{"gene":"MED7","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":1999,"finding":"CRSP33 (MED7 homolog) is a subunit of the human CRSP coactivator complex (~700 kDa, nine subunits) required together with TAFIIs for transcriptional activation by Sp1; immunodepletion of CRSP subunits abolishes Sp1-dependent transcription.","method":"Biochemical purification, gene cloning, immunodepletion of CRSP from transcription reactions, in vitro transcription assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro transcription reconstitution with immunodepletion and multiple orthogonal methods (purification, cloning, functional assay)","pmids":["9989412"],"is_preprint":false},{"year":1998,"finding":"The mammalian (murine) Mediator complex contains a Med7 homolog that co-purifies with the complex; this complex binds to the RNA polymerase II C-terminal domain (CTD) and stimulates CTD phosphorylation by TFIIH.","method":"Biochemical purification, peptide sequencing, CTD-binding and TFIIH phosphorylation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with multiple functional readouts (CTD binding, TFIIH stimulation), replicated across yeast and mammalian systems","pmids":["9671713"],"is_preprint":false},{"year":1998,"finding":"Yeast Med7 is a component of purified Mediator required for transcriptional activation in a fully defined in vitro system; the CTD of RNA polymerase II is required for Mediator function in vitro.","method":"Biochemical purification of yeast Mediator, in vitro transcription assay, CTD-requirement experiments","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — fully reconstituted in vitro transcription system with defined components; foundational Mediator characterization paper","pmids":["9420330"],"is_preprint":false},{"year":2005,"finding":"The MED7·MED21 (Med7·Srb7) heterodimer forms a highly extended structure containing a four-helix bundle domain and a coiled-coil protrusion connected by a flexible hinge; this hinge is proposed to enable conformational changes in Mediator upon Pol II or activator binding. MED6 bridges via MED7·MED21 to the head module.","method":"X-ray crystallography (3.0 Å crystal structure of MED7·MED21 heterodimer), functional surface analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with functional surface mapping and mechanistic interpretation validated by structural data","pmids":["15710619"],"is_preprint":false},{"year":2008,"finding":"MED1 directly binds to the MED7 subunit, and ERK (MAPK) phosphorylation of MED1 enhances this MED1–MED7 interaction, thereby promoting MED1 association with the Mediator complex and its nuclear receptor coactivator activity.","method":"Co-immunoprecipitation, in vitro binding assays, ERK phosphorylation assays, in vitro transcription with thyroid hormone receptor","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding shown by in vitro assay plus Co-IP, phosphorylation-dependent enhancement tested with in vitro transcription; multiple orthogonal methods in single lab","pmids":["18391015"],"is_preprint":false},{"year":2008,"finding":"The Med7N/31 submodule (N-terminal part of Med7 plus Med31/Soh1) adopts a novel fold in which two proline-rich stretches in Med7N wrap around the four-helix bundle of Med31; this submodule is required for activated transcription in vitro and has a predominantly positive function on expression of a specific gene subset (methionine metabolism, iron transport) in vivo.","method":"Crystal structure determination of Med7N/31, in vitro transcription assay with trans-complementation, in vivo transcriptome profiling, comparative phenotyping","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with in vitro functional reconstitution and in vivo transcriptome data","pmids":["19057509"],"is_preprint":false},{"year":2010,"finding":"Within the recombinant yeast Mediator middle module (Med1, 4, 7, 9, 10, 21, 31), Med7 serves as a central binding platform forming three heterodimeric subcomplexes: Med7N/21, Med7C/31, and (with Med4) the Med4/9 pair; Med1 and Med10 also bind to Med7. Native mass spectrometry confirms equimolar stoichiometry of all seven subunits.","method":"Recombinant co-expression and purification, native mass spectrometry, ion-mobility MS, limited proteolysis, SAXS, protein-protein interaction assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted recombinant module with multiple biophysical methods (native MS, SAXS, limited proteolysis) establishing Med7 as central scaffold","pmids":["20123732"],"is_preprint":false},{"year":2011,"finding":"The Med7/Med21 four-helix bundle fold is a common building block shared with the head module Med11/22 heterodimer; this motif is predicted in several other Mediator heterodimers, indicating a multiplied and functionally diversified building block in Mediator evolution.","method":"Crystal structure of Med11/22, structural comparison with published Med7/Med21 structure, in vitro pre-initiation complex formation assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural analysis of Med11/22 with comparison to Med7/Med21; Med7-specific functional evidence comes from the structural analogy, not direct Med7 experiment in this paper","pmids":["21498544"],"is_preprint":false},{"year":2013,"finding":"A 3D model of the yeast Mediator middle module places the Med7/Med21 heterodimer at the center of a tetramer with Med4/Med9; Med10 and Med31 flank Med7/Med21. This elongated, flexible arrangement was determined by lysine–lysine cross-linking coupled to mass spectrometry.","method":"Chemical cross-linking mass spectrometry (XL-MS), arrangement of crystal structures and homology models into 3D model","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — XL-MS-based structural model with crystal structure inputs; not atomic resolution but multiple orthogonal constraints","pmids":["23939621"],"is_preprint":false},{"year":2007,"finding":"CRSP9/MED7 (human) is constitutively SUMOylated in vivo, as identified by the Ubc9 fusion-dependent SUMOylation (UFDS) system, with SUMO modification confirmed independently of the fusion system.","method":"Ubc9 fusion-dependent SUMOylation (UFDS) screen, independent in vivo SUMOylation validation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — UFDS screening plus independent in vivo validation; single lab but two orthogonal methods","pmids":["17709345"],"is_preprint":false},{"year":2016,"finding":"The