{"gene":"MED9","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1999,"finding":"Yeast Med9/Cse2 is a subunit of the Rgr1 subcomplex of the Mediator complex and is specifically required for Bas1/Bas2-mediated transcriptional activation of amino acid biosynthetic genes, demonstrating an activator-specific role distinct from other Mediator subunits.","method":"Cloning of MED9/CSE2, mutant isolation, differential display and Northern analysis of mRNAs in wild-type vs. Mediator mutant yeast cells","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined transcriptional phenotype, two orthogonal methods (differential display + Northern), single lab","pmids":["9891034"],"is_preprint":false},{"year":2001,"finding":"Yeast Med9/Cse2 forms a distinct 'Med9/10 module' within the Rgr1 subcomplex of Mediator; this module is required for both transcriptional activation and repression, and proteins in the Med9 submodule interact physically and genetically with Srb10/11, implying the Med9 submodule mediates repression of RNA polymerase II.","method":"Recombinant protein expression, protein-protein interaction assays, genetic interaction analysis, in vitro transcription assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical reconstitution of module interactions and genetic epistasis, single lab with multiple methods","pmids":["11555651"],"is_preprint":false},{"year":2001,"finding":"The Med9/Cse2 module of yeast Mediator is required for transcriptional repression of a distinct group of genes, as revealed by genome-wide gene expression analysis in med9 deletion mutants; additionally, GST pull-down analysis showed that the transcriptional repressor Tup1 binds to overlapping but distinct regions of the Gal11 module, suggesting competition between activators and repressors for Mediator binding sites.","method":"Biochemical fractionation defining modular Rgr1 structure, genome-wide gene expression analysis, Northern analysis, GST pull-down assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide expression + GST pull-down + Northern in single lab, multiple orthogonal methods","pmids":["11470794"],"is_preprint":false},{"year":2003,"finding":"The mammalian protein encoded by FLJ10193 (MED9/Med25 as named in this paper) is a bona fide subunit of the mammalian Mediator complex, sharing structural and functional properties with Saccharomyces cerevisiae Mediator subunit Cse2 and identified as a potential mammalian Cse2 ortholog.","method":"Tandem mass spectrometry identification from purified rat Mediator fractions, direct biochemical co-purification evidence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical purification and mass spectrometry from native complex, single lab","pmids":["14638676"],"is_preprint":false},{"year":2003,"finding":"Artificial recruitment of Med9 (fused to the copper-inducible activator Ace1) to the CUP1 promoter did not circumvent the TFIIE requirement for transcriptional activation, in contrast to fusions with Med2 or Pgd1, indicating that Med9 does not transmit the activator signal through a TFIIE-bypass pathway.","method":"Protein fusion-based artificial recruitment to promoter, genetic assays for TFIIE requirement, chromatin immunoprecipitation","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined negative functional result using artificial recruitment and ChIP, single lab, single study; result is informative negative","pmids":["12558798"],"is_preprint":false},{"year":2004,"finding":"MED9 (referred to as Med25 in this study) was identified as a consensus subunit of the mammalian Mediator complex by MudPIT proteomic analysis of six independent immunoaffinity-purified Mediator preparations.","method":"Multidimensional protein identification technology (MudPIT) proteomics from six independent immunoaffinity-purified mammalian Mediator complexes","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — six independent Mediator preparations from different subunit immunopurifications, replicated across multiple preparations in same study","pmids":["15175163"],"is_preprint":false},{"year":2013,"finding":"A 3D structural model of the yeast Mediator middle module places Med9 as part of a central tetramer, forming a heterodimer with Med4; this Med4/Med9 heterodimer pairs with the Med7/Med21 heterodimer to form the core of the middle module, which is flanked by Med10 and Med31.","method":"Protein cross-linking coupled with mass spectrometric analysis of lysine-lysine cross-links, combined with crystal structures and homology models to build a 3D middle module model","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structural model from cross-linking mass spectrometry plus crystal structures, single lab, no mutagenesis validation reported in abstract","pmids":["23939621"],"is_preprint":false}],"current_model":"MED9 is an evolutionarily conserved subunit of the Mediator transcriptional coactivator complex, where it forms a heterodimer with Med4 within the central tetramer of the Mediator middle module; in yeast, the Med9/Cse2 submodule within the Rgr1 subcomplex is required for activator-specific (Bas1/Bas2-mediated) transcriptional activation, repression of distinct gene subsets through genetic and physical interactions with the Srb10/11 kinase module, while artificial recruitment experiments show Med9 does not mediate TFIIE bypass; in mammals, MED9 (FLJ10193) is a consensus Mediator subunit confirmed by proteomic analysis of purified complexes."