{"gene":"MED30","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2002,"finding":"TRAP25 (MED30) was identified as a previously uncharacterized integral subunit of the human TRAP/Mediator complex that is metazoan-specific. Antibody-mediated immunodepletion of TRAP25 quantitatively removed essentially all TRAP/Mediator components from HeLa nuclear extract without affecting RNA polymerase II or general transcription factors, demonstrating MED30 is required for both basal and activator-dependent transcription. Adding back purified TRAP/Mediator restored both activities, and simultaneous depletion of TRAP/Mediator and TFIID required addition of both TBP/TAFIIs and TRAP/Mediator for rescue, establishing that TAFIIs and Mediator are jointly required for transcription.","method":"Antibody immunodepletion of HeLa nuclear extract, reconstitution with purified TRAP/Mediator, in vitro transcription assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with quantitative immunodepletion and functional rescue, rigorous controls for specificity","pmids":["11909976"],"is_preprint":false},{"year":2021,"finding":"Cryo-EM structure of the human Mediator-RNA polymerase II pre-initiation complex revealed that metazoan subunits MED27-MED30 associate with exposed regions in MED14 and MED17 to form the proximal part of the Mediator tail module, which binds transcriptional activators. MED30 thus structurally anchors the tail module to the Mediator core.","method":"Cryo-electron microscopy of reconstituted 50-subunit human Mediator-PIC complex","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure of reconstituted human complex, direct structural localization of MED30","pmids":["33902108"],"is_preprint":false},{"year":2021,"finding":"Cardiomyocyte-specific deletion of MED30 (constitutive or inducible) in mice caused rapid cardiac defects and lethality. Critically, ablation of MED30 destabilized the majority of Mediator core subunits (head, middle, tail modules) while the kinase module was preserved, demonstrating MED30 is essential for the structural stability of the overall Mediator complex in vivo. RNAseq identified cardiac transcriptional networks controlled by MED30-dependent Mediator.","method":"Conditional knockout mouse models (constitutive and inducible cardiomyocyte-specific Cre), western blot quantification of Mediator subunit levels, RNAseq","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo KO with defined phenotype, multiple orthogonal methods (histology, proteomics, transcriptomics), two independent KO models","pmids":["34506481"],"is_preprint":false},{"year":2011,"finding":"A hypomorphic missense mutation in Med30 in mice caused progressive mitochondrial cardiomyopathy with lethality after weaning. Expression profiling revealed pleiotropic downregulation of cardiac genes required for oxidative phosphorylation and mitochondrial integrity, establishing a mechanistic connection between MED30-dependent Mediator function and induction of the metabolic program for oxidative phosphorylation and fatty acid oxidation.","method":"ENU-generated hypomorphic mouse 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 / Strong — in vivo genetic model with defined molecular phenotype (transcriptome), dietary rescue providing functional validation","pmids":["22106289"],"is_preprint":false},{"year":2024,"finding":"MED30 overexpression/amplification (co-amplified with MYC in cancers) recruits additional Mediator components and redirects MYC binding to a novel subset of genomic regulatory sites, alters epigenetic marks, and induces formation of new enhancers driving oncogenic target gene expression. In vivo, MED30 overexpression promotes PDAC tumor growth, and this is attenuated by MYC knockdown, placing MED30 upstream of MYC in this oncogenic transcriptional program.","method":"Transcriptional profiling of MYC/MED30 single and double overexpression, ChIP-seq for Mediator components and MYC binding sites, epigenetic mark profiling, in vivo xenograft models with MYC knockdown rescue","journal":"Research square","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP-seq, transcriptomics, in vivo), single lab, preprint not yet peer-reviewed","pmids":["38766212"],"is_preprint":true},{"year":2014,"finding":"siRNA-mediated knockdown of MED30 in HIV-1-infected cells significantly impaired viral replication at a post-integration step, specifically affecting the formation of unspliced viral transcripts, and compromised HIV transcription induced by Tat. MED30 knockdown thus reduces HIV-1 transcription at the level of transcript elongation/splicing.","method":"siRNA knockdown in HIV-1-infected cells, RT-PCR for early and