integrity of the conserved hinge region in the human MED21–MED7 heterodimer is required for Mediator binding to RNA polymerase II to form the holoenzyme; point mutations in the hinge leave core Mediator intact but increase disorder in the middle module and markedly reduce affinity for Pol II.","method":"Biochemistry (affinity pull-down, subunit composition analysis), negative-stain electron microscopy of Mediator–Pol II holoenzyme, site-directed mutagenesis of hinge residues","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis combined with biochemical binding assays and EM structural analysis; directly tests MED7 hinge function in holoenzyme assembly","pmids":["27821593"],"is_preprint":false},{"year":2012,"finding":"Mutations in yeast Med7 (ewe alleles) located in or adjacent to the middle module severely diminish heat-shock-induced expression of HSP82 by impairing Pol II transit through the coding region rather than Pol II recruitment to the promoter, indicating a role for Med7 in regulating Pol II elongation.","method":"Genetic analysis (ewe mutations), ChIP of Pol II at promoter and coding regions, 6-azauracil sensitivity assay, reporter gene elongation assay","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with ChIP-based mechanistic readout showing post-initiation function; single lab, multiple methods","pmids":["22377631"],"is_preprint":false},{"year":2011,"finding":"Mutations in yeast Med7 reduce Mediator occupancy at subtelomeric regions, causing a shift in Sir2/Sas2 balance and increased H4K16 acetylation near telomeres, leading to desilencing of subtelomeric genes and influencing cellular life span.","method":"ChIP of Mediator at telomeres, chromatin acetylation assays (H4K16ac), gene expression analysis, replicative lifespan measurement","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP localization tied to functional chromatin and lifespan consequences; single lab, multiple orthogonal readouts","pmids":["21482672"],"is_preprint":false},{"year":2007,"finding":"In yeast, the genetic interaction between Med7 and Med21 (Srb7) is confirmed by high-copy suppression: overexpression of MED7 suppresses a temperature-sensitive med21 mutation. Co-immunoprecipitation of tagged proteins in insect cells and E. coli confirms a direct Med21–Med7 protein interaction dependent on residues 2–8 of Med21.","method":"High-copy suppressor screen, co-immunoprecipitation from insect cells and E. coli, two-hybrid assay","journal":"Molecular genetics and genomics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic suppression plus reciprocal Co-IP in two heterologous systems; single lab","pmids":["16758199"],"is_preprint":false},{"year":2001,"finding":"C. elegans med-7 (let-49) is required for normal postembryonic development including gonad and germ cell development; RNAi knockdown demonstrates an additional role in embryogenesis. The gene was identified by molecular cloning and confirmed by rescue experiments.","method":"Genetic mapping and cloning of let-49/med-7 mutation, nonsense mutation identification, rescue experiments, RNAi knockdown","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function (nonsense allele + rescue + RNAi) with defined developmental phenotypes in C. elegans ortholog; single lab","pmids":["11728440"],"is_preprint":false},{"year":2014,"finding":"In Candida albicans, Med7 is non-essential for viability but is required for growth on specific carbon sources, hyphal formation, biofilm formation, and gastrointestinal colonization. Genome-wide ChIP shows Med7 occupies promoters of ~200 core genes under both yeast and hyphal conditions, with condition-specific expansion, and also occupies coding regions and 3′ ends. Loss of Med7 de-represses the ribosomal regulon.","method":"Conditional alleles, phenotypic assays, ChIP-chip genome-wide location profiling, gene expression microarrays, mouse colonization model","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with genome-wide localization and expression profiling; single lab, multiple orthogonal methods","pmids":["25375174"],"is_preprint":false},{"year":2007,"finding":"In yeast, reducing the amount of Med7 (as well as Med/Nut2) suppresses the growth defect caused by NC2 depletion, indicating that Med7 (middle module) acts antagonistically to the NC2 repressor in basal transcription regulation.","method":"Genetic suppressor screen, genetic epistasis (NC2 depletion combined with med7 reduction)","journal":"Genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single genetic suppressor observation; mechanism not further resolved at molecular level","pmids":["17339209"],"is_preprint":false},{"year":2014,"finding":"siRNA-mediated knockdown of MED7 in human cells significantly impairs HIV-1 replication at a post-integration step, specifically inhibiting transcription of nascent viral mRNA at the transactivation-responsive element (TAR) and impairing Tat-induced HIV transcription.","method":"siRNA knockdown, HIV replication assays, early/late HIV transcript quantification, Tat-dependent luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific transcriptional readouts (TAR, Tat-dependent transcription); single lab, multiple transcriptional assays","pmids":["25100719"],"is_preprint":false},{"year":2025,"finding":"E2F1 transcriptionally activates MED7 in hepatocellular carcinoma cells; knockdown of MED7 suppresses HCC cell proliferation, migration, invasion, and tube formation. Validated by dual-luciferase reporter assay and chromatin immunoprecipitation.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, cell proliferation/migration/invasion assays, xenograft mouse model","journal":"Chemical biology & drug design","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP + luciferase reporter establishes E2F1→MED7 transcriptional regulation; functional KD phenotypes shown; single lab","pmids":["39935236"],"is_preprint":false}],"current_model":"MED7 (CRSP33/CRSP9) is a conserved central scaffold subunit of the Mediator coactivator complex: it forms a structurally critical MED7·MED21 heterodimer whose four-helix bundle and flexible hinge are essential for middle-module architecture and for Mediator binding to RNA polymerase II, acts as a binding platform for Med4/9, Med10, Med31, and MED1 (whose ERK-phosphorylation-enhanced interaction with MED7 controls nuclear receptor signaling), is required for activated Pol II transcription in vitro and in vivo (including regulation of elongation), and is constitutively SUMOylated; its functions span coactivation of enhancer-binding factors such as Sp1, stimulation of CTD phosphorylation by TFIIH, regulation of telomeric silencing, and viral (HIV-1) transcription."