},"narrative":{"mechanistic_narrative":"MED9 is an evolutionarily conserved subunit of the Mediator transcriptional coactivator complex that bridges gene-specific regulators to the RNA polymerase II machinery [PMID:9891034, PMID:15175163]. In yeast, Med9 (Cse2) resides in the Rgr1 subcomplex as part of a discrete Med9/10 submodule, where it is specifically required for Bas1/Bas2-mediated activation of amino acid biosynthetic genes and for repression of a distinct subset of genes [PMID:9891034, PMID:11470794]. This dual activating and repressive function is linked to physical and genetic interactions with the Srb10/11 kinase module, positioning the Med9 submodule as a contact point through which Mediator exerts negative control over polymerase II [PMID:11555651]. Med9 does not transmit activator signals through a TFIIE-bypass pathway, distinguishing its mechanism from that of Med2 and Pgd1 [PMID:12558798]. Structurally, Med9 forms a heterodimer with Med4 that, paired with the Med7/Med21 heterodimer, constitutes the central tetramer at the core of the Mediator middle module [PMID:23939621]. The mammalian ortholog (FLJ10193) is a bona fide consensus subunit of purified Mediator, sharing structural and functional features with yeast Cse2 [PMID:14638676, PMID:15175163].","teleology":[{"year":1999,"claim":"Established that Med9/Cse2 is a Mediator subunit with an activator-specific role rather than a general coactivator function, showing that distinct Mediator subunits serve distinct regulatory programs.","evidence":"Cloning, mutant isolation, and differential display/Northern analysis of mRNAs in wild-type vs. Mediator mutant yeast","pmids":["9891034"],"confidence":"Medium","gaps":["Direct molecular contact between Med9 and Bas1/Bas2 not demonstrated","Mechanism of activator selectivity unresolved"]},{"year":2001,"claim":"Defined Med9 as part of a discrete Med9/10 submodule within the Rgr1 subcomplex that mediates both activation and repression, and connected this submodule to the Srb10/11 kinase module, explaining how Mediator can exert negative control over RNA polymerase II.","evidence":"Recombinant protein interaction assays, genetic epistasis, in vitro transcription, genome-wide expression analysis in med9 deletion mutants, and GST pull-down of the repressor Tup1","pmids":["11555651","11470794"],"confidence":"Medium","gaps":["Precise Med9 residues contacting Srb10/11 not mapped","Whether activator/repressor competition acts directly on Med9 not shown"]},{"year":2003,"claim":"Showed that Med9 does not signal through a TFIIE-bypass pathway, narrowing the mechanistic route by which it transmits regulatory information compared to other Mediator subunits.","evidence":"Artificial recruitment of Ace1-Med9 fusion to the CUP1 promoter with genetic TFIIE-requirement assays and ChIP","pmids":["12558798"],"confidence":"Medium","gaps":["Informative negative result; the actual signal-transmission pathway used by Med9 remains undefined","Single study without orthogonal confirmation"]},{"year":2003,"claim":"Identified the mammalian FLJ10193 product as a Mediator subunit orthologous to yeast Cse2, extending the conservation of Med9 function to mammals.","evidence":"Tandem mass spectrometry of purified rat Mediator fractions","pmids":["14638676"],"confidence":"Medium","gaps":["Functional role of mammalian MED9 not tested","Ortholog naming inconsistent with later nomenclature"]},{"year":2004,"claim":"Confirmed mammalian MED9 as a consensus Mediator subunit across independent purifications, solidifying its status as a stable component of the complex.","evidence":"MudPIT proteomics of six independent immunoaffinity-purified mammalian Mediator preparations","pmids":["15175163"],"confidence":"High","gaps":["Does not address mammalian-specific function or target genes","Submodule assignment in mammals not resolved"]},{"year":2013,"claim":"Placed Med9 structurally within the central tetramer of the Mediator middle module as a Med4 heterodimer partner, providing an architectural basis for its position in the complex.","evidence":"Cross-linking mass spectrometry combined with crystal structures and homology models of the yeast middle module","pmids":["23939621"],"confidence":"Medium","gaps":["No mutagenesis validation of the Med4/Med9 interface","Structural model does not link architecture to the activation/repression functions"]},{"year":null,"claim":"How the Med9 submodule mechanistically couples activator binding, Srb10/11 kinase activity, and polymerase II regulation in a single integrated pathway remains unresolved, as does the function of mammalian MED9 beyond complex membership.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct mammalian MED9 functional assays in the corpus","Mechanism linking Med9 architecture to gene-specific output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,5]}],"complexes":["Mediator complex","Mediator middle module","Rgr1 subcomplex (Med9/10 submodule)"],"partners":["MED4","MED10","MED7","MED21","MED31","SRB10","SRB11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NWA0","full_name":"Mediator of RNA polymerase II transcription subunit 9","aliases":["Mediator complex subunit 9"],"length_aa":146,"mass_kda":16.4,"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/Q9NWA0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MED9","classification":"Common