{"gene":"MED30","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2002,"finding":"TRAP25 (MED30) was identified as a previously uncharacterized integral subunit of the human TRAP/Mediator complex; immunodepletion of TRAP25 removed essentially all TRAP/Mediator components from HeLa nuclear extract, and both basal and activator-dependent transcription were severely reduced, demonstrating that TRAP/Mediator (including MED30) is required for both basal and activated transcription in conjunction with TFIID-associated TAFIIs.","method":"Antibody-based immunodepletion of HeLa nuclear extract followed by in vitro transcription reconstitution assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with quantitative depletion and add-back, multiple transcription readouts","pmids":["11909976"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the human Mediator-RNA polymerase II pre-initiation complex showed that MED30 (together with MED27, MED28, MED29) associates with MED14 and MED17 to form the proximal part of the Mediator tail module that binds transcriptional activators; this structural context places MED30 at the interface anchoring Head and Tail modules.","method":"Cryo-electron microscopy of reconstituted 50-subunit human Mediator-PIC complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure of reconstituted human complex with functional validation of module organization","pmids":["33902108"],"is_preprint":false},{"year":2011,"finding":"A hypomorphic missense mutation in Med30 in mice caused progressive mitochondrial cardiomyopathy with pleiotropic downregulation of cardiac genes required for oxidative phosphorylation and mitochondrial integrity, establishing a mechanistic link between MED30 and the transcriptional program controlling oxidative phosphorylation and fatty acid oxidation.","method":"Mouse genetics (hypomorphic missense mutation), expression profiling, dietary intervention (ketogenic diet rescue)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo loss-of-function with defined transcriptional phenotype and rescue experiment","pmids":["22106289"],"is_preprint":false},{"year":2021,"finding":"Cardiomyocyte-specific deletion of MED30 in mice destabilized Mediator core subunits (while the kinase module was preserved), demonstrating that MED30 is essential for the structural integrity and stability of the overall Mediator complex in vivo; deletion caused rapid cardiac defects and lethality, and RNAseq revealed loss of critical cardiomyocyte transcription networks.","method":"Conditional and inducible cardiomyocyte-specific Med30 knockout mice, Western blot for Mediator subunit levels, RNAseq","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with multiple orthogonal readouts (protein stability, transcriptomics, physiology)","pmids":["34506481"],"is_preprint":false},{"year":2014,"finding":"siRNA-mediated knockdown of MED30 in HIV-infected cells significantly impaired HIV-1 replication at a post-integration step, specifically affecting formation of unspliced viral transcripts; MED30 knockdown also compromised HIV transcription induced by Tat.","method":"siRNA knockdown in HIV-infected cells, RT-PCR for viral transcripts, Tat-induced transcription assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined transcriptional phenotype but single lab, no direct interaction with Tat shown for MED30","pmids":["25100719"],"is_preprint":false},{"year":2019,"finding":"In Drosophila cells, the MED30 subunit of the Mediator complex directs Nipped-B (cohesin loader) and Rad21 (cohesin) to gene promoters, as shown by genome-wide ChIP; this is distinct from enhancers where SA and Fs(1)h recruit cohesin, indicating MED30 plays a specific role in promoter-localized cohesin recruitment.","method":"Genome-wide chromatin immunoprecipitation (ChIP-seq) in Drosophila cells, genetic analysis","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide ChIP with genetic validation, but findings in Drosophila (ortholog context)","pmids":["30796039"],"is_preprint":false},{"year":2015,"finding":"MED30 overexpression increased proliferation, migration, and invasion of gastric cancer cells, while MED30 knockdown inhibited these effects and suppressed tumorigenicity in SCID mice; MED30 also promoted expression of epithelial-mesenchymal transition genes.","method":"siRNA knockdown and overexpression in gastric cancer cell lines, proliferation/migration/invasion assays, xenograft in SCID mice","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — bidirectional manipulation with in vivo validation, but no direct molecular mechanism identified","pmids":["26110885"],"is_preprint":false},{"year":2020,"finding":"MED30 expression in glioblastoma cells is regulated by HIF1α and p53 through hypoxia response elements (HREs) and p53 binding sites in the MED30 promoter; MED30 promotes cell