{"gene":"MED27","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2000,"finding":"Yeast Hrs1/Med3 (ortholog of MED27) physically interacts with the Cyc8-Tup1 corepressor via direct binding, and this interaction allows Cyc8-Tup1 to co-purify with the Mediator complex in a Hrs1-dependent manner; increased Hrs1 dosage alleviates Cyc8-Tup1-mediated repression, suggesting that Mediator function is inhibited upon this interaction, thereby preventing RNA pol II holoenzyme recruitment to the core promoter.","method":"Two-hybrid assay, GST pulldown, affinity chromatography, genetic dosage suppression, artificial holoenzyme recruitment assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (two-hybrid, GST pulldown, affinity chromatography, genetic epistasis) in a single focused study on this subunit","pmids":["10722672"],"is_preprint":false},{"year":2012,"finding":"In Candida albicans, Med3 (MED27 ortholog) directly and physically interacts with Tlo proteins (Med2-module subunits); Med3 is required for Tlo incorporation into the Mediator complex, as Mediator purified from a med3Δ/Δ strain lacks Tlo subunits.","method":"Mediator complex purification, co-purification of tagged proteins, reconstitution of direct interaction by coexpression and copurification in E. coli","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct physical interaction reconstituted in E. coli plus genetic deletion showing requirement for complex assembly","pmids":["22562472"],"is_preprint":false},{"year":2014,"finding":"Yeast Med3 (MED27 ortholog) is phosphorylated by Cdk8 (the Mediator kinase module subunit); site-specific phosphorylation triggers interaction with the Grr1 ubiquitin ligase and subsequent Med3 degradation, thereby suppressing transcription activation; this autoregulatory mechanism explains the substoichiometric levels of tail-module Med3 in purified Mediator.","method":"In vitro kinase assay, site-specific mutagenesis, Co-IP/interaction assay between Med3 and Grr1, genetic analysis of cdk8 mutants and grr1 mutants, protein stability assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (kinase assay, mutagenesis, interaction assay, genetic epistasis) in a single focused study","pmids":["24550274"],"is_preprint":false},{"year":2006,"finding":"Loss of Crsp34/Med27 (zebrafish ortholog of MED27) decreases amacrine cell number and increases rod photoreceptor cells in the retina, and eliminates dopaminergic amacrine cells, demonstrating a specific role for MED27 in retinal cell-type determination during vertebrate CNS development distinct from other Mediator subunits.","method":"Zebrafish forward genetic mutation analysis (m885 allele disrupts Crsp34/Med27), histological and cell-type specific marker analysis of mutant retinas","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function genetic model with defined cellular phenotype, but single lab, single organism","pmids":["16582438"],"is_preprint":false},{"year":2016,"finding":"MED27 interacts with NF-κB and with the acetyltransferase p300, and is acetylated by p300; MED27 knockdown inactivates PI3K/AKT and MAPK/ERK signaling and reduces NF-κB nuclear translocation and iNOS expression in melanoma cells.","method":"Co-immunoprecipitation (MED27 with NF-κB and p300), acetylation assay, siRNA knockdown with Western blot and xenograft tumor model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for interactions, acetylation assay, knockdown with multiple downstream readouts, single lab","pmids":["26797421"],"is_preprint":false},{"year":2020,"finding":"CRSP8/MED27 binds to the IKKα promoter region (positions -257 to -143) to negatively regulate IKKα transcription; knockdown of CRSP8 upregulates IKKα, and IKKα knockdown/overexpression reverses the differentiation and EMT marker changes caused by CRSP8 manipulation in thyroid cancer cells.","method":"Luciferase promoter assay with deletion constructs, ChIP or promoter binding assay, siRNA knockdown, rescue experiments, xenograft mouse model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter binding defined by reporter assay with deletion constructs, epistasis rescue experiments, in vivo validation, single lab","pmids":["33162555"],"is_preprint":false},{"year":2023,"finding":"MED27 transcriptionally regulates KLF4 by binding to its promoter region (positions -156 to +177); KLF4 overexpression reverses the suppression of metastasis and stemness caused by MED27 silencing in breast cancer cells.","method":"RNA-seq to identify downstream targets, luciferase reporter assay/ChIP to map promoter binding, rescue experiments with KLF4 overexpression in vitro and in vivo","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter binding with reporter assay, epistasis rescue, in vivo validation, single lab","pmids":["36786527"],"is_preprint":false},{"year":2024,"finding":"Cardiomyocyte-specific deletion of MED27 in mice causes embryonic lethality (constitutive) or heart failure and mortality (inducible adult deletion); MED27 loss decreases protein levels of most Mediator subunits in cardiomyocytes, indicating MED27 is required for stability of the Mediator