{"gene":"MED11","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1998,"finding":"MED11 (Med11) was identified as a bona fide subunit of the yeast Mediator complex, verified by copurification and co-immunoprecipitation with RNA polymerase II holoenzyme.","method":"Copurification and co-immunoprecipitation with RNA Pol II holoenzyme; peptide sequence determination","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and biochemical copurification, foundational discovery replicated across labs","pmids":["9812975"],"is_preprint":false},{"year":1999,"finding":"Med11 is specifically required for MFalpha1 transcription in yeast, demonstrating an activator-specific role distinct from the broadly required Med6, and placing Med11 within the Rgr1 subcomplex of Mediator.","method":"Northern analysis of mRNAs in wild-type vs. med11 mutant yeast; genetic mutant analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined transcriptional phenotype, single lab","pmids":["9891034"],"is_preprint":false},{"year":2003,"finding":"Mammalian MED11, identified by sequence similarity to yeast Med11, is a bona fide subunit of the mammalian Mediator complex and was shown to have direct pairwise binding partners among known mammalian Mediator subunits.","method":"Tandem mass spectrometry identification from purified Med8-containing Mediator fractions; direct biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — MS-based identification plus direct biochemical binding evidence, single lab","pmids":["12584197"],"is_preprint":false},{"year":2008,"finding":"The Med11 Mediator head subunit directly interacts with the Rad3 subunit of TFIIH, and this interaction is required for recruitment of TFIIH and TFIIE to the preinitiation complex (PIC); a med11 mutation that impairs this interaction reduces genome-wide TFIIK kinase module occupancy at promoters and Pol II CTD serine 5 phosphorylation.","method":"In vivo interaction studies, ChIP genome-wide occupancy analysis, genetic mutant analysis with Med11/Med17/Med22 interaction mutations","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic, ChIP, interaction mapping), strongly cited and replicated in concept","pmids":["18691966"],"is_preprint":false},{"year":2011,"finding":"Med11 and Med22 form a conserved four-helix bundle heterodimer with C-terminal extensions that bind the central head subunit Med17; a highly conserved surface patch on the bundle is required for stable transcription pre-initiation complex (PIC) formation in vitro and in vivo, and likely recruits TFIIH.","method":"Structure-function analysis, in vitro PIC formation assay, mutational analysis of conserved surface patch, in vivo transcription assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — structural characterization combined with in vitro and in vivo functional validation and mutagenesis","pmids":["21498544"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of the Mediator head module from S. pombe at 3.4 Å resolution reveals that Med11 is part of the neck submodule (helical spine/limb) and contributes to the conserved, flexible architecture that mediates interactions with Pol II and its CTD.","method":"X-ray crystallography (3.4 Å); structural modeling and comparison with S. cerevisiae module","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with architectural and functional interpretation","pmids":["23123849"],"is_preprint":false},{"year":2014,"finding":"siRNA-mediated knockdown of human MED11 significantly impairs HIV-1 replication at a post-integration step, specifically affecting transcription of the nascent viral mRNA transactivation-responsive element, indicating MED11 is required for Pol II-dependent HIV-1 transcription initiation.","method":"siRNA knockdown; RT-PCR quantification of HIV transcripts; viral replication assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined transcriptional phenotype, single lab","pmids":["25100719"],"is_preprint":false},{"year":2022,"finding":"A homozygous truncating variant in MED11 (p.Arg109Ter) disrupts the C-terminal region of MED11, likely impairing its binding to other Mediator subunits rather than causing complete loss of protein; zebrafish med11 knockout recapitulates key neurodegenerative phenotypes including microcephaly and neurodegeneration.","method":"Western blotting and RT-PCR on patient-derived fibroblasts; CRISPR/Cas9 zebrafish knockout; computational structural analysis","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — patient-derived cell functional studies plus in vivo vertebrate KO model with defined phenotype","pmids":["36001086"],"is_preprint":false},{"year":2024,"finding":"Nuclear lncRNA EYA4-au1 recruits Med11 to the EYA4 promoter for transcriptional activation, thereby activating the EYA4/p27kip1/CK2α/HDAC2 cascade that drives cardiomyocyte hypertrophy in an AngII-stimulated in vitro model.","method":"In vitro cardiomyocyte hypertrophy model (AngII); lncRNA overexpression/knockdown; promoter-recruitment assays","journal":"Ecotoxicology and environmental safety","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single model system, limited mechanistic detail on Med11-lncRNA interaction","pmids":["39471666"],"is_preprint":false}],"current_model":"MED11 is an essential subunit of the Mediator head module that forms a conserved four-helix bundle heterodimer with Med22, binds the central head subunit Med17, and directly contacts the TFIIH subunit Rad3 to recruit TFIIH and TFIIE into the RNA Pol II preinitiation complex, thereby facilitating Pol II CTD serine 5 phosphorylation and transcription initiation at most Pol II promoters; loss of its C-terminal domain impairs binding to other Mediator subunits and causes lethal neurodegeneration in humans."