proliferation while reducing migration in GBM cells, and MED30 modulates p53 levels and confers sensitivity to temozolomide.","method":"Promoter analysis, HIF1α/p53 dependency experiments, MED30 overexpression and knockdown in GBM cell lines, proliferation/migration assays","journal":"Cellular and molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab with functional assays and promoter analysis but limited mechanistic depth","pmids":["32705436"],"is_preprint":false},{"year":2024,"finding":"MED30 overexpression/amplification recruits other Mediator components and redirects MYC binding to a novel subset of genomic regulatory sites, inducing new enhancer formation with altered epigenetic marks and driving expression of cancer progression genes; MED30 knockdown reduced tumor growth particularly in MYC-high GBM and PDAC models.","method":"Transcriptional profiling, ChIP-seq for MYC and epigenetic marks, in vivo tumor models (PDAC, GBM), siRNA knockdown","journal":"Research square (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP-seq, transcriptomics, in vivo), but preprint not yet peer-reviewed","pmids":["38766212"],"is_preprint":true},{"year":2024,"finding":"Loss of MED30 in human pancreatic β-cells (EndoC-βH3) markedly reduced cell viability, demonstrating a cell-autonomous role for MED30 in β-cell survival, identified via CRISPR-Cas9 enhancer deletion.","method":"CRISPR-Cas9 deletion of enhancer regions in EndoC-βH3 cells, cell viability assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 — direct CRISPR loss-of-function with defined cellular phenotype, but indirect (enhancer deletion lowers MED30 expression)","pmids":["38661000"],"is_preprint":false},{"year":2024,"finding":"Overexpression of MED30 fails to restore Mediator subunit protein levels in MED27-deficient cardiomyocytes, demonstrating that MED27's role in maintaining Mediator core integrity is independent of MED30, and that MED30 and MED27 are non-redundant upper Tail subunits each required for Mediator stability.","method":"Cardiomyocyte-specific Med27 knockout mice, MED30 overexpression rescue experiment, Western blot for Mediator subunits","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with direct protein-level readout, single lab","pmids":["39209248"],"is_preprint":false},{"year":2017,"finding":"siRNA-mediated knockdown of MED30 significantly decreased proliferation, migration, and invasion in clear cell renal cell carcinoma cell lines, demonstrating a functional role for MED30 in RCC cell behavior.","method":"siRNA knockdown in ccRCC cell lines (ACHN, A-498), proliferation, migration, and invasion assays","journal":"Annals of diagnostic pathology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single approach, no molecular mechanism identified","pmids":["29661722"],"is_preprint":false},{"year":2017,"finding":"siRNA-mediated knockdown of MED30 reduced proliferation, migration, and invasion in bladder cancer cell lines (T24 and TCCSUP).","method":"siRNA knockdown in bladder cancer cell lines, proliferation, migration, invasion assays","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single approach, functional phenotype only","pmids":["29187445"],"is_preprint":false},{"year":2026,"finding":"Genome-wide CRISPR loss-of-function screening identified MED30 as a positive regulator of endogenous MYC expression in multiple myeloma cells; functional validation confirmed that MED30 knockout strongly reduced MYC protein levels.","method":"Genome-wide CRISPR-Cas9 screen using GFP-tagged endogenous MYC reporter, validation by individual sgRNA knockouts","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — pooled genome-wide screen with functional validation of hit, direct readout of endogenous MYC levels","pmids":["41965876"],"is_preprint":false}],"current_model":"MED30 is a metazoan-specific integral subunit of the Mediator complex that localizes to the proximal tail module (anchoring Head and Tail modules), is essential for structural stability of the overall Mediator core complex in vivo, supports both basal and activator-dependent RNA Pol II transcription, regulates oxidative phosphorylation and metabolic gene programs in cardiomyocytes, recruits cohesin to gene promoters, facilitates MYC-driven oncogenic transcriptional programs by directing Mediator assembly at novel enhancers, and is required for HIV-1 post-integration transcription."