complex; this role is independent of MED30, as MED30 overexpression fails to rescue Mediator subunit levels in MED27-deficient cardiomyocytes.","method":"Conditional (floxed) cardiomyocyte-specific knockout mouse (cKO and icKO), Western blot for Mediator subunit protein levels, MED30 overexpression rescue experiment, RNAseq, morphological/histological/physiological analysis","journal":"Life sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean in vivo conditional knockout with multiple phenotypic readouts, protein-level mechanistic follow-up, and negative rescue experiment establishing independence from MED30","pmids":["39209248"],"is_preprint":false},{"year":2025,"finding":"Patient-specific MED27 variants destabilize the Mediator complex and impair its chromatin occupancy and chromatin interactions; in vitro stem cell models and in vivo mouse LoF models recapitulate cerebellar atrophy and motor deficits; transcriptomic profiling identifies dysregulation of master regulatory transcription factors involved in neurogenesis and cerebellar development as downstream consequences.","method":"iPSC models with patient variants, Med27 LoF mouse models, molecular analyses of Mediator complex stability, chromatin occupancy assay (ChIP or related), chromatin interaction assay, single-cell spatial transcriptomics","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (patient iPSC lines, in vivo LoF mouse, chromatin occupancy, spatial transcriptomics) in a focused mechanistic study","pmids":["41017421"],"is_preprint":false},{"year":2024,"finding":"A missense variant MED27 p.Arg25His causes a significant reduction in MED27 protein expression and, by molecular dynamics modeling, is predicted to weaken the interaction between MED27 and MED14 subunits.","method":"Western blot of transfected cells expressing Arg25His variant, molecular dynamics structural modeling","journal":"Heliyon","confidence":"Low","confidence_rationale":"Tier 3–4 / Weak — protein reduction confirmed by Western blot, but MED14 interaction weakening is only from computational modeling, single lab","pmids":["39296199"],"is_preprint":false},{"year":2025,"finding":"CRSP8/MED27 transcriptionally activates RAN expression; enhanced RAN/CRM1-mediated nuclear export induced by CRSP8 promotes cytoplasmic translocation of PPARα (formation of RAN/CRM1/PPARα heterotrimer), impairing nuclear PPARα-dependent lipophagy and fatty acid oxidation, thereby driving lipid droplet accumulation and HCC progression.","method":"Co-immunoprecipitation, luciferase reporter assay, live cell imaging of lipid droplets, transmission electron microscopy, targeted lipidomics, in vitro and in vivo HCC models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP for heterotrimer, luciferase reporter for RAN transcriptional activation, multiple functional readouts, single lab","pmids":["40069732"],"is_preprint":false},{"year":2024,"finding":"In Saccharomyces cerevisiae, Med3 interacts with the transcription factor Stb5 (by yeast two-hybrid) to regulate expression of gnd1 and ald6 (NADPH-generating genes) under hyperosmotic stress; Med3 deletion reduces intracellular NADPH, increases ROS, and impairs bud formation under hyperosmotic conditions.","method":"Yeast two-hybrid (Med3–Stb5 interaction), deletion strain phenotypic analysis, NADPH and ROS measurements, gene expression analysis","journal":"Applied and environmental microbiology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus genetic deletion with biochemical readouts, single lab, yeast ortholog","pmids":["39082808"],"is_preprint":false}],"current_model":"MED27 is a tail/upper-tail module subunit of the Mediator complex that is required for the stability and integrity of the entire Mediator complex (loss of MED27 reduces protein levels of most other Mediator subunits); it physically interacts with corepressors (Cyc8-Tup1 via yeast ortholog), transcription factors (NF-κB, Stb5), acetyltransferases (p300, by which it is acetylated), and other Mediator subunits (Med14, Tlo/Med2-module proteins), is subject to Cdk8-dependent phosphorylation that targets it for Grr1-mediated ubiquitin-proteasomal degradation as an autoregulatory mechanism, and directly occupies gene promoters (IKKα, KLF4, RAN) to regulate transcription; in vivo, MED27 is essential for cardiac and cerebellar/neural development, and disease-causing variants destabilize the Mediator complex and impair its chromatin occupancy, disrupting neurogenic transcription programs."