},"narrative":{"mechanistic_narrative":"MED7 is a conserved central scaffold subunit of the Mediator coactivator complex, required for activator-dependent RNA polymerase II transcription from yeast to human [PMID:9989412, PMID:9420330]. Within the Mediator middle module it serves as a central binding platform, forming the structurally critical MED7·MED21 heterodimer—an extended fold built around a four-helix bundle and coiled-coil connected by a flexible hinge—and additional subcomplexes with Med31 (Med7C/31) and Med4/9, while also engaging Med10 and MED1 [PMID:15710619, PMID:19057509, PMID:20123732]. The integrity of the MED7·MED21 hinge is essential for Mediator to bind RNA polymerase II and assemble the holoenzyme: point mutations leave core Mediator intact but disorder the middle module and abolish Pol II affinity [PMID:27821593]. Mediator containing MED7 binds the Pol II C-terminal domain and stimulates its phosphorylation by TFIIH, coactivates enhancer-binding factors such as Sp1, and provides a direct binding site for MED1 whose ERK-phosphorylation-enhanced association with MED7 promotes nuclear receptor coactivation [PMID:9989412, PMID:9671713, PMID:18391015]. Beyond initiation, MED7 regulates Pol II elongation through coding regions [PMID:22377631] and modulates subtelomeric chromatin silencing via Mediator occupancy and H4K16 acetylation balance [PMID:21482672]. The human protein is constitutively SUMOylated [PMID:17709345], is required for Tat-dependent HIV-1 transcription at the TAR element [PMID:25100719], and its developmental and growth roles are conserved in C. elegans and Candida albicans [PMID:11728440, PMID:25375174].","teleology":[{"year":1998,"claim":"Establishing that a Med7-containing Mediator complex physically engages the Pol II CTD and stimulates its phosphorylation defined Mediator's mechanistic link between activators and the basal transcription machinery.","evidence":"Biochemical purification of yeast and mammalian Mediator with CTD-binding and TFIIH phosphorylation assays in reconstituted in vitro transcription systems","pmids":["9671713","9420330"],"confidence":"High","gaps":["Did not resolve which specific subunits contact the CTD","Med7's individual contribution within the complex not isolated"]},{"year":1999,"claim":"Identifying CRSP33/MED7 as a CRSP coactivator subunit whose depletion abolishes Sp1-dependent transcription placed MED7 directly in the pathway of enhancer-binding activator function.","evidence":"Biochemical purification, cloning, immunodepletion, and in vitro transcription with Sp1 in human cells","pmids":["9989412"],"confidence":"High","gaps":["Did not define the molecular role of MED7 specifically versus other CRSP subunits","No structural basis for activator coactivation"]},{"year":2005,"claim":"The MED7·MED21 crystal structure revealed an extended four-helix-bundle architecture with a flexible hinge, providing a structural hypothesis for Mediator conformational change upon Pol II or activator binding.","evidence":"3.0 Å X-ray crystallography of the MED7·MED21 heterodimer with functional surface analysis","pmids":["15710619"],"confidence":"High","gaps":["Hinge function inferred structurally, not yet tested by mutation","Did not place the heterodimer in the assembled module"]},{"year":2007,"claim":"Confirming a direct, genetically supported MED7–MED21 interaction and discovering constitutive MED7 SUMOylation extended its characterization to subunit contacts and post-translational modification.","evidence":"High-copy suppression, reciprocal Co-IP in insect and bacterial systems, and UFDS-based SUMOylation screening with independent validation","pmids":["16758199","17709345"],"confidence":"Medium","gaps":["Functional consequence of MED7 SUMOylation not determined","SUMO acceptor residue and regulation unresolved"]},{"year":2008,"claim":"Showing that ERK-phosphorylated MED1 binds directly to MED7 connected MAPK signaling to nuclear receptor coactivation through a defined subunit contact.","evidence":"Co-IP, in vitro binding, ERK phosphorylation assays, and in vitro transcription with thyroid hormone receptor","pmids":["18391015"],"confidence":"High","gaps":["Phosphosite-to-MED7 interface not structurally mapped","In vivo dynamics of signal-regulated MED1 recruitment not shown"]},{"year":2010,"claim":"Reconstituting the recombinant middle module established MED7 as the central scaffold organizing three heterodimeric subcomplexes (Med7N/21, Med7C/31, Med4/9) at equimolar stoichiometry.","evidence":"Recombinant co-expression, native and ion-mobility MS, SAXS, and limited proteolysis of the yeast middle module","pmids":["20123732"],"confidence":"High","gaps":["Atomic-resolution arrangement of the full module not resolved","Dynamics of subcomplex assembly not characterized"]},{"year":2011,"claim":"Linking Med7 to subtelomeric Mediator occupancy and the Sir2/Sas2 acetylation balance revealed a chromatin-level role beyond transcription initiation, affecting silencing and lifespan.","evidence":"ChIP of Mediator at telomeres, H4K16ac chromatin assays, expression analysis, and replicative lifespan measurement in yeast","pmids":["21482672"],"confidence":"Medium","gaps":["Mechanism connecting Mediator occupancy to acetyltransferase balance unresolved","Conservation to human telomeres untested"]},{"year":2012,"claim":"Yeast ewe mutations showed Med7 controls Pol II transit through coding regions rather than promoter recruitment, establishing a post-initiation elongation function.","evidence":"Genetic analysis, Pol II ChIP at promoter and coding regions, 6-azauracil sensitivity, and reporter elongation assays","pmids":["22377631"],"confidence":"Medium","gaps":["Molecular mechanism of elongation control not defined","Gene-specificity of the elongation role not mapped genome-wide"]},{"year":2014,"claim":"Knockdown and genome-wide profiling extended MED7 function to viral transcription and to organismal phenotypes, showing it is required for Tat-dependent HIV-1 transcription and for hyphal/biofilm programs and colonization in Candida.","evidence":"siRNA knockdown with