unspliced viral transcripts, Tat-induced transcription assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with specific transcript-level readouts, single lab, no rescue experiment","pmids":["25100719"],"is_preprint":false},{"year":2015,"finding":"MED30 overexpression in gastric cancer cells increased proliferation, migration, and invasion, whereas MED30 knockdown inhibited these effects and significantly reduced tumorigenicity in SCID mice. MED30 also promoted expression of epithelial-mesenchymal transition (EMT)-related genes.","method":"Overexpression and siRNA knockdown in gastric cancer cell lines, proliferation/migration/invasion assays, SCID mouse tumorigenicity assay, EMT gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both gain- and loss-of-function with in vivo validation, single lab","pmids":["26110885"],"is_preprint":false},{"year":2019,"finding":"In Drosophila cells, the MED30 subunit of the Mediator complex directs Nipped-B and Rad21 (cohesin subunit) to gene promoters, as shown by genome-wide ChIP-seq. This is distinct from the role of SA and Fs(1)h (BRD4) in directing cohesin to enhancers, indicating that MED30 mediates promoter-specific cohesin recruitment.","method":"Genome-wide ChIP-seq in Drosophila cells for cohesin subunits (Nipped-B, SA, SMC1, Rad21) combined with MED30 perturbation data","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with functional genetic data, Drosophila ortholog, single lab","pmids":["30796039"],"is_preprint":false},{"year":2022,"finding":"CRISPR-Cas9-mediated deletion of enhancer regions at the SLC30A8 locus reduced MED30 expression, and subsequent loss of MED30 markedly reduced pancreatic beta cell viability, establishing a required role for MED30 in beta cell survival.","method":"CRISPR-Cas9 enhancer deletion in human EndoC-βH3 cells, cell viability assays after MED30 loss","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function in human-derived cells with defined viability phenotype, single lab","pmids":["38661000"],"is_preprint":false},{"year":2020,"finding":"MED30 is induced in glioblastoma cells under hypoxia and nutrient deprivation in a HIF1α- and p53-dependent manner, with functional HREs and a p53 binding site identified in the MED30 promoter. MED30 overexpression promoted cell proliferation while reducing migration in GBM cell lines; knockdown had the opposite effects and conferred resistance to temozolomide. MED30 also modulated p53 protein levels in vitro.","method":"Promoter analysis (HRE and p53 binding site identification), overexpression and siRNA knockdown in GBM cell lines, proliferation and migration assays, temozolomide sensitivity assays, p53 western blot","journal":"Cellular and molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both gain- and loss-of-function with multiple cellular readouts, promoter element mapping, single lab","pmids":["32705436"],"is_preprint":false},{"year":2024,"finding":"Overexpression of MED30 failed to restore protein levels of Mediator subunits in MED27-deficient cardiomyocytes, demonstrating that MED27's role in maintaining Mediator complex integrity is independent of MED30 (negative epistasis result).","method":"MED30 overexpression in MED27 cardiomyocyte-specific knockout mouse hearts, western blot for Mediator subunit levels","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo genetic epistasis experiment, single lab, negative result is mechanistically informative","pmids":["39209248"],"is_preprint":false},{"year":2017,"finding":"siRNA-mediated knockdown of MED30 in clear cell renal cell carcinoma cell lines (ACHN and A-498) significantly decreased proliferation, migration, and invasion.","method":"siRNA knockdown in ccRCC cell lines, proliferation, migration, and invasion assays","journal":"Annals of diagnostic pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (siRNA KD), single lab, phenotypic readout without pathway placement","pmids":["29661722"],"is_preprint":false},{"year":2017,"finding":"siRNA-mediated knockdown of MED30 in bladder cancer cell lines (T24 and TCCSUP) reduced proliferation, migration, and invasion despite higher MED30 expression being associated with better patient survival at the clinical level.","method":"siRNA knockdown in bladder cancer cell lines, proliferation, migration, and invasion assays","journal":"Anticancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (siRNA KD), single lab, no pathway mechanism established","pmids":["29187445"],"is_preprint":false},{"year":2026,"finding":"Genome-wide CRISPR loss-of-function screen in multiple myeloma cells identified MED30 (Mediator complex subunit) as an activator of endogenous MYC expression; functional