},"narrative":{"mechanistic_narrative":"MED27 is a tail-module subunit of the Mediator complex that is required for the structural integrity of the entire complex and for the transcriptional programs that drive cell-type specification and organ development [PMID:39209248, PMID:41017421]. As a core architectural subunit, loss of MED27 reduces the protein levels of most other Mediator subunits in cardiomyocytes, a destabilizing role that cannot be substituted by MED30 [PMID:39209248]; patient-derived MED27 variants likewise destabilize Mediator and impair its chromatin occupancy and chromatin interactions, dysregulating master neurogenic transcription factors and producing cerebellar atrophy and motor deficits in stem-cell and mouse models [PMID:41017421]. Work on the yeast ortholog (Hrs1/Med3) established conserved features of this subunit: it binds the Cyc8-Tup1 corepressor to bring repressive activity into Mediator [PMID:10722672], and it is required for incorporation of Med2-module Tlo proteins into the complex [PMID:22562472]. The substoichiometric levels of this tail subunit are explained by an autoregulatory loop in which the Mediator kinase Cdk8 phosphorylates Med3, triggering Grr1 ubiquitin-ligase-mediated proteasomal degradation that limits transcription activation [PMID:24550274]. In vivo, MED27 directs vertebrate tissue patterning, including retinal cell-type determination [PMID:16582438] and cardiac development, where its deletion is embryonic-lethal or causes adult heart failure [PMID:39209248]. In cancer contexts MED27 acts as a sequence-specific transcriptional regulator, occupying the IKKα, KLF4, and RAN promoters and interacting with NF-κB and the acetyltransferase p300 [PMID:26797421, PMID:33162555, PMID:36786527, PMID:40069732].","teleology":[{"year":2000,"claim":"Established that this Mediator subunit physically links the complex to a corepressor, defining a mechanism by which Mediator activity can be inhibited rather than only activated.","evidence":"Two-hybrid, GST pulldown, affinity chromatography and genetic dosage suppression in yeast (Hrs1/Med3)","pmids":["10722672"],"confidence":"High","gaps":["Whether human MED27 binds an equivalent corepressor is untested","Structural basis of the Cyc8-Tup1 contact not resolved"]},{"year":2006,"claim":"Showed MED27 has a specific developmental role in vertebrate CNS cell-fate determination, distinct from a generic Mediator housekeeping function.","evidence":"Zebrafish forward-genetic mutant (Crsp34/Med27 m885) with retinal cell-type marker analysis","pmids":["16582438"],"confidence":"Medium","gaps":["Transcriptional targets driving the retinal phenotype not identified","Single organism, single lab"]},{"year":2012,"claim":"Defined MED27's role as an assembly factor required to bring a specific module (Tlo/Med2) into Mediator, beyond being a passive subunit.","evidence":"Mediator purification from med3 deletion strain and reconstituted direct interaction in E. coli (Candida albicans)","pmids":["22562472"],"confidence":"High","gaps":["Whether human MED27 has an analogous module-recruitment role unknown","Stoichiometry and interface of the Med3-Tlo contact not mapped"]},{"year":2014,"claim":"Explained the substoichiometric abundance of this tail subunit through a Cdk8-phosphorylation/Grr1-ubiquitination autoregulatory degradation loop.","evidence":"In vitro kinase assay, site-specific mutagenesis, Med3-Grr1 interaction assay and genetic epistasis in yeast","pmids":["24550274"],"confidence":"High","gaps":["Conservation of the Cdk8/Grr1 axis in human MED27 not demonstrated","Phosphosite identity in the human protein unknown"]},{"year":2016,"claim":"Connected MED27 to specific transcription factors and a chromatin modifier in mammalian cells, showing it is acetylated by p300 and influences NF-κB-dependent output.","evidence":"Co-IP, acetylation assay and siRNA knockdown with signaling readouts in melanoma cells","pmids":["26797421"],"confidence":"Medium","gaps":["Functional consequence of MED27 acetylation not defined","Direct versus Mediator-mediated NF-κB contact not distinguished"]},{"year":2020,"claim":"Demonstrated promoter-level sequence-specific occupancy by MED27, here as a negative regulator of IKKα transcription.","evidence":"Luciferase deletion-construct mapping, promoter binding assay and rescue experiments in thyroid cancer cells plus xenografts","pmids":["33162555"],"confidence":"Medium","gaps":["Whether MED27 binds DNA directly or via partner factors unresolved","Single lab"]},{"year":2023,"claim":"Extended MED27's promoter-targeting activity to KLF4 regulation controlling metastasis and stemness.","evidence":"RNA-seq target discovery, reporter/promoter mapping and KLF4 rescue in breast cancer models","pmids":["36786527"],"confidence":"Medium","gaps":["DNA-binding mechanism not established","Relationship to full Mediator complex at the KLF4 promoter unclear"]},{"year":2024,"claim":"Established MED27 as essential for Mediator complex stability in a mammalian organ and for cardiac development, independent of MED30.","evidence":"Cardiomyocyte-specific conditional knockout mice, Western blot of subunit levels and negative MED30 rescue","pmids":["39209248"],"confidence":"High","gaps":["Which subunit contacts MED27 stabilizes not defined structurally","Direct transcriptional targets in heart not pinpointed"]},{"year":2025,"claim":"Defined the disease mechanism: patient MED27 variants destabilize Mediator and impair chromatin occupancy, dysregulating neurogenic master transcription factors and causing cerebellar pathology.","evidence":"Patient iPSC lines, Med27 LoF mice, chromatin occupancy/interaction assays and spatial transcriptomics","pmids":["41017421"],"confidence":"High","gaps":["Specific