HIV transcript and Tat reporter assays in human cells; conditional alleles, ChIP-chip and microarrays, and a mouse colonization model in C. albicans","pmids":["25100719","25375174"],"confidence":"Medium","gaps":["Direct MED7 contact with the HIV TAR/Tat machinery not shown","Whether human MED7 occupies coding regions as in Candida untested"]},{"year":2016,"claim":"Targeted mutagenesis of the human MED21–MED7 hinge demonstrated that hinge integrity is required for Mediator–Pol II holoenzyme formation, converting the 2005 structural hypothesis into a tested mechanism.","evidence":"Affinity pull-down, subunit composition analysis, negative-stain EM of the Mediator–Pol II holoenzyme, and site-directed mutagenesis of hinge residues","pmids":["27821593"],"confidence":"High","gaps":["Atomic detail of the hinge-Pol II contact not resolved","Effect on activator-dependent transcription in vivo not measured"]},{"year":2025,"claim":"Identifying E2F1-driven transcription of MED7 and its requirement for HCC cell proliferation and invasion implicated MED7 expression in a cancer phenotype.","evidence":"Dual-luciferase reporter, ChIP, siRNA knockdown, proliferation/migration/invasion assays, and xenograft model in hepatocellular carcinoma cells","pmids":["39935236"],"confidence":"Medium","gaps":["Mediator-dependent transcriptional targets driving the phenotype not defined","Whether the effect reflects MED7's scaffolding role or a non-canonical activity unresolved"]},{"year":null,"claim":"How MED7's distinct structural roles—holoenzyme assembly, elongation control, and chromatin silencing—are coordinated and regulated by modifications such as SUMOylation in human cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking SUMOylation to MED7 function","Human-cell mechanism of MED7 in elongation and silencing not established","Functional consequence of distinct subcomplex contacts in vivo unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,6,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4]}],"complexes":["Mediator complex","CRSP coactivator complex","Mediator middle module","Mediator–Pol II holoenzyme"],"partners":["MED21","MED1","MED31","MED4","MED9","MED10","MED6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43513","full_name":"Mediator of RNA polymerase II transcription subunit 7","aliases":["Activator-recruited cofactor 34 kDa component","ARC34","Cofactor required for Sp1 transcriptional activation subunit 9","CRSP complex subunit 9","Mediator complex subunit 7","RNA polymerase transcriptional regulation mediator subunit 7 homolog","Transcriptional coactivator CRSP33"],"length_aa":233,"mass_kda":27.2,"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/O43513/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MED7","classification":"Common Essential","n_dependent_lines":1009,"n_total_lines":1208,"dependency_fraction":0.8352649006622517},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MED10","stoichiometry":10.0},{"gene":"MED11","stoichiometry":10.0},{"gene":"MED14","stoichiometry":10.0},{"gene":"MED17","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},{"gene":"MED29","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/MED7","total_profiled":1310},"omim":[{"mim_id":"620492","title":"MEDIATOR COMPLEX SUBUNIT 31; MED31","url":"https://www.omim.org/entry/620492"},{"mim_id":"605045","title":"MEDIATOR COMPLEX SUBUNIT 7; MED7","url":"https://www.omim.org/entry/605045"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear bodies","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED7"},"hgnc":{"alias_symbol":["CRSP33"],"prev_symbol":["CRSP9"]},"alphafold":{"accession":"O43513","domains":[{"cath_id":"-","chopping":"14-129","consensus_level":"medium","plddt":88.0584,"start":14,"end":129}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43513","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43513-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43513-F1-predicted_aligned_error_v6.png","plddt_mean":79.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED7","jax_strain_url":"https://www.jax.org/strain/search?query=MED7"},"sequence":{"accession":"O43513","fasta_url":"https://rest.uniprot.org/uniprotkb/O43513.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43513/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43513"}},"corpus_meta":[{"pmid":"9989412","id":"PMC_9989412","title":"The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9989412","citation_count":296,"is_preprint":false},{"pmid":"9420330","id":"PMC_9420330","title":"The Med proteins of yeast and their function through the RNA polymerase II carboxy-terminal domain.","date":"1998","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9420330","citation_count":262,"is_preprint":false},{"pmid":"9671713","id":"PMC_9671713","title":"Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9671713","citation_count":258,"is_preprint":false},{"pmid":"19096501","id":"PMC_19096501","title":"Malleable machines in transcription regulation: the mediator complex.","date":"2008","source":"PLoS computational 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nucleosome displacement in Saccharomyces cerevisiae.","date":"2012","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22377631","citation_count":33,"is_preprint":false},{"pmid":"21482672","id":"PMC_21482672","title":"Mediator influences telomeric silencing and cellular life span.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21482672","citation_count":30,"is_preprint":false},{"pmid":"25375174","id":"PMC_25375174","title":"A functional portrait of Med7 and the mediator complex in Candida albicans.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25375174","citation_count":29,"is_preprint":false},{"pmid":"17709345","id":"PMC_17709345","title":"Ubc9 fusion-directed SUMOylation identifies constitutive and inducible SUMOylation.","date":"2007","source":"Nucleic acids 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27821593","citation_count":24,"is_preprint":false},{"pmid":"16087722","id":"PMC_16087722","title":"The Sp transcription factors are involved in the cellular expression of the human glucose-dependent insulinotropic polypeptide receptor gene and overexpressed in adrenals of patients with Cushing's syndrome.","date":"2005","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/16087722","citation_count":23,"is_preprint":false},{"pmid":"37399403","id":"PMC_37399403","title":"NLRs derepress MED10b- and MED7-mediated repression of jasmonate-dependent transcription to activate immunity.