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing MED11 as a genuine Mediator subunit resolved whether this polypeptide was an integral component of the Pol II holoenzyme or a contaminant.","evidence":"Copurification and reciprocal co-immunoprecipitation with RNA Pol II holoenzyme from yeast","pmids":["9812975"],"confidence":"High","gaps":["Subunit position within Mediator architecture unknown","No functional role assigned beyond complex membership"]},{"year":1999,"claim":"Demonstration that med11 mutation selectively impairs MFalpha1 transcription established that Med11 has activator-specific functions and placed it within the Rgr1 subcomplex.","evidence":"Northern analysis comparing mRNA profiles between wild-type and med11 mutant yeast","pmids":["9891034"],"confidence":"Medium","gaps":["Molecular basis for activator specificity uncharacterized","No direct interaction partners identified","Later work reassigned Med11 to the head module rather than Rgr1 subcomplex"]},{"year":2003,"claim":"Identification of mammalian MED11 as a Mediator subunit with direct pairwise binding to other subunits confirmed evolutionary conservation and opened the system to human studies.","evidence":"Tandem mass spectrometry of purified mammalian Mediator fractions and direct biochemical binding assays","pmids":["12584197"],"confidence":"Medium","gaps":["Identity of direct mammalian binding partners within Mediator not fully mapped","Functional relevance of mammalian MED11 not yet tested"]},{"year":2008,"claim":"Discovery that Med11 directly contacts the TFIIH subunit Rad3 and is required for TFIIH/TFIIE recruitment and CTD Ser5 phosphorylation answered how Mediator mechanistically links to the general transcription machinery.","evidence":"In vivo interaction studies, genome-wide ChIP occupancy analysis, and genetic mutant analysis in yeast","pmids":["18691966"],"confidence":"High","gaps":["Structural basis of the Med11–Rad3 interface unresolved","Whether the same contact operates in metazoans not tested"]},{"year":2011,"claim":"Structural and functional characterization of the Med11–Med22 four-helix bundle heterodimer, including identification of a conserved surface patch essential for PIC assembly, defined the minimal architectural unit through which Med11 operates.","evidence":"Structure-function analysis with mutagenesis, in vitro PIC formation, and in vivo transcription assays","pmids":["21498544"],"confidence":"High","gaps":["Atomic-resolution structure of Med11–Med22 bundle not yet determined at this point","Whether the conserved patch directly contacts Rad3 or acts indirectly not distinguished"]},{"year":2012,"claim":"The crystal structure of the S. pombe Mediator head module at 3.4 Å placed Med11 within the neck/helical spine, revealing how it contributes to the flexible architecture that interfaces with Pol II and its CTD.","evidence":"X-ray crystallography of the head module; structural comparison with S. cerevisiae","pmids":["23123849"],"confidence":"High","gaps":["Full human Mediator head module structure with Med11 not available","Conformational dynamics of the Med11-containing neck during PIC assembly unresolved"]},{"year":2014,"claim":"Demonstrating that MED11 knockdown impairs HIV-1 transcription at the post-integration step extended MED11's role to a specific human pathological context dependent on Pol II transcription initiation.","evidence":"siRNA knockdown in human cells with RT-PCR quantification and viral replication assays","pmids":["25100719"],"confidence":"Medium","gaps":["Whether the effect is direct or indirect through global Mediator disruption not distinguished","No rescue experiment reported"]},{"year":2022,"claim":"Linking a homozygous MED11 truncating variant to lethal neurodegeneration in humans, with phenocopy in zebrafish knockout, established MED11 as a disease gene and showed that its C-terminal domain is critical for Mediator subunit interactions in vivo.","evidence":"Patient fibroblast biochemistry (Western blot, RT-PCR), CRISPR/Cas9 zebrafish med11 KO, computational structural modeling","pmids":["36001086"],"confidence":"Medium","gaps":["Why neural tissue is preferentially vulnerable is unexplained","Specific Mediator subunit interactions disrupted by the truncation not biochemically mapped","No patient-derived neuronal cell models tested"]},{"year":null,"claim":"High-resolution structural detail of how Med11 engages TFIIH in the human PIC, the basis for tissue-specific vulnerability in MED11-associated neurodegeneration, and whether Med11 participates in gene-selective regulatory