 physical interaction not demonstrated","Whether G1 arrest is a direct or indirect consequence of Med15 loss unclear"]},{"year":2013,"claim":"Implicating MED15 in TGF-β/SMAD signaling and cancer proliferation: MED15 knockdown in prostate cancer cells reduced p-SMAD3 nuclear shuttling and TGF-β-enhanced proliferation, positioning MED15 as a functional node in oncogenic TGF-β signaling.","evidence":"siRNA/shRNA knockdown, proliferation assays, p-SMAD3 immunostaining, and nuclear fractionation in prostate cancer cells","pmids":["24374838"],"confidence":"Medium","gaps":["Direct MED15–SMAD3 physical interaction not shown","Whether MED15 acts on SMAD3 phosphorylation or nuclear import specifically not resolved"]},{"year":2014,"claim":"Broadening MED15's role to innate immunity and xenobiotic defense: C. elegans MDT-15 was required for p38/PMK-1-dependent immune gene induction and xenobiotic detoxification, linking MED15's metabolic coactivator function to pathogen defense.","evidence":"RNAi knockdown, qRT-PCR, and Pseudomonas aeruginosa infection survival assays in C. elegans","pmids":["24875643"],"confidence":"Medium","gaps":["Direct MDT-15–PMK-1 interaction not established","Mammalian relevance of this immune role not tested"]},{"year":2014,"claim":"Validating MED15 as a human coactivator at endogenous promoters: MED15 knockdown in HeLa cells reduced VP16- and SREBP1a-mediated transcription, and ChIP placed MED15 at the p21 promoter alongside TFIIE and TFIIH, confirming its coactivator function in human cells.","evidence":"siRNA knockdown with rescue, immunostaining, and ChIP in HeLa cells","pmids":["25382556"],"confidence":"Medium","gaps":["Whether MED15 directly contacts TFIIE/TFIIH or is in the same promoter complex indirectly not distinguished","Genome-wide target repertoire in human cells not defined"]},{"year":2019,"claim":"Revealing a conserved metal stress response function: MDT-15/MED15 physically interacted with nuclear hormone receptor HIZR-1 to drive zinc/cadmium-responsive gene expression in C. elegans, and human MED15 was required for metallothionein gene induction in cadmium-exposed lung cancer cells, establishing cross-species conservation.","evidence":"Yeast two-hybrid, qRT-PCR, reporter assays, ChIP in mammalian cells, and C. elegans loss-of-function mutants","pmids":["31815936"],"confidence":"High","gaps":["Whether MED15 KIX domain mediates HIZR-1 binding not tested","Mammalian nuclear receptor partner for metal response not identified"]},{"year":2021,"claim":"Generalizing the fuzzy binding paradigm: NMR showed that Gal4 and Gcn4 activation domains, despite unrelated sequences, engage Med15 through nearly identical hydrophobic-cloud mechanisms, establishing sequence-independent activator recognition as a fundamental Mediator property.","evidence":"Comparative NMR chemical shift perturbation of Gal4 AD and Gcn4 AD binding to Med15","pmids":["33850123"],"confidence":"High","gaps":["Whether mammalian activators use the same fuzzy mechanism with human MED15 not directly shown","Thermodynamic parameters of fuzzy vs. structured binding not compared"]},{"year":2021,"claim":"Discovering MED15 phase separation capacity: the glutamine-rich IDR and a downstream hydrophobic motif of MED15 drive formation of liquid-like nuclear condensates with rapid FRAP recovery, sensitive to hexanediol and DYRK3 kinase, introducing a biophysical dimension to MED15 coactivator function.","evidence":"Live cell imaging, FRAP, 1,6-hexanediol treatment, optodroplet assay, and DYRK3 overexpression in mammalian cells","pmids":["34789250"],"confidence":"Medium","gaps":["Whether MED15 condensates contain active transcription machinery not shown","In vivo transcriptional relevance of condensate formation not demonstrated"]},{"year":2021,"claim":"Identifying prion-like aggregation potential: the MED15 prion-like domain forms amyloid-like aggregates via a coiled-coil-to-β-sheet transition that can sequester endogenous MED15, suggesting a pathological aggregation risk.","evidence":"Biochemical aggregation assays, coiled-coil disruption mutagenesis, and cell imaging in human cells","pmids":["33772081"],"confidence":"Medium","gaps":["Physiological or disease relevance of PrLD aggregation not established","Whether aggregation occurs at endogenous expression levels unknown"]},{"year":2024,"claim":"Establishing MED15 as a direct coactivator of SREBP-dependent lipogenesis in cancer: MED15 physically interacted with SREBP1/2 and promoted lipid biosynthesis gene expression in renal cell carcinoma, with HIF-2α transcriptionally activating MED15 expression, placing MED15 in a HIF-2α→MED15→SREBP lipogenic axis.","evidence":"Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression, and reporter assays in renal cancer cells","pmids":["38649345"],"confidence":"Medium","gaps":["Which MED15 domain mediates SREBP binding not mapped","Whether MED15–SREBP interaction is direct or Mediator-complex-mediated not distinguished"]},{"year":2024,"claim":"Defining a β-cell maturation role: Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 and occupies their target loci; conditional knockout in mouse β-cells impairs maturation without affecting mass or insulin expression, and MED15 overexpression in human ESC-derived β-like cells enhances maturation markers.","evidence":"ChIP-seq, co-immunoprecipitation, conditional knockout mouse, and human ESC overexpression model","pmids":["39379383"],"confidence":"High","gaps":["Which MED15 domain engages Nkx6-1 and NeuroD1 not mapped","Whether MED15 condensate formation is relevant to β-cell maturation unknown"]},{"year":2024,"claim":"Revealing intrinsic chromatin-targeting ability: Med15 shows inherent preference for 'fuzzy-nucleosome' promoter architecture independent of promoter-bound transcription factors, suggesting Med15 actively contributes