subunit interfaces disrupted by variants not resolved","Causal target genes among dysregulated TFs not isolated"]},{"year":2025,"claim":"Added a cancer-relevant transcriptional axis whereby MED27 activates RAN to drive RAN/CRM1-mediated nuclear export of PPARα and lipid droplet accumulation.","evidence":"Co-IP, luciferase reporter, lipid imaging, lipidomics and HCC models","pmids":["40069732"],"confidence":"Medium","gaps":["Direct MED27 occupancy of the RAN promoter versus indirect effect not separated","Single lab"]},{"year":null,"claim":"How MED27 selects specific target promoters and whether the yeast Cdk8/Grr1 autoregulatory and corepressor-bridging mechanisms operate on human MED27 remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of human MED27 within Mediator","DNA-binding versus partner-mediated promoter targeting undefined","Conservation of degradation control in mammals untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,6,10]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[7,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,8]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,6,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7,8]}],"complexes":["Mediator complex"],"partners":["MED14","MED30","P300","NF-KB","CYC8-TUP1","STB5","GRR1","CDK8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P2C8","full_name":"Mediator of RNA polymerase II transcription subunit 27","aliases":["Cofactor required for Sp1 transcriptional activation subunit 8","CRSP complex subunit 8","Mediator complex subunit 27","P37 TRAP/SMCC/PC2 subunit","Transcriptional coactivator CRSP34"],"length_aa":311,"mass_kda":35.4,"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/Q6P2C8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MED27","classification":"Common Essential","n_dependent_lines":1167,"n_total_lines":1208,"dependency_fraction":0.9660596026490066},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000160563","cell_line_id":"CID000252","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":"MED17","stoichiometry":10.0},{"gene":"MED18","stoichiometry":10.0},{"gene":"MED19","stoichiometry":10.0},{"gene":"MED20","stoichiometry":10.0},{"gene":"MED21","stoichiometry":10.0},{"gene":"MED22","stoichiometry":10.0},{"gene":"MED7","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000252","total_profiled":1310},"omim":[{"mim_id":"619286","title":"NEURODEVELOPMENTAL DISORDER WITH SPASTICITY, CATARACTS, AND CEREBELLAR ATROPHY; NEDSCAC","url":"https://www.omim.org/entry/619286"},{"mim_id":"612385","title":"MEDIATOR COMPLEX SUBUNIT 19; MED19","url":"https://www.omim.org/entry/612385"},{"mim_id":"605044","title":"MEDIATOR COMPLEX SUBUNIT 27; MED27","url":"https://www.omim.org/entry/605044"},{"mim_id":"185641","title":"MEDIATOR COMPLEX SUBUNIT 22; MED22","url":"https://www.omim.org/entry/185641"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MED27"},"hgnc":{"alias_symbol":["TRAP37","CRSP34","MED3"],"prev_symbol":["CRSP8"]},"alphafold":{"accession":"Q6P2C8","domains":[{"cath_id":"-","chopping":"158-274","consensus_level":"high","plddt":93.0507,"start":158,"end":274},{"cath_id":"1.10.287","chopping":"10-77","consensus_level":"high","plddt":86.2613,"start":10,"end":77}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P2C8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P2C8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P2C8-F1-predicted_aligned_error_v6.png","plddt_mean":82.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MED27","jax_strain_url":"https://www.jax.org/strain/search?query=MED27"},"sequence":{"accession":"Q6P2C8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P2C8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P2C8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P2C8"}},"corpus_meta":[{"pmid":"10722672","id":"PMC_10722672","title":"Hrs1/Med3 is a Cyc8-Tup1 corepressor target in the RNA polymerase II holoenzyme.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10722672","citation_count":87,"is_preprint":false},{"pmid":"22562472","id":"PMC_22562472","title":"The Tlo proteins are stoichiometric components of Candida albicans mediator anchored via the Med3 subunit.","date":"2012","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/22562472","citation_count":45,"is_preprint":false},{"pmid":"24550274","id":"PMC_24550274","title":"Suppression of Mediator is regulated by Cdk8-dependent Grr1 turnover of the Med3 coactivator.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24550274","citation_count":41,"is_preprint":false},{"pmid":"26797421","id":"PMC_26797421","title":"MED27 promotes melanoma growth by targeting AKT/MAPK and NF-κB/iNOS signaling pathways.