Essential","n_dependent_lines":1030,"n_total_lines":1208,"dependency_fraction":0.8526490066225165},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000141026","cell_line_id":"CID000253","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MED10","stoichiometry":10.0},{"gene":"MED11","stoichiometry":10.0},{"gene":"MED14","stoichiometry":10.0},{"gene":"MED17","stoichiometry":10.0},{"gene":"MED18","stoichiometry":10.0},{"gene":"MED19","stoichiometry":10.0},{"gene":"MED20","stoichiometry":10.0},{"gene":"MED21","stoichiometry":10.0},{"gene":"MED27","stoichiometry":10.0},{"gene":"MED28","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000253","total_profiled":1310},"omim":[{"mim_id":"609878","title":"MEDIATOR COMPLEX SUBUNIT 9; MED9","url":"https://www.omim.org/entry/609878"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Midbody","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED9"},"hgnc":{"alias_symbol":["FLJ10193","MED25"],"prev_symbol":[]},"alphafold":{"accession":"Q9NWA0","domains":[{"cath_id":"4.10.860","chopping":"57-104","consensus_level":"medium","plddt":91.4763,"start":57,"end":104},{"cath_id":"1.20.5","chopping":"109-140","consensus_level":"medium","plddt":91.7366,"start":109,"end":140}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWA0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWA0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWA0-F1-predicted_aligned_error_v6.png","plddt_mean":75.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED9","jax_strain_url":"https://www.jax.org/strain/search?query=MED9"},"sequence":{"accession":"Q9NWA0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NWA0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NWA0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWA0"}},"corpus_meta":[{"pmid":"15175163","id":"PMC_15175163","title":"A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology.","date":"2004","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15175163","citation_count":266,"is_preprint":false},{"pmid":"25205790","id":"PMC_25205790","title":"Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.","date":"2014","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/25205790","citation_count":212,"is_preprint":false},{"pmid":"32547891","id":"PMC_32547891","title":"Computational analysis of microRNA-mediated interactions in SARS-CoV-2 infection.","date":"2020","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/32547891","citation_count":156,"is_preprint":false},{"pmid":"11555651","id":"PMC_11555651","title":"The structural and functional organization of the yeast mediator complex.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11555651","citation_count":119,"is_preprint":false},{"pmid":"9891034","id":"PMC_9891034","title":"Activator-specific requirement of yeast mediator proteins for RNA polymerase II transcriptional activation.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9891034","citation_count":73,"is_preprint":false},{"pmid":"11470794","id":"PMC_11470794","title":"Med9/Cse2 and Gal11 modules are required for transcriptional repression of distinct group of genes.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11470794","citation_count":37,"is_preprint":false},{"pmid":"23939621","id":"PMC_23939621","title":"Model of the Mediator middle module based on protein cross-linking.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23939621","citation_count":37,"is_preprint":false},{"pmid":"23873866","id":"PMC_23873866","title":"Differential regulation of white-opaque switching by individual subunits of Candida albicans mediator.","date":"2013","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/23873866","citation_count":37,"is_preprint":false},{"pmid":"14638676","id":"PMC_14638676","title":"A mammalian mediator subunit that shares properties with Saccharomyces cerevisiae mediator subunit Cse2.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14638676","citation_count":23,"is_preprint":false},{"pmid":"19177570","id":"PMC_19177570","title":"In vitro-targeted gene identification in patients with hepatitis C using a genome-wide microarray technology.","date":"2009","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/19177570","citation_count":19,"is_preprint":false},{"pmid":"24952135","id":"PMC_24952135","title":"RNA-Seq for the identification of novel Mediator transcripts in endothelial progenitor cells.","date":"2014","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24952135","citation_count":10,"is_preprint":false},{"pmid":"12558798","id":"PMC_12558798","title":"Artificial recruitment of certain Mediator components affects requirement of basal transcription factor IIE.","date":"2003","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/12558798","citation_count":6,"is_preprint":false},{"pmid":"40963758","id":"PMC_40963758","title":"Eight decades of follow-up link life course exposures to proteomic organ ageing and longevity.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40963758","citation_count":3,"is_preprint":false},{"pmid":"38474301","id":"PMC_38474301","title":"Familial Dilated Cardiomyopathy: A Novel MED9 Short Isoform Identification.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38474301","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8868,"output_tokens":1778,"usd":0.026637,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8613,"output_tokens":2264,"usd":0.049833,"stage2_stop_reason":"end_turn"},"total_usd":0.07647,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"Yeast Med9/Cse2 is a subunit of the Rgr1 subcomplex of the Mediator complex and is specifically required for Bas1/Bas2-mediated transcriptional activation of amino acid biosynthetic genes, demonstrating an activator-specific role distinct from other Mediator subunits.