to Mediator target site selection rather than passively following activators.","evidence":"ChIP-seq with DBD-Med15 fusion proteins and transcriptional assays in budding yeast","pmids":["39187372"],"confidence":"Medium","gaps":["Molecular basis of fuzzy-nucleosome recognition by Med15 not determined","Whether mammalian MED15 shows similar chromatin preferences untested"]},{"year":2024,"claim":"Uncovering polyQ tract modulation of coactivator function: Med15 polyglutamine tract composition and length modulate ABD activity and transcription factor interaction strength, with the Q1 tract required for robust Msn2-Med15 interaction and phosphorylation affecting KIX domain activities.","evidence":"Phenotypic assays, gene expression analysis, and transcription factor interaction assays with defined polyQ mutants in yeast","pmids":["39717019"],"confidence":"Medium","gaps":["Kinase(s) responsible for Med15 phosphorylation affecting KIX not identified in this context","Whether polyQ length variation in human MED15 has functional consequences unknown"]},{"year":2024,"claim":"Connecting MED15 to nuclear actin-dependent heat shock gene regulation: Drosophila Moesin directly binds Med15 and, together with Hsf and monomeric actin, forms a nuclear complex at Hsp gene regulatory regions; this interaction is conserved in human orthologs.","evidence":"Reciprocal co-immunoprecipitation, ChIP, RNAi knockdown, and direct binding assays in Drosophila and human cells","pmids":["39353569"],"confidence":"Medium","gaps":["Which Med15 domain binds Moesin not mapped","Functional significance of actin in this complex not mechanistically resolved"]},{"year":2025,"claim":"Decoding a phospho-switch controlling senescence: TGF-β-induced CDK1-mediated phosphorylation of MED15 at T603 disrupts FOXA1 binding, releasing repression of SASP genes; a T603A knock-in in aging mice attenuates SASP and improves cognition, establishing a direct post-translational mechanism linking MED15 to aging.","evidence":"Phospho-mutagenesis (T603A/T603D), co-immunoprecipitation, in vivo knock-in mouse model, behavioral assays, and gene expression analysis","pmids":["40825935"],"confidence":"High","gaps":["Whether T603 phosphorylation affects MED15 condensate formation unknown","How CDK1 specificity for MED15 is achieved in the TGF-β context not resolved"]},{"year":2025,"claim":"Revealing a non-transcriptional role in YAP1 stabilization: MED15 interacts with YAP1 and attenuates TRIM11-mediated YAP1 ubiquitination, promoting EMT; under stress, MED15 forms condensates with increased YAP1 colocalization, suggesting a phase-separation-dependent protein stabilization function.","evidence":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, migration assays, and condensate imaging in bladder cancer cells","pmids":["41685983"],"confidence":"Medium","gaps":["Whether MED15–YAP1 interaction is direct or bridged by other factors not resolved","Transcription-dependent vs. -independent contributions to EMT not separated"]},{"year":null,"claim":"Key unresolved questions include: how MED15 condensate formation relates to transcriptional activation at specific loci; whether fuzzy activator binding operates through the same ABD surfaces in mammals; how polyQ tract variation in human MED15 affects disease susceptibility; and the structural basis of MED15 engagement with metazoan-specific partners such as SMADs, SREBPs, and Nkx6-1.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted transcription assay linking MED15 condensates to transcriptional output","No high-resolution structure of mammalian MED15 with any activator","Disease-causative mutations in human MED15 not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,3,4,8,14,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,10,15]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,12,17]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[12,18]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2,3,4,8,15,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,13,18]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,7,14]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,10,18]}],"complexes":["Mediator complex (tail module)"],"partners":["TRIM11","SREBP1","SREBP2","FOXA1","NKX6-1","NEUROD1","YAP1","MSN"],"other_free_text":[]},"mechanistic_narrative":"MED15 is a tail-module subunit of the Mediator co-activator complex that serves as a critical interface between DNA-bound transcription factors and the RNA Pol II machinery, with conserved roles in lipid metabolism, stress responses, innate immunity, and developmental gene regulation. Its N-terminal KIX domain and additional activator-binding domains (ABDs) engage intrinsically disordered acidic activation domains of diverse transcription factors—including Gcn4, Gal4, Oaf1, Hsf1, SREBP1/2, Nkx6-1, and NeuroD1—through a sequence-independent 'fuzzy' hydrophobic binding mechanism, as demonstrated by NMR structural studies and functional mutagenesis [PMID:22195967, PMID:33850123, PMID:19056732, PMID:39379383]. MED15 undergoes CDK1-mediated phosphorylation at T603 downstream of TGF-β, which disrupts FOXA1 binding and de-represses senescence-associated secretory phenotype (SASP) genes; a non-phosphorylatable T603A knock-in in aging mice attenuates SASP and improves cognition [PMID:40825935]. MED15 also forms phase-separated nuclear condensates via its glutamine-rich intrinsically disordered region and hydrophobic motif, and its polyglutamine tract composition modulates activator interaction strength and transcriptional output [PMID:34789250, PMID:39717019]."