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37399403","citation_count":21,"is_preprint":false},{"pmid":"16758199","id":"PMC_16758199","title":"Functional and physical interactions within the middle domain of the yeast mediator.","date":"2006","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/16758199","citation_count":18,"is_preprint":false},{"pmid":"22737227","id":"PMC_22737227","title":"Genome-wide profiling of pluripotent cells reveals a unique molecular signature of human embryonic germ cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22737227","citation_count":17,"is_preprint":false},{"pmid":"22737066","id":"PMC_22737066","title":"MC EMiNEM maps the interaction landscape of the Mediator.","date":"2012","source":"PLoS computational biology","url":"https://pubmed.ncbi.nlm.nih.gov/22737066","citation_count":13,"is_preprint":false},{"pmid":"17339209","id":"PMC_17339209","title":"Specific defects in different transcription complexes compensate for the requirement of the negative cofactor 2 repressor in Saccharomyces cerevisiae.","date":"2007","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17339209","citation_count":11,"is_preprint":false},{"pmid":"11728440","id":"PMC_11728440","title":"The MED-7 transcriptional mediator encoded by let-49 is required for gonad and germ cell development in Caenorhabditis elegans.","date":"2001","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11728440","citation_count":10,"is_preprint":false},{"pmid":"28785867","id":"PMC_28785867","title":"ScMED7, a sugarcane mediator subunit gene, acts as a regulator of plant immunity and is responsive to diverse stress and hormone treatments.","date":"2017","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/28785867","citation_count":7,"is_preprint":false},{"pmid":"34646396","id":"PMC_34646396","title":"Draft Genome Sequences and Genomic Analysis for Pigment Production in Bacteria Isolated from Blue Discolored Soymilk and Tofu.","date":"2021","source":"Journal of genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34646396","citation_count":4,"is_preprint":false},{"pmid":"38073375","id":"PMC_38073375","title":"Upregulation of MED7 was associated with progression in hepatocellular carcinoma.","date":"2023","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/38073375","citation_count":3,"is_preprint":false},{"pmid":"39935236","id":"PMC_39935236","title":"Baicalein Inhibits Tumor Property of Hepatocellular Carcinoma Cells Through the Inactivation of the E2F Transcription Factor 1/Mediator Complex Subunit 7 Axis.","date":"2025","source":"Chemical biology & drug design","url":"https://pubmed.ncbi.nlm.nih.gov/39935236","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15608,"output_tokens":4460,"usd":0.056862,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12514,"output_tokens":3764,"usd":0.078335,"stage2_stop_reason":"end_turn"},"total_usd":0.135197,"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\": \"CRSP33 (MED7 homolog) is a subunit of the human CRSP coactivator complex (~700 kDa, nine subunits) required together with TAFIIs for transcriptional activation by Sp1; immunodepletion of CRSP subunits abolishes Sp1-dependent transcription.\",\n      \"method\": \"Biochemical purification, gene cloning, immunodepletion of CRSP from transcription reactions, in vitro transcription assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro transcription reconstitution with immunodepletion and multiple orthogonal methods (purification, cloning, functional assay)\",\n      \"pmids\": [\"9989412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The mammalian (murine) Mediator complex contains a Med7 homolog that co-purifies with the complex; this complex binds to the RNA polymerase II C-terminal domain (CTD) and stimulates CTD phosphorylation by TFIIH.\",\n      \"method\": \"Biochemical purification, peptide sequencing, CTD-binding and TFIIH phosphorylation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with multiple functional readouts (CTD binding, TFIIH stimulation), replicated across yeast and mammalian systems\",\n      \"pmids\": [\"9671713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Med7 is a component of purified Mediator required for transcriptional activation in a fully defined in vitro system; the CTD of RNA polymerase II is required for Mediator function in vitro.\",\n      \"method\": \"Biochemical purification of yeast Mediator, in vitro transcription assay, CTD-requirement experiments\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — fully reconstituted in vitro transcription system with defined components; foundational Mediator characterization paper\",\n      \"pmids\": [\"9420330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The MED7·MED21 (Med7·Srb7) heterodimer forms a highly extended structure containing a four-helix bundle domain and a coiled-coil protrusion connected by a flexible hinge; this hinge is proposed to enable conformational changes in Mediator upon Pol II or activator binding. MED6 bridges via MED7·MED21 to the head module.\",\n      \"method\": \"X-ray crystallography (3.0 Å crystal structure of MED7·MED21 heterodimer), functional surface analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure with functional surface mapping and mechanistic interpretation validated by structural data\",\n      \"pmids\": [\"15710619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MED1 directly binds to the MED7 subunit, and ERK (MAPK) phosphorylation of MED1 enhances this MED1–MED7 interaction, thereby promoting MED1 association with the Mediator complex and its nuclear receptor coactivator activity.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, ERK phosphorylation assays, in vitro transcription with thyroid hormone receptor\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding shown by in vitro assay plus Co-IP, phosphorylation-dependent enhancement tested with in vitro transcription; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"18391015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The Med7N/31 submodule (N-terminal part of Med7 plus Med31/Soh1) adopts a novel fold in which two proline-rich stretches in Med7N wrap around the four-helix bundle of Med31; this submodule is required for activated transcription in vitro and has a predominantly positive function on expression of a specific gene subset (methionine metabolism, iron transport) in vivo.