},"narrative":{"teleology":[{"year":2002,"claim":"Establishing that MED30 (TRAP25) is an integral Mediator subunit required for transcription resolved its identity among the ~30 Mediator components and showed the complex is needed for both basal and activator-dependent RNA Pol II activity.","evidence":"Immunodepletion of TRAP25 from HeLa nuclear extract followed by in vitro transcription reconstitution","pmids":["11909976"],"confidence":"High","gaps":["Role of MED30 within Mediator architecture not resolved","Contribution of MED30 versus other subunits to in vivo transcription unknown","No loss-of-function data in intact organisms"]},{"year":2011,"claim":"A mouse hypomorphic Med30 mutation linked the subunit to a specific transcriptional program — oxidative phosphorylation and fatty acid oxidation in cardiomyocytes — moving understanding beyond a generic coactivator role to tissue-specific metabolic regulation.","evidence":"Mouse missense mutation causing progressive cardiomyopathy; expression profiling and ketogenic diet rescue","pmids":["22106289"],"confidence":"High","gaps":["Direct target genes versus secondary effects not delineated","Mechanism by which MED30 selectively controls metabolic gene programs unclear","Whether human MED30 mutations cause cardiomyopathy not established"]},{"year":2014,"claim":"Demonstrating that MED30 knockdown impairs HIV-1 post-integration transcription, including Tat-induced transcription, extended the subunit's functional scope to viral gene regulation.","evidence":"siRNA knockdown in HIV-infected cells with RT-PCR for viral transcripts","pmids":["25100719"],"confidence":"Medium","gaps":["No direct physical interaction between MED30 and Tat demonstrated","Whether MED30 is specifically required or reflects general Mediator dependence not resolved","Not independently replicated in a second laboratory"]},{"year":2019,"claim":"Genome-wide ChIP in Drosophila showed MED30 specifically directs cohesin and its loader Nipped-B to gene promoters, revealing a non-transcriptional structural role at chromatin distinct from enhancer-localized cohesin loading.","evidence":"ChIP-seq for MED30, Nipped-B, Rad21, SA in Drosophila cells with genetic analysis","pmids":["30796039"],"confidence":"Medium","gaps":["Conservation of promoter-specific cohesin recruitment by MED30 in mammals not tested","Mechanism of physical coupling between MED30 and cohesin loader unknown","Functional consequence of promoter cohesin loss upon MED30 depletion not determined"]},{"year":2021,"claim":"Cryo-EM of the human Mediator–PIC complex and conditional cardiac knockout together resolved MED30's structural position in the proximal tail module and demonstrated that loss of MED30 destabilizes the entire Mediator core in vivo, establishing it as a linchpin subunit.","evidence":"Cryo-EM of 50-subunit reconstituted human Mediator–PIC; cardiomyocyte-specific Med30 knockout with Western blot and RNA-seq","pmids":["33902108","34506481"],"confidence":"High","gaps":["Atomic-resolution contacts between MED30 and neighboring subunits not fully resolved","Whether Mediator destabilization is the sole cause of transcriptional defects or MED30 has additional direct functions unresolved","Non-redundancy with neighboring proximal tail subunits only partially addressed"]},{"year":2024,"claim":"Epistasis experiments showed MED27 overexpression cannot rescue MED30 loss and vice versa, establishing that MED30 and MED27 are independently required proximal tail subunits for Mediator stability — they are non-redundant despite proximity.","evidence":"Med27 cardiomyocyte-specific knockout with MED30 overexpression rescue, Western blot for Mediator subunits","pmids":["39209248"],"confidence":"Medium","gaps":["Whether MED30 and MED27 stabilize overlapping or distinct subunit contacts not determined","Single laboratory finding","No structural data on the specific contacts each subunit contributes"]},{"year":2024,"claim":"CRISPR screening in multiple myeloma and ChIP-seq in GBM/PDAC models converged on MED30 as a positive regulator of MYC expression and MYC-driven enhancer formation, implicating it as a specific node in oncogenic transcriptional rewiring.","evidence":"Genome-wide CRISPR screen with endogenous MYC-GFP reporter; ChIP-seq for MYC and epigenetic marks; in vivo tumor models (preprint for ChIP-seq data)","pmids":["41965876","38766212"],"confidence":"Medium","gaps":["ChIP-seq/enhancer findings are from a preprint not yet peer-reviewed","Direct physical interaction between MED30 and MYC not demonstrated","Whether MED30's effect on MYC expression is direct transcriptional regulation or Mediator stability dependent is unclear"]},{"year":null,"claim":"How MED30 selectively controls tissue-specific transcriptional programs (metabolic, oncogenic, viral) despite being an apparently constitutive Mediator subunit remains the central unresolved mechanistic question.","evidence":"","pmids":[],"confidence":"High","gaps":["No activator-specific binding surface on MED30 has been mapped","No separation-of-function mutations distinguishing structural versus regulatory roles exist","Whether MED30's cohesin-recruiting function operates in mammals and contributes to gene regulation is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]}],"complexes":["Mediator