circuits beyond HIV-1 transcription remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No cryo-EM or crystal structure of Med11–TFIIH interface in the human PIC","Mechanism of neural-selective pathology unknown","Gene-selective versus global transcriptional role of Med11 in mammalian cells not systematically profiled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,4,6]}],"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":[0,1,3,4,5,6]}],"complexes":["Mediator complex","Mediator head module"],"partners":["MED22","MED17","RAD3","MED8"],"other_free_text":[]},"mechanistic_narrative":"MED11 is an essential subunit of the Mediator complex head module that functions as a critical bridge between Mediator and the general transcription machinery during RNA polymerase II transcription initiation. MED11 forms a conserved four-helix bundle heterodimer with Med22, whose C-terminal extensions bind the central head subunit Med17; a highly conserved surface patch on this bundle directly contacts the TFIIH subunit Rad3, and this interaction is required for recruitment of both TFIIH and TFIIE into the preinitiation complex, enabling Pol II CTD serine 5 phosphorylation genome-wide [PMID:18691966, PMID:21498544, PMID:23123849]. A homozygous truncating variant (p.Arg109Ter) in MED11, which disrupts its C-terminal Mediator-binding domain, causes lethal neurodegeneration with microcephaly, a phenotype recapitulated by zebrafish med11 knockout [PMID:36001086]. MED11 is also required for HIV-1 transcription at a post-integration step, consistent with its general role in Pol II-dependent transcription initiation [PMID:25100719]."},"prefetch_data":{"uniprot":{"accession":"Q9P086","full_name":"Mediator of RNA polymerase II transcription subunit 11","aliases":["Mediator complex subunit 11"],"length_aa":117,"mass_kda":13.1,"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 pre-initiation complex with RNA polymerase II and the general transcription factors","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9P086/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MED11","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000161920","cell_line_id":"CID000250","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MED7","stoichiometry":10.0},{"gene":"MED14","stoichiometry":10.0},{"gene":"IXL;MED29","stoichiometry":10.0},{"gene":"MED25","stoichiometry":10.0},{"gene":"MED24","stoichiometry":10.0},{"gene":"MED6","stoichiometry":10.0},{"gene":"MED17","stoichiometry":10.0},{"gene":"MED22","stoichiometry":10.0},{"gene":"MED21","stoichiometry":10.0},{"gene":"MED18","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000250","total_profiled":1310},"omim":[{"mim_id":"620327","title":"NEURODEGENERATION WITH DEVELOPMENTAL DELAY, EARLY RESPIRATORY FAILURE, MYOCLONIC SEIZURES, AND BRAIN ABNORMALITIES; NDDRSB","url":"https://www.omim.org/entry/620327"},{"mim_id":"612385","title":"MEDIATOR COMPLEX SUBUNIT 19; MED19","url":"https://www.omim.org/entry/612385"},{"mim_id":"612384","title":"MEDIATOR COMPLEX SUBUNIT 18; MED18","url":"https://www.omim.org/entry/612384"},{"mim_id":"612383","title":"MEDIATOR COMPLEX SUBUNIT 11; MED11","url":"https://www.omim.org/entry/612383"},{"mim_id":"612382","title":"MEDIATOR COMPLEX SUBUNIT 10; MED10","url":"https://www.omim.org/entry/612382"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nuclear bodies","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED11"},"hgnc":{"alias_symbol":["HSPC296","MGC88387"],"prev_symbol":[]},"alphafold":{"accession":"Q9P086","domains":[{"cath_id":"1.10.287","chopping":"1-81","consensus_level":"medium","plddt":86.1122,"start":1,"end":81},{"cath_id":"1.20.5","chopping":"83-117","consensus_level":"medium","plddt":91.0214,"start":83,"end":117}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P086","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P086-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P086-F1-predicted_aligned_error_v6.png","plddt_mean":87.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED11","jax_strain_url":"https://www.jax.org/strain/search?query=MED11"},"sequence":{"accession":"Q9P086","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P086.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P086/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P086"}},"corpus_meta":[{"pmid":"18691966","id":"PMC_18691966","title":"Mediator-dependent recruitment of TFIIH modules in preinitiation complex.","date":"2008","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/18691966","citation_count":126,"is_preprint":false},{"pmid":"23123849","id":"PMC_23123849","title":"Structure of the Mediator head module.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23123849","citation_count":87,"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":"12584197","id":"PMC_12584197","title":"Identification of mammalian Mediator subunits with similarities to yeast Mediator subunits Srb5, Srb6, Med11, and Rox3.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12584197","citation_count":48,"is_preprint":false},{"pmid":"9812975","id":"PMC_9812975","title":"Identification of new mediator subunits in the RNA polymerase II holoenzyme from Saccharomyces cerevisiae.