},"prefetch_data":{"uniprot":{"accession":"Q96RN5","full_name":"Mediator of RNA polymerase II transcription subunit 15","aliases":["Activator-recruited cofactor 105 kDa component","ARC105","CTG repeat protein 7a","Mediator complex subunit 15","Positive cofactor 2 glutamine/Q-rich-associated protein","PC2 glutamine/Q-rich-associated protein","TPA-inducible gene 1 protein","TIG-1","Trinucleotide repeat-containing gene 7 protein"],"length_aa":788,"mass_kda":86.8,"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. Required for cholesterol-dependent gene regulation. 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Gcn4 binds the Mediator subunit Gal11/Med15 activator-binding domain 1 (ABD1) through a 'fuzzy' protein interface: ABD1 has a four-helix fold with a shallow hydrophobic cleft, and eight residues of Gcn4 adopt a helical conformation allowing three aromatic/aliphatic residues to insert into the cleft via hydrophobic interactions only, with no single fixed conformation (fuzzy complex). Functional mutagenesis in yeast confirmed the importance of interface residues for transcriptional activation.\",\n      \"method\": \"NMR structure determination of bound complex + mutagenesis + yeast functional assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural analysis with mutagenesis and functional validation in vivo\",\n      \"pmids\": [\"22195967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The yeast Mediator subunit Gal11p/MED15 and its KIX domain is required for fatty acid-dependent transcriptional activation by the yeast PPAR-alpha analog Oaf1p. NMR spectroscopy showed that the Oaf1p activation domain interacts with the Gal11p/MED15 KIX domain in a manner similar to the zinc cluster family member Pdr1p, identifying the KIX domain as a key target of ligand-dependent transcription factors.\",\n      \"method\": \"NMR spectroscopy + genetic loss-of-function (deletion mutants) + transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural data combined with genetic and transcriptional functional validation\",\n      \"pmids\": [\"19056732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Gcn4 recruits Mediator to target promoters in vivo through additive contributions from three distinct N-terminal segments of Gal11/Med15: the KIX domain, a B-box region (conserved with mammalian SRC-1), and a third segment. NMR chemical shift analysis identified the Gcn4 binding site on the KIX domain surface, and mutational studies showed B-box is a critical determinant of Mediator recruitment.\",\n      \"method\": \"In vitro binding assays + ChIP (chromatin immunoprecipitation) + NMR chemical shift perturbation + mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including NMR, in vitro binding, and in vivo ChIP with mutagenesis\",\n      \"pmids\": [\"19940160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Med15 and Med16 are two Mediator tail subunits required for heat shock factor 1 (Hsf1)-dependent recruitment of Mediator to HSP gene promoters upon heat stress. Dual activation domains of Hsf1 cooperatively recruit holo-Mediator through the Tail module; loss of Med15 or Med16 individually reduces Mediator occupancy while loss of both abolishes it and substantially diminishes RNA Pol II recruitment.\",\n      \"method\": \"ChIP (chromatin immunoprecipitation) + genetic deletion mutants + Mediator/Pol II recruitment assays in yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal ChIP epistasis with double mutants, multiple subunit validations\",\n      \"pmids\": [\"23447536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The acidic activation domains of both Gal4 and Gcn4, which are intrinsically disordered and of different sequence, interact with Med15 using nearly identical 'fuzzy' binding mechanisms as shown by NMR chemical shift perturbation analysis. This reveals a common sequence-independent mechanism for activation domain–Mediator binding through a hydrophobic cloud, distinct from the structured complex formed by Gal4 AD with its repressor Gal80.\",\n      \"method\": \"NMR chemical shift perturbation analysis of Gal4 AD and Gcn4 AD binding to Med15\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR with comparative structural analysis and functional context\",\n      \"pmids\": [\"33850123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRIM11 physically interacts with MED15 (ARC105) and promotes its ubiquitin-proteasome-dependent degradation. Co-expression of TRIM11 increases ARC105 ubiquitination and degradation (blocked by proteasome inhibitor), and suppresses ARC105-mediated TGF-beta-induced transcriptional activation in reporter assays.\",\n      \"method\": \"Co-immunoprecipitation + ubiquitination assay + proteasome inhibitor treatment + transcriptional reporter assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional ubiquitination and reporter assays in single study\",\n      \"pmids\": [\"16904669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Inactivation of Med15 in yeast leads to down-regulation of Ace2 transcriptional activator target genes and a G1 cell cycle arrest phenotype. Synthetic lethality of med5/med15 and med15/med16 double mutations indicates that the Mediator Tail performs essential functions even as a separate complex.\",\n      \"method\": \"N-Degron temperature-sensitive mutants + genome-wide expression profiling + cell cycle analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — inducible loss-of-function with defined transcriptional and cell cycle phenotype\",\n      \"pmids\": [\"23991176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The C. elegans MDT-15/MED15 ortholog is required for xenobiotic-induced expression of p38 MAP kinase (PMK-1)-dependent immune effector genes and detoxification genes, linking xenobiotic detoxification to innate immunity; RNAi knockdown of mdt-15 abrogates induction of PMK-1-dependent immune genes and increases susceptibility to Pseudomonas aeruginosa infection.