complex"],"partners":["MED27","MED28","MED29","MED14","MED17","MYC"],"other_free_text":[]},"mechanistic_narrative":"MED30 is a metazoan-specific subunit of the Mediator transcriptional coactivator complex that is essential for both basal and activator-dependent RNA polymerase II transcription and for the structural integrity of the Mediator core. Cryo-EM structures place MED30 in the proximal tail module at the Head–Tail interface together with MED27, MED28, MED29, MED14, and MED17, and conditional deletion in cardiomyocytes destabilizes core Mediator subunits, causing rapid organ failure [PMID:33902108, PMID:34506481]. MED30 controls tissue-specific transcriptional programs including oxidative phosphorylation and mitochondrial gene networks in the heart, cohesin recruitment to gene promoters, and MYC-dependent enhancer activation in cancer contexts [PMID:22106289, PMID:30796039, PMID:41965876]. A hypomorphic Med30 missense mutation in mice causes progressive mitochondrial cardiomyopathy, establishing MED30 as a disease-relevant gene for cardiac metabolism [PMID:22106289]."},"prefetch_data":{"uniprot":{"accession":"Q96HR3","full_name":"Mediator of RNA polymerase II transcription subunit 30","aliases":["Mediator complex subunit 30","TRAP/Mediator complex component TRAP25","Thyroid hormone receptor-associated protein 6","Thyroid hormone receptor-associated protein complex 25 kDa component","Trap25"],"length_aa":178,"mass_kda":20.3,"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/Q96HR3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MED30","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"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":"MED22","stoichiometry":10.0},{"gene":"MED25","stoichiometry":10.0},{"gene":"MED27","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/MED30","total_profiled":1310},"omim":[{"mim_id":"610237","title":"MEDIATOR COMPLEX SUBUNIT 30; MED30","url":"https://www.omim.org/entry/610237"},{"mim_id":"185641","title":"MEDIATOR COMPLEX SUBUNIT 22; MED22","url":"https://www.omim.org/entry/185641"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED30"},"hgnc":{"alias_symbol":["TRAP25"],"prev_symbol":["THRAP6"]},"alphafold":{"accession":"Q96HR3","domains":[{"cath_id":"1.10.287","chopping":"29-105","consensus_level":"high","plddt":89.6861,"start":29,"end":105},{"cath_id":"1.20.5","chopping":"144-178","consensus_level":"medium","plddt":94.0151,"start":144,"end":178}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HR3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HR3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96HR3-F1-predicted_aligned_error_v6.png","plddt_mean":77.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED30","jax_strain_url":"https://www.jax.org/strain/search?query=MED30"},"sequence":{"accession":"Q96HR3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96HR3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96HR3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96HR3"}},"corpus_meta":[{"pmid":"17925008","id":"PMC_17925008","title":"High-resolution 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TFIID-associated TAFIIs.\",\n      \"method\": \"Antibody-based immunodepletion of HeLa nuclear extract followed by in vitro transcription reconstitution assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with quantitative depletion and add-back, multiple transcription readouts\",\n      \"pmids\": [\"11909976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structure of the human Mediator-RNA polymerase II pre-initiation complex showed that MED30 (together with MED27, MED28, MED29) associates with MED14 and MED17 to form the proximal part of the Mediator tail module that binds transcriptional activators; this structural context places MED30 at the interface anchoring Head and Tail modules.\",\n      \"method\": \"Cryo-electron microscopy of reconstituted 50-subunit human Mediator-PIC complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure of reconstituted human complex with functional validation of module organization\",\n      \"pmids\": [\"33902108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A hypomorphic missense mutation in Med30 in mice caused progressive mitochondrial cardiomyopathy with pleiotropic downregulation of cardiac genes required for oxidative phosphorylation and mitochondrial integrity, establishing a mechanistic link between MED30 and the transcriptional program controlling oxidative phosphorylation and fatty acid oxidation.