{"gene":"MED4","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2014,"finding":"MED4 (Mediator subunit) is a survival gene in retinoblastoma: RB1-/- retinoblastoma cells cannot survive in the absence of MED4, both in vitro and in orthotopic xenograft models in vivo, establishing a synthetic lethal relationship between RB1 loss and MED4 loss.","method":"In vitro cell viability assays and orthotopic xenograft models with MED4 knockdown/loss in RB1-/- retinoblastoma cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular and in vivo phenotype, two orthogonal model systems (in vitro + xenograft), single lab","pmids":["24858910"],"is_preprint":false},{"year":2024,"finding":"MED4 maintains 3D chromatin compaction and enhancer landscape by preventing enhancer priming or activation through suppression of H3K4me1 deposition; contrary to the canonical Mediator role in activating gene expression. MED4 haploinsufficiency disrupts enhancer poise and reprograms enhancer dynamics to facilitate ECM gene expression and integrin-mediated mechanotransduction, driving metastatic growth.","method":"Genome-scale genetic screen, syngeneic xenograft models, chromatin conformation assays, histone modification profiling (H3K4me1), enhancer landscape analysis, gene expression profiling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple orthogonal methods (chromatin, histone marks, xenograft) but single lab, preprint only, not yet peer-reviewed","pmids":["38014033"],"is_preprint":true}],"current_model":"MED4 is a subunit of the Mediator transcriptional coactivator complex that, contrary to the canonical Mediator role in activating transcription, maintains 3D chromatin compaction and suppresses enhancer priming by preventing H3K4me1 deposition; its loss creates a synthetic lethal interaction in RB1-deficient retinoblastoma cells and, in breast cancer, its haploinsufficiency disrupts enhancer poise to drive ECM gene expression and integrin-mediated mechanotransduction, enabling metastatic reactivation from dormancy."},"narrative":{"mechanistic_narrative":"MED4 is a subunit of the Mediator transcriptional coactivator complex that functions in chromatin architecture and enhancer regulation [PMID:38014033]. In retinoblastoma, MED4 is a survival gene: RB1-deficient cells cannot survive its loss in vitro or in orthotopic xenografts, defining a synthetic lethal interaction between RB1 loss and MED4 loss [PMID:24858910]. Contrary to the canonical Mediator role in activating transcription, MED4 maintains 3D chromatin compaction and suppresses enhancer priming by preventing H3K4me1 deposition; its haploinsufficiency disrupts enhancer poise and reprograms enhancer dynamics to drive ECM gene expression and integrin-mediated mechanotransduction, enabling metastatic growth [PMID:38014033]. Beyond these two contexts, no further mechanistic detail of MED4 has been characterized in the available corpus.","teleology":[{"year":2014,"claim":"Established that MED4 is selectively required for survival of RB1-deficient cancer cells, identifying a genetic dependency exploitable in retinoblastoma rather than a generic essential role.","evidence":"MED4 knockdown/loss in RB1-/- retinoblastoma cells assayed by in vitro viability and orthotopic xenograft models","pmids":["24858910"],"confidence":"Medium","gaps":["Molecular mechanism linking RB1 loss to MED4 dependence not defined","Whether the synthetic lethality extends beyond retinoblastoma untested","No biochemical characterization of MED4's role within Mediator in this context"]},{"year":2024,"claim":"Reframed MED4 as a repressive chromatin regulator that maintains 3D compaction and enhancer poise, showing that its haploinsufficiency reprograms enhancers to drive ECM expression, mechanotransduction, and metastatic growth.","evidence":"Genome-scale genetic screen, syngeneic xenografts, chromatin conformation assays, H3K4me1 profiling, and enhancer/gene expression analysis (preprint)","pmids":["38014033"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed and from a single lab","Mechanism by which MED4 suppresses H3K4me1 deposition not resolved","Direct link between MED4 chromatin function and the RB1 synthetic lethality not established"]},{"year":null,"claim":"How MED4's role within the Mediator complex mechanistically connects chromatin compaction, enhancer suppression, and RB1-dependent survival remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or biochemical model of MED4 within Mediator in the corpus","No direct MED4 physical partners or substrates identified","Whether enhancer regulation and RB1 synthetic lethality share a common mechanism is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1]}],"complexes":["Mediator complex"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NPJ6","full_name":"Mediator of RNA polymerase II transcription subunit 4","aliases":["Activator-recruited cofactor 36 kDa component","ARC36","Mediator complex subunit 4","TRAP/SMCC/PC2 subunit p36 subunit","Vitamin D3 receptor-interacting protein complex 36 kDa component","DRIP36"],"length_aa":270,"mass_kda":29.7,"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/Q9NPJ6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MED4","classification":"Common