\",\n      \"method\": \"RNAi screen + qRT-PCR + infection survival assays in C. elegans\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined immune and detoxification phenotype in C. elegans ortholog\",\n      \"pmids\": [\"24875643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human MED15 promotes transcriptional activation by VP16 and SREBP1a in HeLa cells, as shown by siRNA knockdown (reducible by overexpression rescue). MED15 colocalizes with general transcription factors TFIIE and TFIIH in the nucleus, and ChIP shows MED15 localizes to both the p53 binding site and the p21 promoter region along with TFIIE and TFIIH upon Nutlin-3 treatment.\",\n      \"method\": \"siRNA knockdown + overexpression rescue + immunostaining colocalization + ChIP\",\n      \"journal\": \"Drug discoveries & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (knockdown, rescue, ChIP) in human cells\",\n      \"pmids\": [\"25382556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MED15 knockdown in prostate cancer cells reduces phosphorylation and nuclear shuttling of p-SMAD3 and attenuates TGF-beta-enhanced proliferation, indicating MED15 is required for TGF-beta/SMAD3 signaling. MED15 knockdown also decreases both androgen-dependent and -independent proliferation.\",\n      \"method\": \"siRNA/shRNA knockdown + proliferation assays + p-SMAD3 immunostaining + nuclear fractionation\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined signaling and proliferation phenotype\",\n      \"pmids\": [\"24374838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C. elegans MDT-15 physically interacts with nuclear hormone receptor HIZR-1 to promote zinc and cadmium stress-responsive gene expression; this interaction is enhanced by zinc or cadmium. mdt-15 and hizr-1 cooperate to regulate zinc storage in the gut and protect against zinc/cadmium toxicity. Mammalian MED15 orthologs bind genomic regulatory regions of metallothionein and zinc transporter genes in a cadmium/zinc-stimulated manner, and human MED15 is required for metallothionein gene induction in lung adenocarcinoma cells exposed to cadmium.\",\n      \"method\": \"Yeast two-hybrid + qRT-PCR + reporter assays + ChIP (mammalian cells) + loss-of-function mutants in C. elegans\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across organisms, yeast-2-hybrid interaction, ChIP, genetic epistasis\",\n      \"pmids\": [\"31815936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The human MED15 prion-like domain (PrLD) forms homodimers sustained by coiled-coil (CC) interactions, and this CC fold mediates transition to a beta-sheet amyloid state; disruption of the CC abolishes aggregation. Expression of MED15-PrLD in human cells promotes cytoplasmic and perinuclear inclusions that sequester endogenous full-length MED15 in a prion-like manner.\",\n      \"method\": \"Biochemical aggregation assays + mutagenesis (CC disruption) + cell imaging + bioinformatics of PrLD\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical and cell-based evidence with mutagenesis in single study\",\n      \"pmids\": [\"33772081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Med15 forms nuclear condensates (foci) in mammalian cells through its glutamine-rich intrinsically disordered region (IDR) and a short downstream hydrophobic motif. Med15 foci are sensitive to 1,6-hexanediol, show rapid FRAP recovery consistent with phase separation, and are disrupted by overexpression of DYRK3 kinase. Both the IDR and C-terminal region contribute to intracellular phase separation as shown by optodroplet assay.\",\n      \"method\": \"Live cell imaging + FRAP + 1,6-hexanediol treatment + optodroplet assay + DYRK3 overexpression\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple live imaging and phase separation assays with functional perturbation\",\n      \"pmids\": [\"34789250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Drosophila Med15, a component of the Mediator complex, is required for transcription of decapentaplegic (Dpp) target genes during wing development; loss-of-function clones show defective wing patterning and reduced Dpp target gene expression.\",\n      \"method\": \"Genetic mosaic screen + loss-of-function clonal analysis in Drosophila wing\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined developmental and transcriptional phenotype in Drosophila ortholog\",\n      \"pmids\": [\"20233856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MED15 acts as a coactivator of SREBP transcription factors by directly interacting with SREBP1 and SREBP2, promoting SREBP-dependent lipid biosynthesis enzyme expression. MED15 also promotes SREBP1 and SREBP2 activation through the PLK1/AKT axis in clear cell renal cell carcinoma. HIF-2α transcriptionally activates MED15 by directly binding its promoter region.\",\n      \"method\": \"Co-immunoprecipitation + ChIP + siRNA knockdown + overexpression assays + reporter assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP interaction plus ChIP and functional assays in single study\",\n      \"pmids\": [\"38649345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mouse Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 as shown by co-immunoprecipitation and ChIP-seq; knockout of Med15 in mouse β-cells causes defects in β-cell maturation without affecting β-cell mass or insulin expression. Human embryonic stem cell-derived β-like cells engineered to overexpress MED15 show increased maturation markers.\",\n      \"method\": \"ChIP-seq + co-immunoprecipitation + conditional knockout mouse + human ESC overexpression model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP-seq, co-IP, and in vivo conditional KO with defined maturation phenotype\",\n      \"pmids\": [\"39379383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Med15 can select genomic target sites independent of promoter-bound transcription factors; it shows inherent preference for 'fuzzy-nucleosome' promoter architecture. Direct DBD-Med15 fusions shift localization toward fuzzy-nucleosome promoters including sites lacking endogenous Mediator, suggesting Med15 actively contributes to target site selection.