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9812975","citation_count":48,"is_preprint":false},{"pmid":"21498544","id":"PMC_21498544","title":"Mediator head subcomplex Med11/22 contains a common helix bundle building block with a specific function in transcription initiation complex stabilization.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/21498544","citation_count":38,"is_preprint":false},{"pmid":"25100719","id":"PMC_25100719","title":"Characterization of the influence of mediator complex in HIV-1 transcription.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25100719","citation_count":27,"is_preprint":false},{"pmid":"33746938","id":"PMC_33746938","title":"Differential Requirements for Mediator Complex Subunits in Drosophila melanogaster Host Defense Against Fungal and Bacterial Pathogens.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33746938","citation_count":18,"is_preprint":false},{"pmid":"36001086","id":"PMC_36001086","title":"A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.","date":"2022","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36001086","citation_count":16,"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":"39471666","id":"PMC_39471666","title":"Exercise in ozone-polluted air evokes pathological cardiac hypertrophy via up-regulation of nuclear lncRNA EYA4-au1 and recruiting Med11 to activating EYA4/p27kip1/CK2α/HDAC2 cascade.","date":"2024","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/39471666","citation_count":4,"is_preprint":false},{"pmid":"39578696","id":"PMC_39578696","title":"Prenatal Phenotypic Expansion: A Fetus With Neurodegeneration With Developmental Delay, Early Respiratory Failure, Myoclonic Seizures, and Brain Abnormalities (NDDRSB) and MED11 Variants.","date":"2024","source":"Prenatal diagnosis","url":"https://pubmed.ncbi.nlm.nih.gov/39578696","citation_count":1,"is_preprint":false},{"pmid":"41465117","id":"PMC_41465117","title":"Genetic, Clinical and Neuroradiological Spectrum of MED-Related Disorders: An Updated Review.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41465117","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7842,"output_tokens":1974,"usd":0.026568},"stage2":{"model":"claude-opus-4-6","input_tokens":5273,"output_tokens":2122,"usd":0.119123},"total_usd":0.145691,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"MED11 (Med11) was identified as a bona fide subunit of the yeast Mediator complex, verified by copurification and co-immunoprecipitation with RNA polymerase II holoenzyme.\",\n      \"method\": \"Copurification and co-immunoprecipitation with RNA Pol II holoenzyme; peptide sequence determination\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and biochemical copurification, foundational discovery replicated across labs\",\n      \"pmids\": [\"9812975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Med11 is specifically required for MFalpha1 transcription in yeast, demonstrating an activator-specific role distinct from the broadly required Med6, and placing Med11 within the Rgr1 subcomplex of Mediator.\",\n      \"method\": \"Northern analysis of mRNAs in wild-type vs. med11 mutant yeast; genetic mutant analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined transcriptional phenotype, single lab\",\n      \"pmids\": [\"9891034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mammalian MED11, identified by sequence similarity to yeast Med11, is a bona fide subunit of the mammalian Mediator complex and was shown to have direct pairwise binding partners among known mammalian Mediator subunits.\",\n      \"method\": \"Tandem mass spectrometry identification from purified Med8-containing Mediator fractions; direct biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-based identification plus direct biochemical binding evidence, single lab\",\n      \"pmids\": [\"12584197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Med11 Mediator head subunit directly interacts with the Rad3 subunit of TFIIH, and this interaction is required for recruitment of TFIIH and TFIIE to the preinitiation complex (PIC); a med11 mutation that impairs this interaction reduces genome-wide TFIIK kinase module occupancy at promoters and Pol II CTD serine 5 phosphorylation.\",\n      \"method\": \"In vivo interaction studies, ChIP genome-wide occupancy analysis, genetic mutant analysis with Med11/Med17/Med22 interaction mutations\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic, ChIP, interaction mapping), strongly cited and replicated in concept\",\n      \"pmids\": [\"18691966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Med11 and Med22 form a conserved four-helix bundle heterodimer with C-terminal extensions that bind the central head subunit Med17; a highly conserved surface patch on the bundle is required for stable transcription pre-initiation complex (PIC) formation in vitro and in vivo, and likely recruits TFIIH.