Essential","n_dependent_lines":1195,"n_total_lines":1208,"dependency_fraction":0.9892384105960265},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000136146","cell_line_id":"CID000249","localizations":[{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"MED10","stoichiometry":10.0},{"gene":"MED11","stoichiometry":10.0},{"gene":"MED14","stoichiometry":10.0},{"gene":"MED19","stoichiometry":10.0},{"gene":"MED21","stoichiometry":10.0},{"gene":"MED27","stoichiometry":10.0},{"gene":"MED28","stoichiometry":10.0},{"gene":"MED29","stoichiometry":10.0},{"gene":"MED31","stoichiometry":10.0},{"gene":"MED23","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000249","total_profiled":1310},"omim":[{"mim_id":"614135","title":"EPIPHYSEAL DYSPLASIA, MULTIPLE, 6; EDM6","url":"https://www.omim.org/entry/614135"},{"mim_id":"609878","title":"MEDIATOR COMPLEX SUBUNIT 9; MED9","url":"https://www.omim.org/entry/609878"},{"mim_id":"605718","title":"MEDIATOR COMPLEX SUBUNIT 4; MED4","url":"https://www.omim.org/entry/605718"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED4"},"hgnc":{"alias_symbol":["HSPC126","DRIP36","TRAP36"],"prev_symbol":["VDRIP"]},"alphafold":{"accession":"Q9NPJ6","domains":[{"cath_id":"1.10.287","chopping":"25-109","consensus_level":"high","plddt":91.5165,"start":25,"end":109}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPJ6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPJ6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NPJ6-F1-predicted_aligned_error_v6.png","plddt_mean":73.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED4","jax_strain_url":"https://www.jax.org/strain/search?query=MED4"},"sequence":{"accession":"Q9NPJ6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NPJ6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NPJ6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NPJ6"}},"corpus_meta":[{"pmid":"12712234","id":"PMC_12712234","title":"A novel type of lycopene epsilon-cyclase in the marine cyanobacterium Prochlorococcus marinus MED4.","date":"2003","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12712234","citation_count":69,"is_preprint":false},{"pmid":"22941652","id":"PMC_22941652","title":"Sequence analysis of a complete 1.66 Mb Prochlorococcus marinus MED4 genome cloned in yeast.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22941652","citation_count":46,"is_preprint":false},{"pmid":"12771216","id":"PMC_12771216","title":"Experimental and computational analysis of transcriptional start sites in the cyanobacterium Prochlorococcus MED4.","date":"2003","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/12771216","citation_count":37,"is_preprint":false},{"pmid":"15133090","id":"PMC_15133090","title":"Effects of high light on transcripts of stress-associated genes for the cyanobacteria Synechocystis sp. PCC 6803 and Prochlorococcus MED4 and MIT9313.","date":"2004","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15133090","citation_count":31,"is_preprint":false},{"pmid":"16156734","id":"PMC_16156734","title":"A green light-absorbing phycoerythrin is present in the high-light-adapted marine cyanobacterium Prochlorococcus sp. MED4.","date":"2005","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16156734","citation_count":31,"is_preprint":false},{"pmid":"13129619","id":"PMC_13129619","title":"Two-component systems in Prochlorococcus MED4: genomic analysis and differential expression under stress.","date":"2003","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/13129619","citation_count":29,"is_preprint":false},{"pmid":"24858910","id":"PMC_24858910","title":"The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24858910","citation_count":27,"is_preprint":false},{"pmid":"25315602","id":"PMC_25315602","title":"The minimal CO2-concentrating mechanism of Prochlorococcus spp. MED4 is effective and efficient.","date":"2014","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25315602","citation_count":27,"is_preprint":false},{"pmid":"23387819","id":"PMC_23387819","title":"Effects of phosphorus starvation versus limitation on the marine cyanobacterium Prochlorococcus MED4 I: uptake physiology.","date":"2013","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23387819","citation_count":24,"is_preprint":false},{"pmid":"20345942","id":"PMC_20345942","title":"UV hyper-resistance in Prochlorococcus MED4 results from a single base pair deletion just upstream of an operon encoding nudix hydrolase and photolyase.","date":"2010","source":"Environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20345942","citation_count":22,"is_preprint":false},{"pmid":"31586076","id":"PMC_31586076","title":"Interplay and Targetome of the Two Conserved Cyanobacterial sRNAs Yfr1 and Yfr2 in Prochlorococcus MED4.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31586076","citation_count":9,"is_preprint":false},{"pmid":"24438106","id":"PMC_24438106","title":"The transcriptome landscape of Prochlorococcus MED4 and the factors for stabilizing the core genome.","date":"2014","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24438106","citation_count":3,"is_preprint":false},{"pmid":"39842488","id":"PMC_39842488","title":"Characterization of extracellular vesicles released from Prochlorococcus MED4 at the steady state and under a light-dark cycle.","date":"2025","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39842488","citation_count":2,"is_preprint":false},{"pmid":"38014033","id":"PMC_38014033","title":"Mediator Subunit Med4 Enforces Metastatic Dormancy in Breast Cancer.