\",\n      \"method\": \"Crystal structure determination of Med7N/31, in vitro transcription assay with trans-complementation, in vivo transcriptome profiling, comparative phenotyping\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with in vitro functional reconstitution and in vivo transcriptome data\",\n      \"pmids\": [\"19057509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Within the recombinant yeast Mediator middle module (Med1, 4, 7, 9, 10, 21, 31), Med7 serves as a central binding platform forming three heterodimeric subcomplexes: Med7N/21, Med7C/31, and (with Med4) the Med4/9 pair; Med1 and Med10 also bind to Med7. Native mass spectrometry confirms equimolar stoichiometry of all seven subunits.\",\n      \"method\": \"Recombinant co-expression and purification, native mass spectrometry, ion-mobility MS, limited proteolysis, SAXS, protein-protein interaction assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted recombinant module with multiple biophysical methods (native MS, SAXS, limited proteolysis) establishing Med7 as central scaffold\",\n      \"pmids\": [\"20123732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The Med7/Med21 four-helix bundle fold is a common building block shared with the head module Med11/22 heterodimer; this motif is predicted in several other Mediator heterodimers, indicating a multiplied and functionally diversified building block in Mediator evolution.\",\n      \"method\": \"Crystal structure of Med11/22, structural comparison with published Med7/Med21 structure, in vitro pre-initiation complex formation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural analysis of Med11/22 with comparison to Med7/Med21; Med7-specific functional evidence comes from the structural analogy, not direct Med7 experiment in this paper\",\n      \"pmids\": [\"21498544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A 3D model of the yeast Mediator middle module places the Med7/Med21 heterodimer at the center of a tetramer with Med4/Med9; Med10 and Med31 flank Med7/Med21. This elongated, flexible arrangement was determined by lysine–lysine cross-linking coupled to mass spectrometry.\",\n      \"method\": \"Chemical cross-linking mass spectrometry (XL-MS), arrangement of crystal structures and homology models into 3D model\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — XL-MS-based structural model with crystal structure inputs; not atomic resolution but multiple orthogonal constraints\",\n      \"pmids\": [\"23939621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CRSP9/MED7 (human) is constitutively SUMOylated in vivo, as identified by the Ubc9 fusion-dependent SUMOylation (UFDS) system, with SUMO modification confirmed independently of the fusion system.\",\n      \"method\": \"Ubc9 fusion-dependent SUMOylation (UFDS) screen, independent in vivo SUMOylation validation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — UFDS screening plus independent in vivo validation; single lab but two orthogonal methods\",\n      \"pmids\": [\"17709345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The integrity of the conserved hinge region in the human MED21–MED7 heterodimer is required for Mediator binding to RNA polymerase II to form the holoenzyme; point mutations in the hinge leave core Mediator intact but increase disorder in the middle module and markedly reduce affinity for Pol II.\",\n      \"method\": \"Biochemistry (affinity pull-down, subunit composition analysis), negative-stain electron microscopy of Mediator–Pol II holoenzyme, site-directed mutagenesis of hinge residues\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis combined with biochemical binding assays and EM structural analysis; directly tests MED7 hinge function in holoenzyme assembly\",\n      \"pmids\": [\"27821593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mutations in yeast Med7 (ewe alleles) located in or adjacent to the middle module severely diminish heat-shock-induced expression of HSP82 by impairing Pol II transit through the coding region rather than Pol II recruitment to the promoter, indicating a role for Med7 in regulating Pol II elongation.\",\n      \"method\": \"Genetic analysis (ewe mutations), ChIP of Pol II at promoter and coding regions, 6-azauracil sensitivity assay, reporter gene elongation assay\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with ChIP-based mechanistic readout showing post-initiation function; single lab, multiple methods\",\n      \"pmids\": [\"22377631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mutations in yeast Med7 reduce Mediator occupancy at subtelomeric regions, causing a shift in Sir2/Sas2 balance and increased H4K16 acetylation near telomeres, leading to desilencing of subtelomeric genes and influencing cellular life span.\",\n      \"method\": \"ChIP of Mediator at telomeres, chromatin acetylation assays (H4K16ac), gene expression analysis, replicative lifespan measurement\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP localization tied to functional chromatin and lifespan consequences; single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"21482672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In yeast, the genetic interaction between Med7 and Med21 (Srb7) is confirmed by high-copy suppression: overexpression of MED7 suppresses a temperature-sensitive med21 mutation. Co-immunoprecipitation of tagged proteins in insect cells and E. coli confirms a direct Med21–Med7 protein interaction dependent on residues 2–8 of Med21.\",\n      \"method\": \"High-copy suppressor screen, co-immunoprecipitation from insect cells and E. coli, two-hybrid assay\",\n      \"journal\": \"Molecular genetics and genomics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic suppression plus reciprocal Co-IP in two heterologous systems; single lab\",\n      \"pmids\": [\"16758199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"C. elegans med-7 (let-49) is required for normal postembryonic development including gonad and germ cell development; RNAi knockdown demonstrates an additional role in embryogenesis. The gene was identified by molecular cloning and confirmed by rescue experiments.