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26797421","citation_count":31,"is_preprint":false},{"pmid":"33162555","id":"PMC_33162555","title":"CRSP8 promotes thyroid cancer progression by antagonizing IKKα-induced cell differentiation.","date":"2020","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/33162555","citation_count":22,"is_preprint":false},{"pmid":"33443317","id":"PMC_33443317","title":"MED27 Variants Cause Developmental Delay, Dystonia, and Cerebellar Hypoplasia.","date":"2021","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33443317","citation_count":21,"is_preprint":false},{"pmid":"29693135","id":"PMC_29693135","title":"MicroRNA-18a inhibits cell growth and induces apoptosis in osteosarcoma by targeting MED27.","date":"2018","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29693135","citation_count":19,"is_preprint":false},{"pmid":"16582438","id":"PMC_16582438","title":"Differential roles of transcriptional mediator complex subunits Crsp34/Med27, Crsp150/Med14 and Trap100/Med24 during zebrafish retinal development.","date":"2006","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16582438","citation_count":17,"is_preprint":false},{"pmid":"37517035","id":"PMC_37517035","title":"Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.","date":"2023","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37517035","citation_count":17,"is_preprint":false},{"pmid":"36786527","id":"PMC_36786527","title":"MED27 plays a tumor-promoting role in breast cancer progression by targeting KLF4.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/36786527","citation_count":14,"is_preprint":false},{"pmid":"35876425","id":"PMC_35876425","title":"MED27, SLC6A7, and MPPE1 Variants in a Complex Neurodevelopmental Disorder with Severe Dystonia.","date":"2022","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/35876425","citation_count":10,"is_preprint":false},{"pmid":"29730647","id":"PMC_29730647","title":"Silencing of MED27 inhibits adrenal cortical carcinogenesis by targeting the Wnt/β-catenin signaling pathway and the epithelial-mesenchymal transition process.","date":"2018","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29730647","citation_count":9,"is_preprint":false},{"pmid":"39209248","id":"PMC_39209248","title":"The essential role of MED27 in stabilizing the mediator complex for cardiac development and function.","date":"2024","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39209248","citation_count":8,"is_preprint":false},{"pmid":"40069732","id":"PMC_40069732","title":"CRSP8-driven fatty acid metabolism reprogramming enhances hepatocellular carcinoma progression by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40069732","citation_count":7,"is_preprint":false},{"pmid":"32633372","id":"PMC_32633372","title":"MED27 promotes malignant behavior of cells by affecting Sp1 in breast cancer.","date":"2020","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32633372","citation_count":7,"is_preprint":false},{"pmid":"29776932","id":"PMC_29776932","title":"Candida glabrata Med3 Plays a Role in Altering Cell Size and Budding Index To Coordinate Cell Growth.","date":"2018","source":"Applied and environmental 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Pucker","date":"2024-11-30","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.29.24318222","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13555,"output_tokens":3238,"usd":0.044617,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10800,"output_tokens":3216,"usd":0.0672,"stage2_stop_reason":"end_turn"},"total_usd":0.111817,"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\": 2000,\n      \"finding\": \"Yeast Hrs1/Med3 (ortholog of MED27) physically interacts with the Cyc8-Tup1 corepressor via direct binding, and this interaction allows Cyc8-Tup1 to co-purify with the Mediator complex in a Hrs1-dependent manner; increased Hrs1 dosage alleviates Cyc8-Tup1-mediated repression, suggesting that Mediator function is inhibited upon this interaction, thereby preventing RNA pol II holoenzyme recruitment to the core promoter.\",\n      \"method\": \"Two-hybrid assay, GST pulldown, affinity chromatography, genetic dosage suppression, artificial holoenzyme recruitment assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (two-hybrid, GST pulldown, affinity chromatography, genetic epistasis) in a single focused study on this subunit\",\n      \"pmids\": [\"10722672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In Candida albicans, Med3 (MED27 ortholog) directly and physically interacts with Tlo proteins (Med2-module subunits); Med3 is required for Tlo incorporation into the Mediator complex, as Mediator purified from a med3Δ/Δ strain lacks Tlo subunits.\",\n      \"method\": \"Mediator complex purification, co-purification of tagged proteins, reconstitution of direct interaction by coexpression and copurification in E. coli\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct physical interaction reconstituted in E. coli plus genetic deletion showing requirement for complex assembly\",\n      \"pmids\": [\"22562472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Yeast Med3 (MED27 ortholog) is phosphorylated by Cdk8 (the Mediator kinase module subunit); site-specific phosphorylation triggers interaction with the Grr1 ubiquitin ligase and subsequent Med3 degradation, thereby suppressing transcription activation; this autoregulatory mechanism explains the substoichiometric levels of tail-module Med3 in purified Mediator.