\",\n      \"method\": \"Mouse genetics (hypomorphic missense mutation), expression profiling, dietary intervention (ketogenic diet rescue)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo loss-of-function with defined transcriptional phenotype and rescue experiment\",\n      \"pmids\": [\"22106289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cardiomyocyte-specific deletion of MED30 in mice destabilized Mediator core subunits (while the kinase module was preserved), demonstrating that MED30 is essential for the structural integrity and stability of the overall Mediator complex in vivo; deletion caused rapid cardiac defects and lethality, and RNAseq revealed loss of critical cardiomyocyte transcription networks.\",\n      \"method\": \"Conditional and inducible cardiomyocyte-specific Med30 knockout mice, Western blot for Mediator subunit levels, RNAseq\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with multiple orthogonal readouts (protein stability, transcriptomics, physiology)\",\n      \"pmids\": [\"34506481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"siRNA-mediated knockdown of MED30 in HIV-infected cells significantly impaired HIV-1 replication at a post-integration step, specifically affecting formation of unspliced viral transcripts; MED30 knockdown also compromised HIV transcription induced by Tat.\",\n      \"method\": \"siRNA knockdown in HIV-infected cells, RT-PCR for viral transcripts, Tat-induced transcription assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined transcriptional phenotype but single lab, no direct interaction with Tat shown for MED30\",\n      \"pmids\": [\"25100719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila cells, the MED30 subunit of the Mediator complex directs Nipped-B (cohesin loader) and Rad21 (cohesin) to gene promoters, as shown by genome-wide ChIP; this is distinct from enhancers where SA and Fs(1)h recruit cohesin, indicating MED30 plays a specific role in promoter-localized cohesin recruitment.\",\n      \"method\": \"Genome-wide chromatin immunoprecipitation (ChIP-seq) in Drosophila cells, genetic analysis\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP with genetic validation, but findings in Drosophila (ortholog context)\",\n      \"pmids\": [\"30796039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MED30 overexpression increased proliferation, migration, and invasion of gastric cancer cells, while MED30 knockdown inhibited these effects and suppressed tumorigenicity in SCID mice; MED30 also promoted expression of epithelial-mesenchymal transition genes.\",\n      \"method\": \"siRNA knockdown and overexpression in gastric cancer cell lines, proliferation/migration/invasion assays, xenograft in SCID mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional manipulation with in vivo validation, but no direct molecular mechanism identified\",\n      \"pmids\": [\"26110885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MED30 expression in glioblastoma cells is regulated by HIF1α and p53 through hypoxia response elements (HREs) and p53 binding sites in the MED30 promoter; MED30 promotes cell proliferation while reducing migration in GBM cells, and MED30 modulates p53 levels and confers sensitivity to temozolomide.\",\n      \"method\": \"Promoter analysis, HIF1α/p53 dependency experiments, MED30 overexpression and knockdown in GBM cell lines, proliferation/migration assays\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab with functional assays and promoter analysis but limited mechanistic depth\",\n      \"pmids\": [\"32705436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MED30 overexpression/amplification recruits other Mediator components and redirects MYC binding to a novel subset of genomic regulatory sites, inducing new enhancer formation with altered epigenetic marks and driving expression of cancer progression genes; MED30 knockdown reduced tumor growth particularly in MYC-high GBM and PDAC models.\",\n      \"method\": \"Transcriptional profiling, ChIP-seq for MYC and epigenetic marks, in vivo tumor models (PDAC, GBM), siRNA knockdown\",\n      \"journal\": \"Research square (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP-seq, transcriptomics, in vivo), but preprint not yet peer-reviewed\",\n      \"pmids\": [\"38766212\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of MED30 in human pancreatic β-cells (EndoC-βH3) markedly reduced cell viability, demonstrating a cell-autonomous role for MED30 in β-cell survival, identified via CRISPR-Cas9 enhancer deletion.\",\n      \"method\": \"CRISPR-Cas9 deletion of enhancer regions in EndoC-βH3 cells, cell viability assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct CRISPR loss-of-function with defined cellular phenotype, but indirect (enhancer deletion lowers MED30 expression)\",\n      \"pmids\": [\"38661000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of MED30 fails to restore Mediator subunit protein levels in MED27-deficient cardiomyocytes, demonstrating that MED27's role in maintaining Mediator core integrity is independent of MED30, and that MED30 and MED27 are non-redundant upper Tail subunits each required for Mediator stability.