\",\n      \"method\": \"ChIP-seq in budding yeast with DBD-AD fusion proteins + direct DBD-Med15 fusions + transcriptional assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genomic localization data with multiple genetic constructs\",\n      \"pmids\": [\"39187372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Drosophila Moesin directly binds the Med15 subunit of the Mediator complex in the nucleus. Both Moesin and Med15 bind heat shock factor (Hsf), and Moesin's presence at regulatory regions of the Hsp70Ab heat shock gene is Med15-dependent. Moesin, Med15, Hsf, and monomeric actin form a nuclear complex required for proper Hsp gene expression. The direct interaction between human orthologs of Drosophila Moesin and Med15 was confirmed.\",\n      \"method\": \"Co-immunoprecipitation + ChIP + RNAi knockdown + direct binding assays (Drosophila and human orthologs)\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and ChIP with functional gene expression readout, confirmed in human orthologs\",\n      \"pmids\": [\"39353569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGF-β selectively induces CDK1-mediated phosphorylation of MED15 at T603, which controls SASP gene expression and cellular senescence. Unphosphorylated MED15 is bound by forkhead box protein A1 (FOXA1) to suppress SASP gene expression; phosphorylation at T603 prevents FOXA1 binding, releasing SASP gene repression. Knock-in of the dephosphorylated T603A mutant in aging mice attenuates SASP and improves cognitive function.\",\n      \"method\": \"Phospho-mutagenesis (T603A/T603D) + co-immunoprecipitation + in vivo knock-in mouse model + behavioral assays + gene expression analysis\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of phosphosite with identified kinase (CDK1) and reader (FOXA1), validated in vivo\",\n      \"pmids\": [\"40825935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MED15 interacts with YAP1 and stabilizes it by attenuating TRIM11-mediated ubiquitination of YAP1, promoting EMT and cell migration in bladder cancer. Under sorbitol-induced stress, MED15 forms stress-inducible protein condensates with increased colocalization with YAP1.\",\n      \"method\": \"Co-immunoprecipitation + ubiquitination assay + siRNA knockdown + migration assays + condensate imaging\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP interaction, ubiquitination assay, and functional assays in single study\",\n      \"pmids\": [\"41685983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDT-15/MED15 (C. elegans ortholog) and downstream fatty acid desaturases FAT-6 and FAT-7 are required for activation of the ESRE mitochondrial surveillance pathway; supplementation with polyunsaturated fatty acids downstream of FAT-6/FAT-7 rescues ESRE activation in mdt-15 knockdowns. Box C/D snoRNPs are required for upregulation of fatty acid metabolism under ESRE-activating conditions and act upstream of MDT-15 in this pathway.\",\n      \"method\": \"RNAi knockdown + ESRE reporter assays + fatty acid supplementation rescue + infection survival assays in C. elegans\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single-lab RNAi-based epistasis without biochemical interaction confirmation\",\n      \"pmids\": [\"40501983\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATXN1 amino acids 99-163 and MED15 amino acids 548-665 are critical for the ATXN1-MED15 protein-protein interaction, and MED15 significantly enhances aggregation of polyQ-expanded ATXN1. A small molecule inhibitor of this interaction (Chembridge ID: 5755483) inhibits both the ATXN1-MED15 interaction and dimerization of polyQ-expanded ATXN1.\",\n      \"method\": \"Computational structure prediction + experimental domain mapping + small molecule inhibitor assay + aggregation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint with partial domain mapping; interaction validated experimentally but structural confirmation pending\",\n      \"pmids\": [\"bio_10.1101_2025.03.17.643445\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MED15 is specifically enriched (relative to other Mediator subunits) in the HTT interactome in the tail domain of Mediator; HTT modulates the subcellular localization and assembly of the Mediator complex as shown in HD and KO models.\",\n      \"method\": \"Multi-epitope immunocapture + mass spectrometry + subcellular fractionation in mouse and fly models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, MS-based interactome without reciprocal validation of specific MED15-HTT interaction\",\n      \"pmids\": [\"bio_10.1101_2024.09.07.611843\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Med15 polyglutamine (polyQ) tract composition and length modulate activator-binding domain (ABD) activity and transcription factor interactions; the Q1 tract is required for robust Med15 activity and its length modulates transcriptional activation by Msn2 by affecting Msn2-Med15 interaction strength. Intramolecular interactions between distant glutamine tracts and Med15 phosphorylation affect KIX domain activities.