\",\n      \"method\": \"Structure-function analysis, in vitro PIC formation assay, mutational analysis of conserved surface patch, in vivo transcription assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural characterization combined with in vitro and in vivo functional validation and mutagenesis\",\n      \"pmids\": [\"21498544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of the Mediator head module from S. pombe at 3.4 Å resolution reveals that Med11 is part of the neck submodule (helical spine/limb) and contributes to the conserved, flexible architecture that mediates interactions with Pol II and its CTD.\",\n      \"method\": \"X-ray crystallography (3.4 Å); structural modeling and comparison with S. cerevisiae module\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with architectural and functional interpretation\",\n      \"pmids\": [\"23123849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"siRNA-mediated knockdown of human MED11 significantly impairs HIV-1 replication at a post-integration step, specifically affecting transcription of the nascent viral mRNA transactivation-responsive element, indicating MED11 is required for Pol II-dependent HIV-1 transcription initiation.\",\n      \"method\": \"siRNA knockdown; RT-PCR quantification of HIV transcripts; viral replication assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined transcriptional phenotype, single lab\",\n      \"pmids\": [\"25100719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous truncating variant in MED11 (p.Arg109Ter) disrupts the C-terminal region of MED11, likely impairing its binding to other Mediator subunits rather than causing complete loss of protein; zebrafish med11 knockout recapitulates key neurodegenerative phenotypes including microcephaly and neurodegeneration.\",\n      \"method\": \"Western blotting and RT-PCR on patient-derived fibroblasts; CRISPR/Cas9 zebrafish knockout; computational structural analysis\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived cell functional studies plus in vivo vertebrate KO model with defined phenotype\",\n      \"pmids\": [\"36001086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nuclear lncRNA EYA4-au1 recruits Med11 to the EYA4 promoter for transcriptional activation, thereby activating the EYA4/p27kip1/CK2α/HDAC2 cascade that drives cardiomyocyte hypertrophy in an AngII-stimulated in vitro model.\",\n      \"method\": \"In vitro cardiomyocyte hypertrophy model (AngII); lncRNA overexpression/knockdown; promoter-recruitment assays\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single model system, limited mechanistic detail on Med11-lncRNA interaction\",\n      \"pmids\": [\"39471666\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED11 is an essential subunit of the Mediator head module that forms a conserved four-helix bundle heterodimer with Med22, binds the central head subunit Med17, and directly contacts the TFIIH subunit Rad3 to recruit TFIIH and TFIIE into the RNA Pol II preinitiation complex, thereby facilitating Pol II CTD serine 5 phosphorylation and transcription initiation at most Pol II promoters; loss of its C-terminal domain impairs binding to other Mediator subunits and causes lethal neurodegeneration in humans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MED11 is an essential subunit of the Mediator complex head module that functions as a critical bridge between Mediator and the general transcription machinery during RNA polymerase II transcription initiation. MED11 forms a conserved four-helix bundle heterodimer with Med22, whose C-terminal extensions bind the central head subunit Med17; a highly conserved surface patch on this bundle directly contacts the TFIIH subunit Rad3, and this interaction is required for recruitment of both TFIIH and TFIIE into the preinitiation complex, enabling Pol II CTD serine 5 phosphorylation genome-wide [PMID:18691966, PMID:21498544, PMID:23123849]. A homozygous truncating variant (p.Arg109Ter) in MED11, which disrupts its C-terminal Mediator-binding domain, causes lethal neurodegeneration with microcephaly, a phenotype recapitulated by zebrafish med11 knockout [PMID:36001086]. MED11 is also required for HIV-1 transcription at a post-integration step, consistent with its general role in Pol II-dependent transcription initiation [PMID:25100719].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing MED11 as a genuine Mediator subunit resolved whether this polypeptide was an integral component of the Pol II holoenzyme or a contaminant.\",\n      \"evidence\": \"Copurification and reciprocal co-immunoprecipitation with RNA Pol II holoenzyme from yeast\",\n      \"pmids\": [\"9812975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Subunit position within Mediator architecture unknown\",\n        \"No functional role assigned beyond complex membership\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstration that med11 mutation selectively impairs MFalpha1 transcription established that Med11 has activator-specific functions and placed it within the Rgr1 subcomplex.