\",\n      \"method\": \"Cardiomyocyte-specific Med27 knockout mice, MED30 overexpression rescue experiment, Western blot for Mediator subunits\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with direct protein-level readout, single lab\",\n      \"pmids\": [\"39209248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA-mediated knockdown of MED30 significantly decreased proliferation, migration, and invasion in clear cell renal cell carcinoma cell lines, demonstrating a functional role for MED30 in RCC cell behavior.\",\n      \"method\": \"siRNA knockdown in ccRCC cell lines (ACHN, A-498), proliferation, migration, and invasion assays\",\n      \"journal\": \"Annals of diagnostic pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single approach, no molecular mechanism identified\",\n      \"pmids\": [\"29661722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA-mediated knockdown of MED30 reduced proliferation, migration, and invasion in bladder cancer cell lines (T24 and TCCSUP).\",\n      \"method\": \"siRNA knockdown in bladder cancer cell lines, proliferation, migration, invasion assays\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single approach, functional phenotype only\",\n      \"pmids\": [\"29187445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Genome-wide CRISPR loss-of-function screening identified MED30 as a positive regulator of endogenous MYC expression in multiple myeloma cells; functional validation confirmed that MED30 knockout strongly reduced MYC protein levels.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen using GFP-tagged endogenous MYC reporter, validation by individual sgRNA knockouts\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pooled genome-wide screen with functional validation of hit, direct readout of endogenous MYC levels\",\n      \"pmids\": [\"41965876\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED30 is a metazoan-specific integral subunit of the Mediator complex that localizes to the proximal tail module (anchoring Head and Tail modules), is essential for structural stability of the overall Mediator core complex in vivo, supports both basal and activator-dependent RNA Pol II transcription, regulates oxidative phosphorylation and metabolic gene programs in cardiomyocytes, recruits cohesin to gene promoters, facilitates MYC-driven oncogenic transcriptional programs by directing Mediator assembly at novel enhancers, and is required for HIV-1 post-integration transcription.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MED30 is a metazoan-specific subunit of the Mediator transcriptional coactivator complex that is essential for both basal and activator-dependent RNA polymerase II transcription and for the structural integrity of the Mediator core. Cryo-EM structures place MED30 in the proximal tail module at the Head–Tail interface together with MED27, MED28, MED29, MED14, and MED17, and conditional deletion in cardiomyocytes destabilizes core Mediator subunits, causing rapid organ failure [PMID:33902108, PMID:34506481]. MED30 controls tissue-specific transcriptional programs including oxidative phosphorylation and mitochondrial gene networks in the heart, cohesin recruitment to gene promoters, and MYC-dependent enhancer activation in cancer contexts [PMID:22106289, PMID:30796039, PMID:41965876]. A hypomorphic Med30 missense mutation in mice causes progressive mitochondrial cardiomyopathy, establishing MED30 as a disease-relevant gene for cardiac metabolism [PMID:22106289].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that MED30 (TRAP25) is an integral Mediator subunit required for transcription resolved its identity among the ~30 Mediator components and showed the complex is needed for both basal and activator-dependent RNA Pol II activity.\",\n      \"evidence\": \"Immunodepletion of TRAP25 from HeLa nuclear extract followed by in vitro transcription reconstitution\",\n      \"pmids\": [\"11909976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Role of MED30 within Mediator architecture not resolved\",\n        \"Contribution of MED30 versus other subunits to in vivo transcription unknown\",\n        \"No loss-of-function data in intact organisms\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"A mouse hypomorphic Med30 mutation linked the subunit to a specific transcriptional program — oxidative phosphorylation and fatty acid oxidation in cardiomyocytes — moving understanding beyond a generic coactivator role to tissue-specific metabolic regulation.