\",\n      \"method\": \"In vitro kinase assay, site-specific mutagenesis, Co-IP/interaction assay between Med3 and Grr1, genetic analysis of cdk8 mutants and grr1 mutants, protein stability assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (kinase assay, mutagenesis, interaction assay, genetic epistasis) in a single focused study\",\n      \"pmids\": [\"24550274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Loss of Crsp34/Med27 (zebrafish ortholog of MED27) decreases amacrine cell number and increases rod photoreceptor cells in the retina, and eliminates dopaminergic amacrine cells, demonstrating a specific role for MED27 in retinal cell-type determination during vertebrate CNS development distinct from other Mediator subunits.\",\n      \"method\": \"Zebrafish forward genetic mutation analysis (m885 allele disrupts Crsp34/Med27), histological and cell-type specific marker analysis of mutant retinas\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function genetic model with defined cellular phenotype, but single lab, single organism\",\n      \"pmids\": [\"16582438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MED27 interacts with NF-κB and with the acetyltransferase p300, and is acetylated by p300; MED27 knockdown inactivates PI3K/AKT and MAPK/ERK signaling and reduces NF-κB nuclear translocation and iNOS expression in melanoma cells.\",\n      \"method\": \"Co-immunoprecipitation (MED27 with NF-κB and p300), acetylation assay, siRNA knockdown with Western blot and xenograft tumor model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for interactions, acetylation assay, knockdown with multiple downstream readouts, single lab\",\n      \"pmids\": [\"26797421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRSP8/MED27 binds to the IKKα promoter region (positions -257 to -143) to negatively regulate IKKα transcription; knockdown of CRSP8 upregulates IKKα, and IKKα knockdown/overexpression reverses the differentiation and EMT marker changes caused by CRSP8 manipulation in thyroid cancer cells.\",\n      \"method\": \"Luciferase promoter assay with deletion constructs, ChIP or promoter binding assay, siRNA knockdown, rescue experiments, xenograft mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter binding defined by reporter assay with deletion constructs, epistasis rescue experiments, in vivo validation, single lab\",\n      \"pmids\": [\"33162555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MED27 transcriptionally regulates KLF4 by binding to its promoter region (positions -156 to +177); KLF4 overexpression reverses the suppression of metastasis and stemness caused by MED27 silencing in breast cancer cells.\",\n      \"method\": \"RNA-seq to identify downstream targets, luciferase reporter assay/ChIP to map promoter binding, rescue experiments with KLF4 overexpression in vitro and in vivo\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter binding with reporter assay, epistasis rescue, in vivo validation, single lab\",\n      \"pmids\": [\"36786527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cardiomyocyte-specific deletion of MED27 in mice causes embryonic lethality (constitutive) or heart failure and mortality (inducible adult deletion); MED27 loss decreases protein levels of most Mediator subunits in cardiomyocytes, indicating MED27 is required for stability of the Mediator complex; this role is independent of MED30, as MED30 overexpression fails to rescue Mediator subunit levels in MED27-deficient cardiomyocytes.\",\n      \"method\": \"Conditional (floxed) cardiomyocyte-specific knockout mouse (cKO and icKO), Western blot for Mediator subunit protein levels, MED30 overexpression rescue experiment, RNAseq, morphological/histological/physiological analysis\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean in vivo conditional knockout with multiple phenotypic readouts, protein-level mechanistic follow-up, and negative rescue experiment establishing independence from MED30\",\n      \"pmids\": [\"39209248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Patient-specific MED27 variants destabilize the Mediator complex and impair its chromatin occupancy and chromatin interactions; in vitro stem cell models and in vivo mouse LoF models recapitulate cerebellar atrophy and motor deficits; transcriptomic profiling identifies dysregulation of master regulatory transcription factors involved in neurogenesis and cerebellar development as downstream consequences.\",\n      \"method\": \"iPSC models with patient variants, Med27 LoF mouse models, molecular analyses of Mediator complex stability, chromatin occupancy assay (ChIP or related), chromatin interaction assay, single-cell spatial transcriptomics\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (patient iPSC lines, in vivo LoF mouse, chromatin occupancy, spatial transcriptomics) in a focused mechanistic study\",\n      \"pmids\": [\"41017421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A missense variant MED27 p.Arg25His causes a significant reduction in MED27 protein expression and, by molecular dynamics modeling, is predicted to weaken the interaction between MED27 and MED14 subunits.