validation confirmed that MED30 loss significantly reduced MYC protein levels.","method":"Genome-wide CRISPR-Cas9 screen with GFP-tagged endogenous MYC reporter, sgRNA validation in MM cell lines","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — screen-based identification with limited mechanistic follow-up for MED30 specifically, single lab","pmids":["41965876"],"is_preprint":false}],"current_model":"MED30 (TRAP25/THRAP6) is a metazoan-specific integral subunit of the Mediator complex that localizes to the proximal tail module (anchored between MED14/MED17), is essential for the structural stability of the entire Mediator core (head, middle, and tail modules) in vivo, and is required for both basal and activator-dependent RNA polymerase II transcription; loss of MED30 in cardiomyocytes destabilizes the Mediator complex and disrupts transcriptional programs for oxidative phosphorylation and mitochondrial function, while in cancer contexts MED30 overexpression redirects MYC to novel genomic regulatory sites to drive oncogenic transcription."},"narrative":{"mechanistic_narrative":"MED30 (TRAP25) is a metazoan-specific integral subunit of the Mediator complex that couples transcriptional activators to RNA polymerase II and is required for both basal and activator-dependent transcription [PMID:11909976]. Structurally, MED30 associates with exposed surfaces of MED14 and MED17 to form the proximal part of the Mediator tail module that engages activators, thereby anchoring the tail to the Mediator core [PMID:33902108]. This architectural role underlies its function in maintaining complex integrity: in vivo ablation of MED30 destabilizes head, middle, and tail module subunits while sparing the kinase module, establishing MED30 as essential for the structural stability of the overall Mediator complex [PMID:34506481]. Through this Mediator-dependent activity, MED30 controls tissue-specific transcriptional programs — loss in cardiomyocytes disrupts the gene networks driving oxidative phosphorylation and mitochondrial integrity, causing mitochondrial cardiomyopathy [PMID:34506481, PMID:22106289]. In cancer contexts, elevated MED30 acts upstream of MYC, redirecting MYC to novel genomic regulatory sites and inducing new enhancers to drive oncogenic transcription [PMID:38766212], and MED30 is required to sustain endogenous MYC expression [PMID:41965876].","teleology":[{"year":2002,"claim":"Established that MED30 is a genuine integral Mediator subunit whose presence is required for the complex to support transcription, answering whether this uncharacterized protein had a functional role in PolII transcription.","evidence":"Antibody immunodepletion of HeLa nuclear extract with reconstitution and in vitro transcription assays","pmids":["11909976"],"confidence":"High","gaps":["Did not localize MED30 within the complex architecture","Did not define which activators or target genes depend on MED30"]},{"year":2011,"claim":"Connected MED30-dependent Mediator function to a specific physiological transcriptional program, showing it drives the metabolic gene network for oxidative phosphorylation and mitochondrial integrity.","evidence":"ENU hypomorphic missense mouse model with expression profiling and ketogenic diet rescue","pmids":["22106289"],"confidence":"High","gaps":["A hypomorph does not reveal the full null phenotype","Did not address how MED30 selectively controls metabolic gene programs"]},{"year":2021,"claim":"Resolved where MED30 sits in the Mediator complex, showing it anchors the activator-binding proximal tail module to the core via MED14 and MED17.","evidence":"Cryo-EM of reconstituted 50-subunit human Mediator-PIC","pmids":["33902108"],"confidence":"High","gaps":["Static structure does not capture dynamics of activator engagement","Does not show which activators bind through the MED30-containing tail surface in vivo"]},{"year":2021,"claim":"Demonstrated in vivo that MED30 is required for the structural stability of the entire Mediator core, distinguishing its scaffolding role from the dispensable kinase module.","evidence":"Constitutive and inducible cardiomyocyte-specific knockout mice with western blot quantification of subunits and RNAseq","pmids":["34506481"],"confidence":"High","gaps":["Mechanism of how MED30 loss propagates to destabilize distal modules not defined","Cardiomyocyte-specific; generality to other tissues untested"]},{"year":2014,"claim":"Tested whether MED30-dependent Mediator activity is co-opted by viral transcription, showing it is needed for HIV-1 transcript elongation/splicing and Tat-induced transcription.","evidence":"siRNA knockdown in HIV-1-infected cells with RT-PCR