\",\n      \"evidence\": \"Mouse missense mutation causing progressive cardiomyopathy; expression profiling and ketogenic diet rescue\",\n      \"pmids\": [\"22106289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct target genes versus secondary effects not delineated\",\n        \"Mechanism by which MED30 selectively controls metabolic gene programs unclear\",\n        \"Whether human MED30 mutations cause cardiomyopathy not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that MED30 knockdown impairs HIV-1 post-integration transcription, including Tat-induced transcription, extended the subunit's functional scope to viral gene regulation.\",\n      \"evidence\": \"siRNA knockdown in HIV-infected cells with RT-PCR for viral transcripts\",\n      \"pmids\": [\"25100719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct physical interaction between MED30 and Tat demonstrated\",\n        \"Whether MED30 is specifically required or reflects general Mediator dependence not resolved\",\n        \"Not independently replicated in a second laboratory\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genome-wide ChIP in Drosophila showed MED30 specifically directs cohesin and its loader Nipped-B to gene promoters, revealing a non-transcriptional structural role at chromatin distinct from enhancer-localized cohesin loading.\",\n      \"evidence\": \"ChIP-seq for MED30, Nipped-B, Rad21, SA in Drosophila cells with genetic analysis\",\n      \"pmids\": [\"30796039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Conservation of promoter-specific cohesin recruitment by MED30 in mammals not tested\",\n        \"Mechanism of physical coupling between MED30 and cohesin loader unknown\",\n        \"Functional consequence of promoter cohesin loss upon MED30 depletion not determined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Cryo-EM of the human Mediator–PIC complex and conditional cardiac knockout together resolved MED30's structural position in the proximal tail module and demonstrated that loss of MED30 destabilizes the entire Mediator core in vivo, establishing it as a linchpin subunit.\",\n      \"evidence\": \"Cryo-EM of 50-subunit reconstituted human Mediator–PIC; cardiomyocyte-specific Med30 knockout with Western blot and RNA-seq\",\n      \"pmids\": [\"33902108\", \"34506481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution contacts between MED30 and neighboring subunits not fully resolved\",\n        \"Whether Mediator destabilization is the sole cause of transcriptional defects or MED30 has additional direct functions unresolved\",\n        \"Non-redundancy with neighboring proximal tail subunits only partially addressed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Epistasis experiments showed MED27 overexpression cannot rescue MED30 loss and vice versa, establishing that MED30 and MED27 are independently required proximal tail subunits for Mediator stability — they are non-redundant despite proximity.\",\n      \"evidence\": \"Med27 cardiomyocyte-specific knockout with MED30 overexpression rescue, Western blot for Mediator subunits\",\n      \"pmids\": [\"39209248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MED30 and MED27 stabilize overlapping or distinct subunit contacts not determined\",\n        \"Single laboratory finding\",\n        \"No structural data on the specific contacts each subunit contributes\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"CRISPR screening in multiple myeloma and ChIP-seq in GBM/PDAC models converged on MED30 as a positive regulator of MYC expression and MYC-driven enhancer formation, implicating it as a specific node in oncogenic transcriptional rewiring.\",\n      \"evidence\": \"Genome-wide CRISPR screen with endogenous MYC-GFP reporter; ChIP-seq for MYC and epigenetic marks; in vivo tumor models (preprint for ChIP-seq data)\",\n      \"pmids\": [\"41965876\", \"38766212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"ChIP-seq/enhancer findings are from a preprint not yet peer-reviewed\",\n        \"Direct physical interaction between MED30 and MYC not demonstrated\",\n        \"Whether MED30's effect on MYC expression is direct transcriptional regulation or Mediator stability dependent is unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MED30 selectively controls tissue-specific transcriptional programs (metabolic, oncogenic, viral) despite being an apparently constitutive Mediator subunit remains the central unresolved mechanistic question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No activator-specific binding surface on MED30 has been mapped\",\n        \"No separation-of-function mutations distinguishing structural versus regulatory roles exist\",\n        \"Whether MED30's cohesin-recruiting function operates in mammals and contributes to gene regulation is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"Mediator complex\"\n    ],\n    \"partners\": [\n      \"MED27\",\n      \"MED28\",\n      \"MED29\",\n      \"MED14\",\n      \"MED17\",\n      \"MYC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}