\",\n      \"method\": \"Western blot of transfected cells expressing Arg25His variant, molecular dynamics structural modeling\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 / Weak — protein reduction confirmed by Western blot, but MED14 interaction weakening is only from computational modeling, single lab\",\n      \"pmids\": [\"39296199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRSP8/MED27 transcriptionally activates RAN expression; enhanced RAN/CRM1-mediated nuclear export induced by CRSP8 promotes cytoplasmic translocation of PPARα (formation of RAN/CRM1/PPARα heterotrimer), impairing nuclear PPARα-dependent lipophagy and fatty acid oxidation, thereby driving lipid droplet accumulation and HCC progression.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, live cell imaging of lipid droplets, transmission electron microscopy, targeted lipidomics, in vitro and in vivo HCC models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP for heterotrimer, luciferase reporter for RAN transcriptional activation, multiple functional readouts, single lab\",\n      \"pmids\": [\"40069732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Saccharomyces cerevisiae, Med3 interacts with the transcription factor Stb5 (by yeast two-hybrid) to regulate expression of gnd1 and ald6 (NADPH-generating genes) under hyperosmotic stress; Med3 deletion reduces intracellular NADPH, increases ROS, and impairs bud formation under hyperosmotic conditions.\",\n      \"method\": \"Yeast two-hybrid (Med3–Stb5 interaction), deletion strain phenotypic analysis, NADPH and ROS measurements, gene expression analysis\",\n      \"journal\": \"Applied and environmental microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus genetic deletion with biochemical readouts, single lab, yeast ortholog\",\n      \"pmids\": [\"39082808\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MED27 is a tail/upper-tail module subunit of the Mediator complex that is required for the stability and integrity of the entire Mediator complex (loss of MED27 reduces protein levels of most other Mediator subunits); it physically interacts with corepressors (Cyc8-Tup1 via yeast ortholog), transcription factors (NF-κB, Stb5), acetyltransferases (p300, by which it is acetylated), and other Mediator subunits (Med14, Tlo/Med2-module proteins), is subject to Cdk8-dependent phosphorylation that targets it for Grr1-mediated ubiquitin-proteasomal degradation as an autoregulatory mechanism, and directly occupies gene promoters (IKKα, KLF4, RAN) to regulate transcription; in vivo, MED27 is essential for cardiac and cerebellar/neural development, and disease-causing variants destabilize the Mediator complex and impair its chromatin occupancy, disrupting neurogenic transcription programs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MED27 is a tail-module subunit of the Mediator complex that is required for the structural integrity of the entire complex and for the transcriptional programs that drive cell-type specification and organ development [#7, #8]. As a core architectural subunit, loss of MED27 reduces the protein levels of most other Mediator subunits in cardiomyocytes, a destabilizing role that cannot be substituted by MED30 [#7]; patient-derived MED27 variants likewise destabilize Mediator and impair its chromatin occupancy and chromatin interactions, dysregulating master neurogenic transcription factors and producing cerebellar atrophy and motor deficits in stem-cell and mouse models [#8]. Work on the yeast ortholog (Hrs1/Med3) established conserved features of this subunit: it binds the Cyc8-Tup1 corepressor to bring repressive activity into Mediator [#0], and it is required for incorporation of Med2-module Tlo proteins into the complex [#1]. The substoichiometric levels of this tail subunit are explained by an autoregulatory loop in which the Mediator kinase Cdk8 phosphorylates Med3, triggering Grr1 ubiquitin-ligase-mediated proteasomal degradation that limits transcription activation [#2]. In vivo, MED27 directs vertebrate tissue patterning, including retinal cell-type determination [#3] and cardiac development, where its deletion is embryonic-lethal or causes adult heart failure [#7]. In cancer contexts MED27 acts as a sequence-specific transcriptional regulator, occupying the IKK\\u03b1, KLF4, and RAN promoters and interacting with NF-\\u03baB and the acetyltransferase p300 [#4, #5, #6, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that this Mediator subunit physically links the complex to a corepressor, defining a mechanism by which Mediator activity can be inhibited rather than only activated.\",\n      \"evidence\": \"Two-hybrid, GST pulldown, affinity chromatography and genetic dosage suppression in yeast (Hrs1/Med3)\",\n      \"pmids\": [\"10722672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human MED27 binds an equivalent corepressor is untested\", \"Structural basis of the Cyc8-Tup1 contact not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed MED27 has a specific developmental role in vertebrate CNS cell-fate determination, distinct from a generic Mediator housekeeping function.