transcript readouts","pmids":["25100719"],"confidence":"Medium","gaps":["No rescue experiment to confirm specificity","Direct interaction with Tat or the viral promoter not established"]},{"year":2015,"claim":"Implicated MED30 dosage in tumor cell behavior, linking its overexpression to proliferation, invasion, and EMT gene induction in gastric cancer.","evidence":"Gain- and loss-of-function in gastric cancer lines with SCID mouse tumorigenicity assays","pmids":["26110885"],"confidence":"Medium","gaps":["Did not identify the direct transcriptional targets driving the phenotype","Single tumor type and lab"]},{"year":2019,"claim":"Revealed a chromatin-organizing function, showing the Mediator MED30 subunit directs cohesin (Nipped-B/Rad21) specifically to gene promoters.","evidence":"Genome-wide ChIP-seq with perturbation in Drosophila cells","pmids":["30796039"],"confidence":"Medium","gaps":["Demonstrated in Drosophila; human conservation untested","Molecular basis of promoter-specific cohesin recruitment unclear"]},{"year":2020,"claim":"Placed MED30 within stress-responsive transcriptional circuits, showing HIF1α/p53-dependent induction and reciprocal modulation of p53 in glioblastoma.","evidence":"Promoter element mapping, gain/loss-of-function in GBM lines, proliferation/migration and temozolomide sensitivity assays","pmids":["32705436"],"confidence":"Medium","gaps":["Mechanism by which MED30 modulates p53 protein levels not defined","Opposing proliferation vs migration effects not mechanistically reconciled"]},{"year":2022,"claim":"Established a required role for MED30 in pancreatic beta cell survival, linking enhancer-driven MED30 expression to viability.","evidence":"CRISPR enhancer deletion at the SLC30A8 locus in human EndoC-βH3 cells with viability assays","pmids":["38661000"],"confidence":"Medium","gaps":["Transcriptional targets mediating survival not identified","Single cell model"]},{"year":2024,"claim":"Defined an oncogenic mechanism placing MED30 upstream of MYC, showing its overexpression redirects MYC genomic binding and creates new enhancers to drive tumor growth.","evidence":"ChIP-seq for Mediator and MYC, transcriptomics, epigenetic profiling, and xenografts with MYC knockdown rescue (preprint)","pmids":["38766212"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Mechanism by which excess MED30 reshapes MYC site selection unresolved"]},{"year":2024,"claim":"Used genetic epistasis to show MED27's role in Mediator integrity is independent of MED30, refining the wiring of tail-module subunit dependencies.","evidence":"MED30 overexpression in MED27-knockout mouse hearts with western blot for subunit levels","pmids":["39209248"],"confidence":"Medium","gaps":["Does not establish MED30's own independent integrity requirements relative to MED27","Negative result; no positive rescue partner identified"]},{"year":2026,"claim":"Confirmed unbiasedly that MED30 sustains endogenous MYC expression, generalizing its MYC-activating role beyond solid tumors to multiple myeloma.","evidence":"Genome-wide CRISPR screen with endogenous MYC reporter and sgRNA validation","pmids":["41965876"],"confidence":"Low","gaps":["Limited mechanistic follow-up specific to MED30","Does not distinguish direct from Mediator-wide effect on MYC"]},{"year":null,"claim":"How MED30's structural anchoring of the tail module is translated into selective activator engagement and gene-specific program control across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No defined set of activators that bind through the MED30 tail surface","Mechanism of context-specific target selection (metabolic vs oncogenic programs) unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7]}],"complexes":["Mediator complex"],"partners":["MED14","MED17","MED27"],"other_free_text":[]}},"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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reports","url":"https://pubmed.ncbi.nlm.nih.gov/41965876","citation_count":0,"is_preprint":false},{"pmid":"32362303","id":"PMC_32362303","title":"Proteomic Interactome of C. elegans Mediator Complex Subunit 28 (MDT-28) Reveals Predominant Association with a Restricted Set of Core Mediator Subunits and an Affinity to Additional Structural and Enzymatic Proteins.","date":"2019","source":"Folia biologica","url":"https://pubmed.ncbi.nlm.nih.gov/32362303","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18501,"output_tokens":3474,"usd":0.053807,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11063,"output_tokens":3369,"usd":0.06977,"stage2_stop_reason":"end_turn"},"total_usd":0.123577,"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\": 2002,\n      \"finding\": \"TRAP25 (MED30) was identified as a previously uncharacterized integral subunit of the human TRAP/Mediator complex that is metazoan-specific. Antibody-mediated immunodepletion of TRAP25 quantitatively removed essentially all TRAP/Mediator components from HeLa nuclear extract without affecting RNA polymerase II or general transcription factors, demonstrating MED30 is required for both basal and activator-dependent transcription. Adding back purified TRAP/Mediator restored both activities, and simultaneous depletion of TRAP/Mediator and TFIID required addition of both TBP/TAFIIs and TRAP/Mediator for rescue, establishing that TAFIIs and Mediator are jointly required for transcription.\",\n      \"method\": \"Antibody immunodepletion of HeLa nuclear extract, reconstitution with purified TRAP/Mediator, in vitro transcription assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with quantitative immunodepletion and functional rescue, rigorous controls for specificity\",\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 revealed that metazoan subunits MED27-MED30 associate with exposed regions in MED14 and MED17 to form the proximal part of the Mediator tail module, which binds transcriptional activators. MED30 thus structurally anchors the tail module to the Mediator core.\",\n      \"method\": \"Cryo-electron microscopy of reconstituted 50-subunit human Mediator-PIC complex\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure of reconstituted human complex, direct structural localization of MED30\",\n      \"pmids\": [\"33902108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cardiomyocyte-specific deletion of MED30 (constitutive or inducible) in mice caused rapid cardiac defects and lethality. Critically, ablation of MED30 destabilized the majority of Mediator core subunits (head, middle, tail modules) while the kinase module was preserved, demonstrating MED30 is essential for the structural stability of the overall Mediator complex in vivo. RNAseq identified cardiac transcriptional networks controlled by MED30-dependent Mediator.\",\n      \"method\": \"Conditional knockout mouse models (constitutive and inducible cardiomyocyte-specific Cre), western blot quantification of Mediator subunit levels, RNAseq\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo KO with defined phenotype, multiple orthogonal methods (histology, proteomics, transcriptomics), two independent KO models\",\n      \"pmids\": [\"34506481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A hypomorphic missense mutation in Med30 in mice caused progressive mitochondrial cardiomyopathy with lethality after weaning. Expression profiling revealed pleiotropic downregulation of cardiac genes required for oxidative phosphorylation and mitochondrial integrity, establishing a mechanistic connection between MED30-dependent Mediator function and induction of the metabolic program for oxidative phosphorylation and fatty acid oxidation.\",\n      \"method\": \"ENU-generated hypomorphic mouse 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 / Strong — in vivo genetic model with defined molecular phenotype (transcriptome), dietary rescue providing functional validation\",\n      \"pmids\": [\"22106289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MED30 overexpression/amplification (co-amplified with MYC in cancers) recruits additional Mediator components and redirects MYC binding to a novel subset of genomic regulatory sites, alters epigenetic marks, and induces formation of new enhancers driving oncogenic target gene expression. In vivo, MED30 overexpression promotes PDAC tumor growth, and this is attenuated by MYC knockdown, placing MED30 upstream of MYC in this oncogenic transcriptional program.\",\n      \"method\": \"Transcriptional profiling of MYC/MED30 single and double overexpression, ChIP-seq for Mediator components and MYC binding sites, epigenetic mark profiling, in vivo xenograft models with MYC knockdown rescue\",\n      \"journal\": \"Research square\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP-seq, transcriptomics, in vivo), single lab, preprint not yet peer-reviewed\",\n      \"pmids\": [\"38766212\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"siRNA-mediated knockdown of MED30 in HIV-1-infected cells significantly impaired viral replication at a post-integration step, specifically affecting the formation of unspliced viral transcripts, and compromised HIV transcription induced by Tat. MED30 knockdown thus reduces HIV-1 transcription at the level of transcript elongation/splicing.