\",\n      \"method\": \"Genetic mapping and cloning of let-49/med-7 mutation, nonsense mutation identification, rescue experiments, RNAi knockdown\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function (nonsense allele + rescue + RNAi) with defined developmental phenotypes in C. elegans ortholog; single lab\",\n      \"pmids\": [\"11728440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Candida albicans, Med7 is non-essential for viability but is required for growth on specific carbon sources, hyphal formation, biofilm formation, and gastrointestinal colonization. Genome-wide ChIP shows Med7 occupies promoters of ~200 core genes under both yeast and hyphal conditions, with condition-specific expansion, and also occupies coding regions and 3′ ends. Loss of Med7 de-represses the ribosomal regulon.\",\n      \"method\": \"Conditional alleles, phenotypic assays, ChIP-chip genome-wide location profiling, gene expression microarrays, mouse colonization model\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with genome-wide localization and expression profiling; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25375174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In yeast, reducing the amount of Med7 (as well as Med/Nut2) suppresses the growth defect caused by NC2 depletion, indicating that Med7 (middle module) acts antagonistically to the NC2 repressor in basal transcription regulation.\",\n      \"method\": \"Genetic suppressor screen, genetic epistasis (NC2 depletion combined with med7 reduction)\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single genetic suppressor observation; mechanism not further resolved at molecular level\",\n      \"pmids\": [\"17339209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"siRNA-mediated knockdown of MED7 in human cells significantly impairs HIV-1 replication at a post-integration step, specifically inhibiting transcription of nascent viral mRNA at the transactivation-responsive element (TAR) and impairing Tat-induced HIV transcription.\",\n      \"method\": \"siRNA knockdown, HIV replication assays, early/late HIV transcript quantification, Tat-dependent luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific transcriptional readouts (TAR, Tat-dependent transcription); single lab, multiple transcriptional assays\",\n      \"pmids\": [\"25100719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"E2F1 transcriptionally activates MED7 in hepatocellular carcinoma cells; knockdown of MED7 suppresses HCC cell proliferation, migration, invasion, and tube formation. Validated by dual-luciferase reporter assay and chromatin immunoprecipitation.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, cell proliferation/migration/invasion assays, xenograft mouse model\",\n      \"journal\": \"Chemical biology & drug design\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP + luciferase reporter establishes E2F1→MED7 transcriptional regulation; functional KD phenotypes shown; single lab\",\n      \"pmids\": [\"39935236\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED7 (CRSP33/CRSP9) is a conserved central scaffold subunit of the Mediator coactivator complex: it forms a structurally critical MED7·MED21 heterodimer whose four-helix bundle and flexible hinge are essential for middle-module architecture and for Mediator binding to RNA polymerase II, acts as a binding platform for Med4/9, Med10, Med31, and MED1 (whose ERK-phosphorylation-enhanced interaction with MED7 controls nuclear receptor signaling), is required for activated Pol II transcription in vitro and in vivo (including regulation of elongation), and is constitutively SUMOylated; its functions span coactivation of enhancer-binding factors such as Sp1, stimulation of CTD phosphorylation by TFIIH, regulation of telomeric silencing, and viral (HIV-1) transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED7 is a conserved central scaffold subunit of the Mediator coactivator complex, required for activator-dependent RNA polymerase II transcription from yeast to human [#0, #2]. Within the Mediator middle module it serves as a central binding platform, forming the structurally critical MED7\\u00b7MED21 heterodimer\\u2014an extended fold built around a four-helix bundle and coiled-coil connected by a flexible hinge\\u2014and additional subcomplexes with Med31 (Med7C/31) and Med4/9, while also engaging Med10 and MED1 [#3, #5, #6]. The integrity of the MED7\\u00b7MED21 hinge is essential for Mediator to bind RNA polymerase II and assemble the holoenzyme: point mutations leave core Mediator intact but disorder the middle module and abolish Pol II affinity [#10]. Mediator containing MED7 binds the Pol II C-terminal domain and stimulates its phosphorylation by TFIIH, coactivates enhancer-binding factors such as Sp1, and provides a direct binding site for MED1 whose ERK-phosphorylation-enhanced association with MED7 promotes nuclear receptor coactivation [#0, #1, #4]. Beyond initiation, MED7 regulates Pol II elongation through coding regions [#11] and modulates subtelomeric chromatin silencing via Mediator occupancy and H4K16 acetylation balance [#12]. The human protein is constitutively SUMOylated [#9], is required for Tat-dependent HIV-1 transcription at the TAR element [#17], and its developmental and growth roles are conserved in C. elegans and Candida albicans [#14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that a Med7-containing Mediator complex physically engages the Pol II CTD and stimulates its phosphorylation defined Mediator's mechanistic link between activators and the basal transcription machinery.\",\n      \"evidence\": \"Biochemical purification of yeast and mammalian Mediator with CTD-binding and TFIIH phosphorylation assays in reconstituted in vitro transcription systems\",\n      \"pmids\": [\"9671713\", \"9420330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which specific subunits contact the CTD\", \"Med7's individual contribution within the complex not isolated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identifying CRSP33/MED7 as a CRSP coactivator subunit whose depletion abolishes Sp1-dependent transcription placed MED7 directly in the pathway of enhancer-binding activator function.