\",\n      \"evidence\": \"Zebrafish forward-genetic mutant (Crsp34/Med27 m885) with retinal cell-type marker analysis\",\n      \"pmids\": [\"16582438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional targets driving the retinal phenotype not identified\", \"Single organism, single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined MED27's role as an assembly factor required to bring a specific module (Tlo/Med2) into Mediator, beyond being a passive subunit.\",\n      \"evidence\": \"Mediator purification from med3 deletion strain and reconstituted direct interaction in E. coli (Candida albicans)\",\n      \"pmids\": [\"22562472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human MED27 has an analogous module-recruitment role unknown\", \"Stoichiometry and interface of the Med3-Tlo contact not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Explained the substoichiometric abundance of this tail subunit through a Cdk8-phosphorylation/Grr1-ubiquitination autoregulatory degradation loop.\",\n      \"evidence\": \"In vitro kinase assay, site-specific mutagenesis, Med3-Grr1 interaction assay and genetic epistasis in yeast\",\n      \"pmids\": [\"24550274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the Cdk8/Grr1 axis in human MED27 not demonstrated\", \"Phosphosite identity in the human protein unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected MED27 to specific transcription factors and a chromatin modifier in mammalian cells, showing it is acetylated by p300 and influences NF-\\u03baB-dependent output.\",\n      \"evidence\": \"Co-IP, acetylation assay and siRNA knockdown with signaling readouts in melanoma cells\",\n      \"pmids\": [\"26797421\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of MED27 acetylation not defined\", \"Direct versus Mediator-mediated NF-\\u03baB contact not distinguished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated promoter-level sequence-specific occupancy by MED27, here as a negative regulator of IKK\\u03b1 transcription.\",\n      \"evidence\": \"Luciferase deletion-construct mapping, promoter binding assay and rescue experiments in thyroid cancer cells plus xenografts\",\n      \"pmids\": [\"33162555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MED27 binds DNA directly or via partner factors unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended MED27's promoter-targeting activity to KLF4 regulation controlling metastasis and stemness.\",\n      \"evidence\": \"RNA-seq target discovery, reporter/promoter mapping and KLF4 rescue in breast cancer models\",\n      \"pmids\": [\"36786527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DNA-binding mechanism not established\", \"Relationship to full Mediator complex at the KLF4 promoter unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established MED27 as essential for Mediator complex stability in a mammalian organ and for cardiac development, independent of MED30.\",\n      \"evidence\": \"Cardiomyocyte-specific conditional knockout mice, Western blot of subunit levels and negative MED30 rescue\",\n      \"pmids\": [\"39209248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which subunit contacts MED27 stabilizes not defined structurally\", \"Direct transcriptional targets in heart not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the disease mechanism: patient MED27 variants destabilize Mediator and impair chromatin occupancy, dysregulating neurogenic master transcription factors and causing cerebellar pathology.\",\n      \"evidence\": \"Patient iPSC lines, Med27 LoF mice, chromatin occupancy/interaction assays and spatial transcriptomics\",\n      \"pmids\": [\"41017421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific subunit interfaces disrupted by variants not resolved\", \"Causal target genes among dysregulated TFs not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a cancer-relevant transcriptional axis whereby MED27 activates RAN to drive RAN/CRM1-mediated nuclear export of PPAR\\u03b1 and lipid droplet accumulation.\",\n      \"evidence\": \"Co-IP, luciferase reporter, lipid imaging, lipidomics and HCC models\",\n      \"pmids\": [\"40069732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MED27 occupancy of the RAN promoter versus indirect effect not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MED27 selects specific target promoters and whether the yeast Cdk8/Grr1 autoregulatory and corepressor-bridging mechanisms operate on human MED27 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of human MED27 within Mediator\", \"DNA-binding versus partner-mediated promoter targeting undefined\", \"Conservation of degradation control in mammals untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 6, 10]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7, 8]}\n    ],\n    \"complexes\": [\"Mediator complex\"],\n    \"partners\": [\"MED14\", \"MED30\", \"p300\", \"NF-kB\", \"Cyc8-Tup1\", \"Stb5\", \"Grr1\", \"Cdk8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}