\",\n      \"method\": \"siRNA knockdown in HIV-1-infected cells, RT-PCR for early and unspliced viral transcripts, Tat-induced transcription assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with specific transcript-level readouts, single lab, no rescue experiment\",\n      \"pmids\": [\"25100719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MED30 overexpression in gastric cancer cells increased proliferation, migration, and invasion, whereas MED30 knockdown inhibited these effects and significantly reduced tumorigenicity in SCID mice. MED30 also promoted expression of epithelial-mesenchymal transition (EMT)-related genes.\",\n      \"method\": \"Overexpression and siRNA knockdown in gastric cancer cell lines, proliferation/migration/invasion assays, SCID mouse tumorigenicity assay, EMT gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both gain- and loss-of-function with in vivo validation, single lab\",\n      \"pmids\": [\"26110885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In Drosophila cells, the MED30 subunit of the Mediator complex directs Nipped-B and Rad21 (cohesin subunit) to gene promoters, as shown by genome-wide ChIP-seq. This is distinct from the role of SA and Fs(1)h (BRD4) in directing cohesin to enhancers, indicating that MED30 mediates promoter-specific cohesin recruitment.\",\n      \"method\": \"Genome-wide ChIP-seq in Drosophila cells for cohesin subunits (Nipped-B, SA, SMC1, Rad21) combined with MED30 perturbation data\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with functional genetic data, Drosophila ortholog, single lab\",\n      \"pmids\": [\"30796039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR-Cas9-mediated deletion of enhancer regions at the SLC30A8 locus reduced MED30 expression, and subsequent loss of MED30 markedly reduced pancreatic beta cell viability, establishing a required role for MED30 in beta cell survival.\",\n      \"method\": \"CRISPR-Cas9 enhancer deletion in human EndoC-βH3 cells, cell viability assays after MED30 loss\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function in human-derived cells with defined viability phenotype, single lab\",\n      \"pmids\": [\"38661000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MED30 is induced in glioblastoma cells under hypoxia and nutrient deprivation in a HIF1α- and p53-dependent manner, with functional HREs and a p53 binding site identified in the MED30 promoter. MED30 overexpression promoted cell proliferation while reducing migration in GBM cell lines; knockdown had the opposite effects and conferred resistance to temozolomide. MED30 also modulated p53 protein levels in vitro.\",\n      \"method\": \"Promoter analysis (HRE and p53 binding site identification), overexpression and siRNA knockdown in GBM cell lines, proliferation and migration assays, temozolomide sensitivity assays, p53 western blot\",\n      \"journal\": \"Cellular and molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both gain- and loss-of-function with multiple cellular readouts, promoter element mapping, single lab\",\n      \"pmids\": [\"32705436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Overexpression of MED30 failed to restore protein levels of Mediator subunits in MED27-deficient cardiomyocytes, demonstrating that MED27's role in maintaining Mediator complex integrity is independent of MED30 (negative epistasis result).\",\n      \"method\": \"MED30 overexpression in MED27 cardiomyocyte-specific knockout mouse hearts, western blot for Mediator subunit levels\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo genetic epistasis experiment, single lab, negative result is mechanistically informative\",\n      \"pmids\": [\"39209248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA-mediated knockdown of MED30 in clear cell renal cell carcinoma cell lines (ACHN and A-498) significantly decreased proliferation, migration, and invasion.\",\n      \"method\": \"siRNA knockdown in ccRCC cell lines, proliferation, migration, and invasion assays\",\n      \"journal\": \"Annals of diagnostic pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (siRNA KD), single lab, phenotypic readout without pathway placement\",\n      \"pmids\": [\"29661722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"siRNA-mediated knockdown of MED30 in bladder cancer cell lines (T24 and TCCSUP) reduced proliferation, migration, and invasion despite higher MED30 expression being associated with better patient survival at the clinical level.