\",\n      \"method\": \"Cloning of MED9/CSE2, mutant isolation, differential display and Northern analysis of mRNAs in wild-type vs. Mediator mutant yeast cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined transcriptional phenotype, two orthogonal methods (differential display + Northern), single lab\",\n      \"pmids\": [\"9891034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Yeast Med9/Cse2 forms a distinct 'Med9/10 module' within the Rgr1 subcomplex of Mediator; this module is required for both transcriptional activation and repression, and proteins in the Med9 submodule interact physically and genetically with Srb10/11, implying the Med9 submodule mediates repression of RNA polymerase II.\",\n      \"method\": \"Recombinant protein expression, protein-protein interaction assays, genetic interaction analysis, in vitro transcription assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical reconstitution of module interactions and genetic epistasis, single lab with multiple methods\",\n      \"pmids\": [\"11555651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Med9/Cse2 module of yeast Mediator is required for transcriptional repression of a distinct group of genes, as revealed by genome-wide gene expression analysis in med9 deletion mutants; additionally, GST pull-down analysis showed that the transcriptional repressor Tup1 binds to overlapping but distinct regions of the Gal11 module, suggesting competition between activators and repressors for Mediator binding sites.\",\n      \"method\": \"Biochemical fractionation defining modular Rgr1 structure, genome-wide gene expression analysis, Northern analysis, GST pull-down assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide expression + GST pull-down + Northern in single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11470794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The mammalian protein encoded by FLJ10193 (MED9/Med25 as named in this paper) is a bona fide subunit of the mammalian Mediator complex, sharing structural and functional properties with Saccharomyces cerevisiae Mediator subunit Cse2 and identified as a potential mammalian Cse2 ortholog.\",\n      \"method\": \"Tandem mass spectrometry identification from purified rat Mediator fractions, direct biochemical co-purification evidence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical purification and mass spectrometry from native complex, single lab\",\n      \"pmids\": [\"14638676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Artificial recruitment of Med9 (fused to the copper-inducible activator Ace1) to the CUP1 promoter did not circumvent the TFIIE requirement for transcriptional activation, in contrast to fusions with Med2 or Pgd1, indicating that Med9 does not transmit the activator signal through a TFIIE-bypass pathway.\",\n      \"method\": \"Protein fusion-based artificial recruitment to promoter, genetic assays for TFIIE requirement, chromatin immunoprecipitation\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined negative functional result using artificial recruitment and ChIP, single lab, single study; result is informative negative\",\n      \"pmids\": [\"12558798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MED9 (referred to as Med25 in this study) was identified as a consensus subunit of the mammalian Mediator complex by MudPIT proteomic analysis of six independent immunoaffinity-purified Mediator preparations.\",\n      \"method\": \"Multidimensional protein identification technology (MudPIT) proteomics from six independent immunoaffinity-purified mammalian Mediator complexes\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — six independent Mediator preparations from different subunit immunopurifications, replicated across multiple preparations in same study\",\n      \"pmids\": [\"15175163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A 3D structural model of the yeast Mediator middle module places Med9 as part of a central tetramer, forming a heterodimer with Med4; this Med4/Med9 heterodimer pairs with the Med7/Med21 heterodimer to form the core of the middle module, which is flanked by Med10 and Med31.\",\n      \"method\": \"Protein cross-linking coupled with mass spectrometric analysis of lysine-lysine cross-links, combined with crystal structures and homology models to build a 3D middle module model\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural model from cross-linking mass spectrometry plus crystal structures, single lab, no mutagenesis validation reported in abstract\",\n      \"pmids\": [\"23939621\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED9 is an evolutionarily conserved subunit of the Mediator transcriptional coactivator complex, where it forms a heterodimer with Med4 within the central tetramer of the Mediator middle module; in yeast, the Med9/Cse2 submodule within the Rgr1 subcomplex is required for activator-specific (Bas1/Bas2-mediated) transcriptional activation, repression of distinct gene subsets through genetic and physical interactions with the Srb10/11 kinase module, while artificial recruitment experiments show Med9 does not mediate TFIIE bypass; in mammals, MED9 (FLJ10193) is a consensus Mediator