\",\n      \"method\": \"Phenotypic assays + gene expression analysis + transcription factor interaction assays (yeast) + phase separation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with defined domain mutations in yeast\",\n      \"pmids\": [\"39717019\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED15 is a tail-module subunit of the Mediator co-activator complex that bridges DNA-bound transcription factors (including acidic activators Gcn4/Gal4, nuclear receptors, SREBP, Nkx6-1, NeuroD1, and Hsf1) to the RNA Pol II transcriptional machinery through a 'fuzzy' hydrophobic protein interface centered on its KIX domain and multiple activator-binding domains; it is subject to CDK1-mediated phosphorylation at T603 (controlled by TGF-β) that regulates FOXA1 binding and SASP gene expression, undergoes TRIM11-mediated ubiquitin-proteasome degradation, forms phase-separated nuclear condensates via its glutamine-rich IDR and hydrophobic motif, and plays conserved roles in regulating fatty acid metabolism, stress responses, TGF-β/SMAD3 signaling, and β-cell maturation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MED15 is a tail-module subunit of the Mediator co-activator complex that serves as a critical interface between DNA-bound transcription factors and the RNA Pol II machinery, with conserved roles in lipid metabolism, stress responses, innate immunity, and developmental gene regulation. Its N-terminal KIX domain and additional activator-binding domains (ABDs) engage intrinsically disordered acidic activation domains of diverse transcription factors—including Gcn4, Gal4, Oaf1, Hsf1, SREBP1/2, Nkx6-1, and NeuroD1—through a sequence-independent 'fuzzy' hydrophobic binding mechanism, as demonstrated by NMR structural studies and functional mutagenesis [PMID:22195967, PMID:33850123, PMID:19056732, PMID:39379383]. MED15 undergoes CDK1-mediated phosphorylation at T603 downstream of TGF-β, which disrupts FOXA1 binding and de-represses senescence-associated secretory phenotype (SASP) genes; a non-phosphorylatable T603A knock-in in aging mice attenuates SASP and improves cognition [PMID:40825935]. MED15 also forms phase-separated nuclear condensates via its glutamine-rich intrinsically disordered region and hydrophobic motif, and its polyglutamine tract composition modulates activator interaction strength and transcriptional output [PMID:34789250, PMID:39717019].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that MED15 protein levels are actively regulated: TRIM11 was shown to promote ubiquitin-proteasome-dependent degradation of MED15, providing the first evidence that MED15 abundance is post-translationally controlled and linking this to attenuation of TGF-β-induced transcription.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, and reporter assays in mammalian cells\",\n      \"pmids\": [\"16904669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal co-IP and endogenous interaction not shown\", \"Physiological contexts triggering TRIM11-mediated MED15 turnover undefined\", \"Ubiquitination sites on MED15 not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying the KIX domain as a conserved activator-docking site: the KIX domain of yeast Gal11/MED15 was shown to be required for fatty acid-dependent transcriptional activation by the PPAR-α analog Oaf1p, establishing MED15 as a key coactivator for ligand-dependent metabolic transcription factors.\",\n      \"evidence\": \"NMR spectroscopy of Oaf1p AD–KIX interaction, genetic deletion mutants, and transcriptional reporter assays in yeast\",\n      \"pmids\": [\"19056732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian PPAR–MED15 KIX interaction not directly tested\", \"Structural details of KIX-Oaf1p interface not fully resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealing that MED15 uses multiple binding surfaces for activator recruitment: three distinct N-terminal segments (KIX, B-box, and a third region) of Med15 additively contribute to Gcn4-mediated Mediator recruitment in vivo, showing that activator engagement is not limited to a single domain.\",\n      \"evidence\": \"ChIP, NMR chemical shift perturbation, mutagenesis, and in vitro binding assays in yeast\",\n      \"pmids\": [\"19940160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative quantitative contribution of each ABD in different promoter contexts unknown\", \"Whether mammalian MED15 retains all three binding surfaces not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extending MED15 function to metazoan developmental signaling: Drosophila Med15 was shown to be required for Dpp (TGF-β/BMP) target gene expression during wing development, establishing an in vivo developmental role.\",\n      \"evidence\": \"Genetic mosaic screen and loss-of-function clonal analysis in Drosophila wing disc\",\n      \"pmids\": [\"20233856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between Med15 and Dpp pathway effectors (Mad/Medea) not shown\", \"Mechanism of Med15 recruitment to Dpp target promoters unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining the structural basis of 'fuzzy' activator binding: NMR revealed that Gcn4's acidic activation domain binds Med15 ABD1 through a dynamic hydrophobic interface with no single fixed conformation, establishing the paradigm that activation domains engage Mediator through a conformational cloud rather than a lock-and-key fit.\",\n      \"evidence\": \"NMR structure of Gcn4 AD–ABD1 complex, mutagenesis, and yeast functional assays\",\n      \"pmids\": [\"22195967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether fuzzy binding applies to all Med15 activator partners unknown\", \"Energetic contribution of individual hydrophobic contacts not fully dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating cooperative Mediator recruitment during stress: Med15 and Med16 were shown to cooperatively recruit Mediator to heat shock promoters through Hsf1's dual activation domains, with double deletion abolishing both Mediator and Pol II occupancy, revealing tail-module subunit cooperativity in stress-responsive transcription.