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38014033","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.20.677525","title":"Transformation of plasmid DNA into  <i>Prochlorococcus</i>  via electroporation","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.20.677525","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.11.628001","title":"Synergy and antagonism in a genome-scale model of metabolic hijacking by bacteriophages","date":"2024-12-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.11.628001","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9374,"output_tokens":652,"usd":0.018951,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7019,"output_tokens":1333,"usd":0.03421,"stage2_stop_reason":"end_turn"},"total_usd":0.053161,"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\": 2014,\n      \"finding\": \"MED4 (Mediator subunit) is a survival gene in retinoblastoma: RB1-/- retinoblastoma cells cannot survive in the absence of MED4, both in vitro and in orthotopic xenograft models in vivo, establishing a synthetic lethal relationship between RB1 loss and MED4 loss.\",\n      \"method\": \"In vitro cell viability assays and orthotopic xenograft models with MED4 knockdown/loss in RB1-/- retinoblastoma cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular and in vivo phenotype, two orthogonal model systems (in vitro + xenograft), single lab\",\n      \"pmids\": [\"24858910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MED4 maintains 3D chromatin compaction and enhancer landscape by preventing enhancer priming or activation through suppression of H3K4me1 deposition; contrary to the canonical Mediator role in activating gene expression. MED4 haploinsufficiency disrupts enhancer poise and reprograms enhancer dynamics to facilitate ECM gene expression and integrin-mediated mechanotransduction, driving metastatic growth.\",\n      \"method\": \"Genome-scale genetic screen, syngeneic xenograft models, chromatin conformation assays, histone modification profiling (H3K4me1), enhancer landscape analysis, gene expression profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple orthogonal methods (chromatin, histone marks, xenograft) but single lab, preprint only, not yet peer-reviewed\",\n      \"pmids\": [\"38014033\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MED4 is a subunit of the Mediator transcriptional coactivator complex that, contrary to the canonical Mediator role in activating transcription, maintains 3D chromatin compaction and suppresses enhancer priming by preventing H3K4me1 deposition; its loss creates a synthetic lethal interaction in RB1-deficient retinoblastoma cells and, in breast cancer, its haploinsufficiency disrupts enhancer poise to drive ECM gene expression and integrin-mediated mechanotransduction, enabling metastatic reactivation from dormancy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED4 is a subunit of the Mediator transcriptional coactivator complex that functions in chromatin architecture and enhancer regulation [#1]. In retinoblastoma, MED4 is a survival gene: RB1-deficient cells cannot survive its loss in vitro or in orthotopic xenografts, defining a synthetic lethal interaction between RB1 loss and MED4 loss [#0]. Contrary to the canonical Mediator role in activating transcription, MED4 maintains 3D chromatin compaction and suppresses enhancer priming by preventing H3K4me1 deposition; its haploinsufficiency disrupts enhancer poise and reprograms enhancer dynamics to drive ECM gene expression and integrin-mediated mechanotransduction, enabling metastatic growth [#1]. Beyond these two contexts, no further mechanistic detail of MED4 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that MED4 is selectively required for survival of RB1-deficient cancer cells, identifying a genetic dependency exploitable in retinoblastoma rather than a generic essential role.\",\n      \"evidence\": \"MED4 knockdown/loss in RB1-/- retinoblastoma cells assayed by in vitro viability and orthotopic xenograft models\",\n      \"pmids\": [\"24858910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism linking RB1 loss to MED4 dependence not defined\",\n        \"Whether the synthetic lethality extends beyond retinoblastoma untested\",\n        \"No biochemical characterization of MED4's role within Mediator in this context\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reframed MED4 as a repressive chromatin regulator that maintains 3D compaction and enhancer poise, showing that its haploinsufficiency reprograms enhancers to drive ECM expression, mechanotransduction, and metastatic growth.\",\n      \"evidence\": \"Genome-scale genetic screen, syngeneic xenografts, chromatin conformation assays, H3K4me1 profiling, and enhancer/gene expression analysis (preprint)\",\n      \"pmids\": [\"38014033\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint, not yet peer-reviewed and from a single lab\",\n        \"Mechanism by which MED4 suppresses H3K4me1 deposition not resolved\",\n        \"Direct link between MED4 chromatin function and the RB1 synthetic lethality not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MED4's role within the Mediator complex mechanistically connects chromatin compaction, enhancer suppression, and RB1-dependent survival remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or biochemical model of MED4 within Mediator in the corpus\",\n        \"No direct MED4 physical partners or substrates identified\",\n        \"Whether enhancer regulation and RB1 synthetic lethality share a common mechanism is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"Mediator complex\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}