subunit confirmed by proteomic analysis of purified complexes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED9 is an evolutionarily conserved subunit of the Mediator transcriptional coactivator complex that bridges gene-specific regulators to the RNA polymerase II machinery [#0, #5]. In yeast, Med9 (Cse2) resides in the Rgr1 subcomplex as part of a discrete Med9/10 submodule, where it is specifically required for Bas1/Bas2-mediated activation of amino acid biosynthetic genes and for repression of a distinct subset of genes [#0, #2]. This dual activating and repressive function is linked to physical and genetic interactions with the Srb10/11 kinase module, positioning the Med9 submodule as a contact point through which Mediator exerts negative control over polymerase II [#1]. Med9 does not transmit activator signals through a TFIIE-bypass pathway, distinguishing its mechanism from that of Med2 and Pgd1 [#4]. Structurally, Med9 forms a heterodimer with Med4 that, paired with the Med7/Med21 heterodimer, constitutes the central tetramer at the core of the Mediator middle module [#6]. The mammalian ortholog (FLJ10193) is a bona fide consensus subunit of purified Mediator, sharing structural and functional features with yeast Cse2 [#3, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that Med9/Cse2 is a Mediator subunit with an activator-specific role rather than a general coactivator function, showing that distinct Mediator subunits serve distinct regulatory programs.\",\n      \"evidence\": \"Cloning, mutant isolation, and differential display/Northern analysis of mRNAs in wild-type vs. Mediator mutant yeast\",\n      \"pmids\": [\"9891034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular contact between Med9 and Bas1/Bas2 not demonstrated\", \"Mechanism of activator selectivity unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined Med9 as part of a discrete Med9/10 submodule within the Rgr1 subcomplex that mediates both activation and repression, and connected this submodule to the Srb10/11 kinase module, explaining how Mediator can exert negative control over RNA polymerase II.\",\n      \"evidence\": \"Recombinant protein interaction assays, genetic epistasis, in vitro transcription, genome-wide expression analysis in med9 deletion mutants, and GST pull-down of the repressor Tup1\",\n      \"pmids\": [\"11555651\", \"11470794\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise Med9 residues contacting Srb10/11 not mapped\", \"Whether activator/repressor competition acts directly on Med9 not shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed that Med9 does not signal through a TFIIE-bypass pathway, narrowing the mechanistic route by which it transmits regulatory information compared to other Mediator subunits.\",\n      \"evidence\": \"Artificial recruitment of Ace1-Med9 fusion to the CUP1 promoter with genetic TFIIE-requirement assays and ChIP\",\n      \"pmids\": [\"12558798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Informative negative result; the actual signal-transmission pathway used by Med9 remains undefined\", \"Single study without orthogonal confirmation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified the mammalian FLJ10193 product as a Mediator subunit orthologous to yeast Cse2, extending the conservation of Med9 function to mammals.\",\n      \"evidence\": \"Tandem mass spectrometry of purified rat Mediator fractions\",\n      \"pmids\": [\"14638676\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of mammalian MED9 not tested\", \"Ortholog naming inconsistent with later nomenclature\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Confirmed mammalian MED9 as a consensus Mediator subunit across independent purifications, solidifying its status as a stable component of the complex.\",\n      \"evidence\": \"MudPIT proteomics of six independent immunoaffinity-purified mammalian Mediator preparations\",\n      \"pmids\": [\"15175163\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address mammalian-specific function or target genes\", \"Submodule assignment in mammals not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed Med9 structurally within the central tetramer of the Mediator middle module as a Med4 heterodimer partner, providing an architectural basis for its position in the complex.\",\n      \"evidence\": \"Cross-linking mass spectrometry combined with crystal structures and homology models of the yeast middle module\",\n      \"pmids\": [\"23939621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mutagenesis validation of the Med4/Med9 interface\", \"Structural model does not link architecture to the activation/repression functions\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the Med9 submodule mechanistically couples activator binding, Srb10/11 kinase activity, and polymerase II regulation in a single integrated pathway remains unresolved, as does the function of mammalian MED9 beyond complex membership.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct mammalian MED9 functional assays in the corpus\", \"Mechanism linking Med9 architecture to gene-specific output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"complexes\": [\"Mediator complex\", \"Mediator middle module\", \"Rgr1 subcomplex (Med9/10 submodule)\"],\n    \"partners\": [\"MED4\", \"MED10\", \"MED7\", \"MED21\", \"MED31\", \"SRB10\", \"SRB11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}