\",\n      \"evidence\": \"ChIP with single and double deletion mutants, Mediator and Pol II occupancy measurements in yeast\",\n      \"pmids\": [\"23447536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Hsf1–Med15 vs. Hsf1–Med16 interaction not resolved\", \"Post-translational modifications of Med15 during heat shock not examined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connecting MED15 to cell cycle control: yeast Med15 inactivation caused G1 arrest and downregulation of Ace2-dependent genes, and synthetic lethality of med15 with med5 or med16 indicated essential tail-module functions beyond simple activator bridging.\",\n      \"evidence\": \"N-Degron temperature-sensitive mutants, genome-wide expression profiling, and cell cycle analysis in yeast\",\n      \"pmids\": [\"23991176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Ace2–Med15 physical interaction not demonstrated\", \"Whether G1 arrest is a direct or indirect consequence of Med15 loss unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Implicating MED15 in TGF-β/SMAD signaling and cancer proliferation: MED15 knockdown in prostate cancer cells reduced p-SMAD3 nuclear shuttling and TGF-β-enhanced proliferation, positioning MED15 as a functional node in oncogenic TGF-β signaling.\",\n      \"evidence\": \"siRNA/shRNA knockdown, proliferation assays, p-SMAD3 immunostaining, and nuclear fractionation in prostate cancer cells\",\n      \"pmids\": [\"24374838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MED15–SMAD3 physical interaction not shown\", \"Whether MED15 acts on SMAD3 phosphorylation or nuclear import specifically not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadening MED15's role to innate immunity and xenobiotic defense: C. elegans MDT-15 was required for p38/PMK-1-dependent immune gene induction and xenobiotic detoxification, linking MED15's metabolic coactivator function to pathogen defense.\",\n      \"evidence\": \"RNAi knockdown, qRT-PCR, and Pseudomonas aeruginosa infection survival assays in C. elegans\",\n      \"pmids\": [\"24875643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MDT-15–PMK-1 interaction not established\", \"Mammalian relevance of this immune role not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Validating MED15 as a human coactivator at endogenous promoters: MED15 knockdown in HeLa cells reduced VP16- and SREBP1a-mediated transcription, and ChIP placed MED15 at the p21 promoter alongside TFIIE and TFIIH, confirming its coactivator function in human cells.\",\n      \"evidence\": \"siRNA knockdown with rescue, immunostaining, and ChIP in HeLa cells\",\n      \"pmids\": [\"25382556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED15 directly contacts TFIIE/TFIIH or is in the same promoter complex indirectly not distinguished\", \"Genome-wide target repertoire in human cells not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealing a conserved metal stress response function: MDT-15/MED15 physically interacted with nuclear hormone receptor HIZR-1 to drive zinc/cadmium-responsive gene expression in C. elegans, and human MED15 was required for metallothionein gene induction in cadmium-exposed lung cancer cells, establishing cross-species conservation.\",\n      \"evidence\": \"Yeast two-hybrid, qRT-PCR, reporter assays, ChIP in mammalian cells, and C. elegans loss-of-function mutants\",\n      \"pmids\": [\"31815936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MED15 KIX domain mediates HIZR-1 binding not tested\", \"Mammalian nuclear receptor partner for metal response not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Generalizing the fuzzy binding paradigm: NMR showed that Gal4 and Gcn4 activation domains, despite unrelated sequences, engage Med15 through nearly identical hydrophobic-cloud mechanisms, establishing sequence-independent activator recognition as a fundamental Mediator property.\",\n      \"evidence\": \"Comparative NMR chemical shift perturbation of Gal4 AD and Gcn4 AD binding to Med15\",\n      \"pmids\": [\"33850123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian activators use the same fuzzy mechanism with human MED15 not directly shown\", \"Thermodynamic parameters of fuzzy vs. structured binding not compared\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovering MED15 phase separation capacity: the glutamine-rich IDR and a downstream hydrophobic motif of MED15 drive formation of liquid-like nuclear condensates with rapid FRAP recovery, sensitive to hexanediol and DYRK3 kinase, introducing a biophysical dimension to MED15 coactivator function.\",\n      \"evidence\": \"Live cell imaging, FRAP, 1,6-hexanediol treatment, optodroplet assay, and DYRK3 overexpression in mammalian cells\",\n      \"pmids\": [\"34789250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED15 condensates contain active transcription machinery not shown\", \"In vivo transcriptional relevance of condensate formation not demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying prion-like aggregation potential: the MED15 prion-like domain forms amyloid-like aggregates via a coiled-coil-to-β-sheet transition that can sequester endogenous MED15, suggesting a pathological aggregation risk.\",\n      \"evidence\": \"Biochemical aggregation assays, coiled-coil disruption mutagenesis, and cell imaging in human cells\",\n      \"pmids\": [\"33772081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological or disease relevance of PrLD aggregation not established\", \"Whether aggregation occurs at endogenous expression levels unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing MED15 as a direct coactivator of SREBP-dependent lipogenesis in cancer: MED15 physically interacted with SREBP1/2 and promoted lipid biosynthesis gene expression in renal cell carcinoma, with HIF-2α transcriptionally activating MED15 expression, placing MED15 in a HIF-2α→MED15→SREBP lipogenic axis.