\",\n      \"method\": \"siRNA knockdown in bladder cancer cell lines, proliferation, migration, and invasion assays\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (siRNA KD), single lab, no pathway mechanism established\",\n      \"pmids\": [\"29187445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Genome-wide CRISPR loss-of-function screen in multiple myeloma cells identified MED30 (Mediator complex subunit) as an activator of endogenous MYC expression; functional validation confirmed that MED30 loss significantly reduced MYC protein levels.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 screen with GFP-tagged endogenous MYC reporter, sgRNA validation in MM cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — screen-based identification with limited mechanistic follow-up for MED30 specifically, single lab\",\n      \"pmids\": [\"41965876\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED30 (TRAP25/THRAP6) is a metazoan-specific integral subunit of the Mediator complex that localizes to the proximal tail module (anchored between MED14/MED17), is essential for the structural stability of the entire Mediator core (head, middle, and tail modules) in vivo, and is required for both basal and activator-dependent RNA polymerase II transcription; loss of MED30 in cardiomyocytes destabilizes the Mediator complex and disrupts transcriptional programs for oxidative phosphorylation and mitochondrial function, while in cancer contexts MED30 overexpression redirects MYC to novel genomic regulatory sites to drive oncogenic transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED30 (TRAP25) is a metazoan-specific integral subunit of the Mediator complex that couples transcriptional activators to RNA polymerase II and is required for both basal and activator-dependent transcription [#0]. Structurally, MED30 associates with exposed surfaces of MED14 and MED17 to form the proximal part of the Mediator tail module that engages activators, thereby anchoring the tail to the Mediator core [#1]. This architectural role underlies its function in maintaining complex integrity: in vivo ablation of MED30 destabilizes head, middle, and tail module subunits while sparing the kinase module, establishing MED30 as essential for the structural stability of the overall Mediator complex [#2]. Through this Mediator-dependent activity, MED30 controls tissue-specific transcriptional programs — loss in cardiomyocytes disrupts the gene networks driving oxidative phosphorylation and mitochondrial integrity, causing mitochondrial cardiomyopathy [#2, #3]. In cancer contexts, elevated MED30 acts upstream of MYC, redirecting MYC to novel genomic regulatory sites and inducing new enhancers to drive oncogenic transcription [#4], and MED30 is required to sustain endogenous MYC expression [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that MED30 is a genuine integral Mediator subunit whose presence is required for the complex to support transcription, answering whether this uncharacterized protein had a functional role in PolII transcription.\",\n      \"evidence\": \"Antibody immunodepletion of HeLa nuclear extract with reconstitution and in vitro transcription assays\",\n      \"pmids\": [\"11909976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not localize MED30 within the complex architecture\", \"Did not define which activators or target genes depend on MED30\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected MED30-dependent Mediator function to a specific physiological transcriptional program, showing it drives the metabolic gene network for oxidative phosphorylation and mitochondrial integrity.\",\n      \"evidence\": \"ENU hypomorphic missense mouse model with expression profiling and ketogenic diet rescue\",\n      \"pmids\": [\"22106289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"A hypomorph does not reveal the full null phenotype\", \"Did not address how MED30 selectively controls metabolic gene programs\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved where MED30 sits in the Mediator complex, showing it anchors the activator-binding proximal tail module to the core via MED14 and MED17.\",\n      \"evidence\": \"Cryo-EM of reconstituted 50-subunit human Mediator-PIC\",\n      \"pmids\": [\"33902108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structure does not capture dynamics of activator engagement\", \"Does not show which activators bind through the MED30-containing tail surface in vivo\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated in vivo that MED30 is required for the structural stability of the entire Mediator core, distinguishing its scaffolding role from the dispensable kinase module.