\",\n      \"evidence\": \"Northern analysis comparing mRNA profiles between wild-type and med11 mutant yeast\",\n      \"pmids\": [\"9891034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular basis for activator specificity uncharacterized\",\n        \"No direct interaction partners identified\",\n        \"Later work reassigned Med11 to the head module rather than Rgr1 subcomplex\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of mammalian MED11 as a Mediator subunit with direct pairwise binding to other subunits confirmed evolutionary conservation and opened the system to human studies.\",\n      \"evidence\": \"Tandem mass spectrometry of purified mammalian Mediator fractions and direct biochemical binding assays\",\n      \"pmids\": [\"12584197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of direct mammalian binding partners within Mediator not fully mapped\",\n        \"Functional relevance of mammalian MED11 not yet tested\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that Med11 directly contacts the TFIIH subunit Rad3 and is required for TFIIH/TFIIE recruitment and CTD Ser5 phosphorylation answered how Mediator mechanistically links to the general transcription machinery.\",\n      \"evidence\": \"In vivo interaction studies, genome-wide ChIP occupancy analysis, and genetic mutant analysis in yeast\",\n      \"pmids\": [\"18691966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the Med11–Rad3 interface unresolved\",\n        \"Whether the same contact operates in metazoans not tested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Structural and functional characterization of the Med11–Med22 four-helix bundle heterodimer, including identification of a conserved surface patch essential for PIC assembly, defined the minimal architectural unit through which Med11 operates.\",\n      \"evidence\": \"Structure-function analysis with mutagenesis, in vitro PIC formation, and in vivo transcription assays\",\n      \"pmids\": [\"21498544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution structure of Med11–Med22 bundle not yet determined at this point\",\n        \"Whether the conserved patch directly contacts Rad3 or acts indirectly not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The crystal structure of the S. pombe Mediator head module at 3.4 Å placed Med11 within the neck/helical spine, revealing how it contributes to the flexible architecture that interfaces with Pol II and its CTD.\",\n      \"evidence\": \"X-ray crystallography of the head module; structural comparison with S. cerevisiae\",\n      \"pmids\": [\"23123849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full human Mediator head module structure with Med11 not available\",\n        \"Conformational dynamics of the Med11-containing neck during PIC assembly unresolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that MED11 knockdown impairs HIV-1 transcription at the post-integration step extended MED11's role to a specific human pathological context dependent on Pol II transcription initiation.\",\n      \"evidence\": \"siRNA knockdown in human cells with RT-PCR quantification and viral replication assays\",\n      \"pmids\": [\"25100719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the effect is direct or indirect through global Mediator disruption not distinguished\",\n        \"No rescue experiment reported\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking a homozygous MED11 truncating variant to lethal neurodegeneration in humans, with phenocopy in zebrafish knockout, established MED11 as a disease gene and showed that its C-terminal domain is critical for Mediator subunit interactions in vivo.\",\n      \"evidence\": \"Patient fibroblast biochemistry (Western blot, RT-PCR), CRISPR/Cas9 zebrafish med11 KO, computational structural modeling\",\n      \"pmids\": [\"36001086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Why neural tissue is preferentially vulnerable is unexplained\",\n        \"Specific Mediator subunit interactions disrupted by the truncation not biochemically mapped\",\n        \"No patient-derived neuronal cell models tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"High-resolution structural detail of how Med11 engages TFIIH in the human PIC, the basis for tissue-specific vulnerability in MED11-associated neurodegeneration, and whether Med11 participates in gene-selective regulatory circuits beyond HIV-1 transcription remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of Med11–TFIIH interface in the human PIC\",\n        \"Mechanism of neural-selective pathology unknown\",\n        \"Gene-selective versus global transcriptional role of Med11 in mammalian cells not systematically profiled\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [4, 5]\n      },\n      {\n        \"term_id\": \"GO:0140110\",\n        \"supporting_discovery_ids\": [3, 4, 6]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005634\",\n        \"supporting_discovery_ids\": [0, 3, 5]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-74160\",\n        \"supporting_discovery_ids\": [0, 1, 3, 4, 5, 6]\n      }\n    ],\n    \"complexes\": [\n      \"Mediator complex\",\n      \"Mediator head module\"\n    ],\n    \"partners\": [\n      \"MED22\",\n      \"MED17\",\n      \"RAD3\",\n      \"MED8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}