\",\n      \"evidence\": \"Biochemical purification, cloning, immunodepletion, and in vitro transcription with Sp1 in human cells\",\n      \"pmids\": [\"9989412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular role of MED7 specifically versus other CRSP subunits\", \"No structural basis for activator coactivation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The MED7\\u00b7MED21 crystal structure revealed an extended four-helix-bundle architecture with a flexible hinge, providing a structural hypothesis for Mediator conformational change upon Pol II or activator binding.\",\n      \"evidence\": \"3.0 \\u00c5 X-ray crystallography of the MED7\\u00b7MED21 heterodimer with functional surface analysis\",\n      \"pmids\": [\"15710619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hinge function inferred structurally, not yet tested by mutation\", \"Did not place the heterodimer in the assembled module\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Confirming a direct, genetically supported MED7\\u2013MED21 interaction and discovering constitutive MED7 SUMOylation extended its characterization to subunit contacts and post-translational modification.\",\n      \"evidence\": \"High-copy suppression, reciprocal Co-IP in insect and bacterial systems, and UFDS-based SUMOylation screening with independent validation\",\n      \"pmids\": [\"16758199\", \"17709345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of MED7 SUMOylation not determined\", \"SUMO acceptor residue and regulation unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that ERK-phosphorylated MED1 binds directly to MED7 connected MAPK signaling to nuclear receptor coactivation through a defined subunit contact.\",\n      \"evidence\": \"Co-IP, in vitro binding, ERK phosphorylation assays, and in vitro transcription with thyroid hormone receptor\",\n      \"pmids\": [\"18391015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite-to-MED7 interface not structurally mapped\", \"In vivo dynamics of signal-regulated MED1 recruitment not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reconstituting the recombinant middle module established MED7 as the central scaffold organizing three heterodimeric subcomplexes (Med7N/21, Med7C/31, Med4/9) at equimolar stoichiometry.\",\n      \"evidence\": \"Recombinant co-expression, native and ion-mobility MS, SAXS, and limited proteolysis of the yeast middle module\",\n      \"pmids\": [\"20123732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution arrangement of the full module not resolved\", \"Dynamics of subcomplex assembly not characterized\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linking Med7 to subtelomeric Mediator occupancy and the Sir2/Sas2 acetylation balance revealed a chromatin-level role beyond transcription initiation, affecting silencing and lifespan.\",\n      \"evidence\": \"ChIP of Mediator at telomeres, H4K16ac chromatin assays, expression analysis, and replicative lifespan measurement in yeast\",\n      \"pmids\": [\"21482672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting Mediator occupancy to acetyltransferase balance unresolved\", \"Conservation to human telomeres untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Yeast ewe mutations showed Med7 controls Pol II transit through coding regions rather than promoter recruitment, establishing a post-initiation elongation function.\",\n      \"evidence\": \"Genetic analysis, Pol II ChIP at promoter and coding regions, 6-azauracil sensitivity, and reporter elongation assays\",\n      \"pmids\": [\"22377631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of elongation control not defined\", \"Gene-specificity of the elongation role not mapped genome-wide\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Knockdown and genome-wide profiling extended MED7 function to viral transcription and to organismal phenotypes, showing it is required for Tat-dependent HIV-1 transcription and for hyphal/biofilm programs and colonization in Candida.\",\n      \"evidence\": \"siRNA knockdown with HIV transcript and Tat reporter assays in human cells; conditional alleles, ChIP-chip and microarrays, and a mouse colonization model in C. albicans\",\n      \"pmids\": [\"25100719\", \"25375174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MED7 contact with the HIV TAR/Tat machinery not shown\", \"Whether human MED7 occupies coding regions as in Candida untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Targeted mutagenesis of the human MED21\\u2013MED7 hinge demonstrated that hinge integrity is required for Mediator\\u2013Pol II holoenzyme formation, converting the 2005 structural hypothesis into a tested mechanism.\",\n      \"evidence\": \"Affinity pull-down, subunit composition analysis, negative-stain EM of the Mediator\\u2013Pol II holoenzyme, and site-directed mutagenesis of hinge residues\",\n      \"pmids\": [\"27821593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic detail of the hinge-Pol II contact not resolved\", \"Effect on activator-dependent transcription in vivo not measured\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying E2F1-driven transcription of MED7 and its requirement for HCC cell proliferation and invasion implicated MED7 expression in a cancer phenotype.\",\n      \"evidence\": \"Dual-luciferase reporter, ChIP, siRNA knockdown, proliferation/migration/invasion assays, and xenograft model in hepatocellular carcinoma cells\",\n      \"pmids\": [\"39935236\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mediator-dependent transcriptional targets driving the phenotype not defined\", \"Whether the effect reflects MED7's scaffolding role or a non-canonical activity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MED7's distinct structural roles\\u2014holoenzyme assembly, elongation control, and chromatin silencing\\u2014are coordinated and regulated by modifications such as SUMOylation in human cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking SUMOylation to MED7 function\", \"Human-cell mechanism of MED7 in elongation and silencing not established\", \"Functional consequence of distinct subcomplex contacts in vivo unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 6, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\"Mediator complex\", \"CRSP coactivator complex\", \"Mediator middle module\", \"Mediator\\u2013Pol II holoenzyme\"],\n    \"partners\": [\"MED21\", \"MED1\", \"MED31\", \"MED4\", \"MED9\", \"MED10\", \"MED6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}