\",\n      \"evidence\": \"Constitutive and inducible cardiomyocyte-specific knockout mice with western blot quantification of subunits and RNAseq\",\n      \"pmids\": [\"34506481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of how MED30 loss propagates to destabilize distal modules not defined\", \"Cardiomyocyte-specific; generality to other tissues untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Tested whether MED30-dependent Mediator activity is co-opted by viral transcription, showing it is needed for HIV-1 transcript elongation/splicing and Tat-induced transcription.\",\n      \"evidence\": \"siRNA knockdown in HIV-1-infected cells with RT-PCR transcript readouts\",\n      \"pmids\": [\"25100719\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue experiment to confirm specificity\", \"Direct interaction with Tat or the viral promoter not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated MED30 dosage in tumor cell behavior, linking its overexpression to proliferation, invasion, and EMT gene induction in gastric cancer.\",\n      \"evidence\": \"Gain- and loss-of-function in gastric cancer lines with SCID mouse tumorigenicity assays\",\n      \"pmids\": [\"26110885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the direct transcriptional targets driving the phenotype\", \"Single tumor type and lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a chromatin-organizing function, showing the Mediator MED30 subunit directs cohesin (Nipped-B/Rad21) specifically to gene promoters.\",\n      \"evidence\": \"Genome-wide ChIP-seq with perturbation in Drosophila cells\",\n      \"pmids\": [\"30796039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated in Drosophila; human conservation untested\", \"Molecular basis of promoter-specific cohesin recruitment unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed MED30 within stress-responsive transcriptional circuits, showing HIF1\\u03b1/p53-dependent induction and reciprocal modulation of p53 in glioblastoma.\",\n      \"evidence\": \"Promoter element mapping, gain/loss-of-function in GBM lines, proliferation/migration and temozolomide sensitivity assays\",\n      \"pmids\": [\"32705436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MED30 modulates p53 protein levels not defined\", \"Opposing proliferation vs migration effects not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a required role for MED30 in pancreatic beta cell survival, linking enhancer-driven MED30 expression to viability.\",\n      \"evidence\": \"CRISPR enhancer deletion at the SLC30A8 locus in human EndoC-\\u03b2H3 cells with viability assays\",\n      \"pmids\": [\"38661000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets mediating survival not identified\", \"Single cell model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined an oncogenic mechanism placing MED30 upstream of MYC, showing its overexpression redirects MYC genomic binding and creates new enhancers to drive tumor growth.\",\n      \"evidence\": \"ChIP-seq for Mediator and MYC, transcriptomics, epigenetic profiling, and xenografts with MYC knockdown rescue (preprint)\",\n      \"pmids\": [\"38766212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Mechanism by which excess MED30 reshapes MYC site selection unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Used genetic epistasis to show MED27's role in Mediator integrity is independent of MED30, refining the wiring of tail-module subunit dependencies.\",\n      \"evidence\": \"MED30 overexpression in MED27-knockout mouse hearts with western blot for subunit levels\",\n      \"pmids\": [\"39209248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish MED30's own independent integrity requirements relative to MED27\", \"Negative result; no positive rescue partner identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Confirmed unbiasedly that MED30 sustains endogenous MYC expression, generalizing its MYC-activating role beyond solid tumors to multiple myeloma.\",\n      \"evidence\": \"Genome-wide CRISPR screen with endogenous MYC reporter and sgRNA validation\",\n      \"pmids\": [\"41965876\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic follow-up specific to MED30\", \"Does not distinguish direct from Mediator-wide effect on MYC\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MED30's structural anchoring of the tail module is translated into selective activator engagement and gene-specific program control across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined set of activators that bind through the MED30 tail surface\", \"Mechanism of context-specific target selection (metabolic vs oncogenic programs) unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"Mediator complex\"],\n    \"partners\": [\"MED14\", \"MED17\", \"MED27\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}