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression, and reporter assays in renal cancer cells\",\n      \"pmids\": [\"38649345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which MED15 domain mediates SREBP binding not mapped\", \"Whether MED15–SREBP interaction is direct or Mediator-complex-mediated not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining a β-cell maturation role: Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 and occupies their target loci; conditional knockout in mouse β-cells impairs maturation without affecting mass or insulin expression, and MED15 overexpression in human ESC-derived β-like cells enhances maturation markers.\",\n      \"evidence\": \"ChIP-seq, co-immunoprecipitation, conditional knockout mouse, and human ESC overexpression model\",\n      \"pmids\": [\"39379383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which MED15 domain engages Nkx6-1 and NeuroD1 not mapped\", \"Whether MED15 condensate formation is relevant to β-cell maturation unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealing intrinsic chromatin-targeting ability: Med15 shows inherent preference for 'fuzzy-nucleosome' promoter architecture independent of promoter-bound transcription factors, suggesting Med15 actively contributes to Mediator target site selection rather than passively following activators.\",\n      \"evidence\": \"ChIP-seq with DBD-Med15 fusion proteins and transcriptional assays in budding yeast\",\n      \"pmids\": [\"39187372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of fuzzy-nucleosome recognition by Med15 not determined\", \"Whether mammalian MED15 shows similar chromatin preferences untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovering polyQ tract modulation of coactivator function: Med15 polyglutamine tract composition and length modulate ABD activity and transcription factor interaction strength, with the Q1 tract required for robust Msn2-Med15 interaction and phosphorylation affecting KIX domain activities.\",\n      \"evidence\": \"Phenotypic assays, gene expression analysis, and transcription factor interaction assays with defined polyQ mutants in yeast\",\n      \"pmids\": [\"39717019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase(s) responsible for Med15 phosphorylation affecting KIX not identified in this context\", \"Whether polyQ length variation in human MED15 has functional consequences unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connecting MED15 to nuclear actin-dependent heat shock gene regulation: Drosophila Moesin directly binds Med15 and, together with Hsf and monomeric actin, forms a nuclear complex at Hsp gene regulatory regions; this interaction is conserved in human orthologs.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ChIP, RNAi knockdown, and direct binding assays in Drosophila and human cells\",\n      \"pmids\": [\"39353569\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which Med15 domain binds Moesin not mapped\", \"Functional significance of actin in this complex not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Decoding a phospho-switch controlling senescence: TGF-β-induced CDK1-mediated phosphorylation of MED15 at T603 disrupts FOXA1 binding, releasing repression of SASP genes; a T603A knock-in in aging mice attenuates SASP and improves cognition, establishing a direct post-translational mechanism linking MED15 to aging.\",\n      \"evidence\": \"Phospho-mutagenesis (T603A/T603D), co-immunoprecipitation, in vivo knock-in mouse model, behavioral assays, and gene expression analysis\",\n      \"pmids\": [\"40825935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether T603 phosphorylation affects MED15 condensate formation unknown\", \"How CDK1 specificity for MED15 is achieved in the TGF-β context not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealing a non-transcriptional role in YAP1 stabilization: MED15 interacts with YAP1 and attenuates TRIM11-mediated YAP1 ubiquitination, promoting EMT; under stress, MED15 forms condensates with increased YAP1 colocalization, suggesting a phase-separation-dependent protein stabilization function.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, migration assays, and condensate imaging in bladder cancer cells\",\n      \"pmids\": [\"41685983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED15–YAP1 interaction is direct or bridged by other factors not resolved\", \"Transcription-dependent vs. -independent contributions to EMT not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how MED15 condensate formation relates to transcriptional activation at specific loci; whether fuzzy activator binding operates through the same ABD surfaces in mammals; how polyQ tract variation in human MED15 affects disease susceptibility; and the structural basis of MED15 engagement with metazoan-specific partners such as SMADs, SREBPs, and Nkx6-1.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstituted transcription assay linking MED15 condensates to transcriptional output\", \"No high-resolution structure of mammalian MED15 with any activator\", \"Disease-causative mutations in human MED15 not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 8, 14, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 10, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 12, 17]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [12, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 8, 15, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 13, 18]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 7, 14]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 10, 18]}\n    ],\n    \"complexes\": [\n      \"Mediator complex (tail module)\"\n    ],\n    \"partners\": [\n      \"TRIM11\",\n      \"SREBP1\",\n      \"SREBP2\",\n      \"FOXA1\",\n      \"NKX6-1\",\n      \"NEUROD1\",\n      \"YAP1\",\n      \"MSN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}