{"gene":"BRD8","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2022,"finding":"BRD8 maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex, creating a repressive chromatin state that prevents p53 transactivation and sustains proliferation in TP53-wild-type GBM. Targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility, and engages p53 transactivation, enforcing cell cycle arrest.","method":"ChIP, chromatin accessibility assays, bromodomain inhibition/targeting, loss-of-function in patient-derived GBM models, gene expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, chromatin accessibility, bromodomain targeting with functional readout) in a focused mechanistic study replicated in patient-derived models","pmids":["36544023"],"is_preprint":false},{"year":2012,"finding":"BRD8, as a subunit of the p400 complex, promotes adipogenesis by targeting and incorporating histone variant H2A.Z into transcriptional regulatory regions of PPARγ target genes; shRNA knockdown of Brd8 blocks H2A.Z incorporation, PPARγ accumulation, p400 and RNA Pol II recruitment, and abrogates fat cell differentiation.","method":"shRNA knockdown, chromatin immunoprecipitation (ChIP), lipid accumulation assays in 3T3-L1 preadipocytes","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal ChIP and functional KD with specific phenotypic readout (adipogenesis failure), multiple orthogonal methods in single lab","pmids":["23064015"],"is_preprint":false},{"year":2009,"finding":"BRD8 is an accessory subunit of the human NuA4-HAT (TRRAP/TIP60) complex and confers resistance to spindle poisons; siRNA knockdown of BRD8 induces cell death/growth delay in colorectal cancer lines and sensitizes surviving cells to spindle poisons and proteasome inhibitor MG132, while overexpression of at least one BRD8 isoform confers growth advantage and taxol resistance.","method":"siRNA knockdown, stable overexpression in HeLa cells, cell viability assays, expression cloning","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with defined phenotypic readout (drug sensitivity), single lab, two complementary approaches","pmids":["19787264"],"is_preprint":false},{"year":2018,"finding":"Knockdown of BRD8 activates the p53 transcriptional pathway, upregulating p21 and pro-apoptotic genes, inducing G1/S arrest and apoptosis. BRD8 depletion also triggers the DNA damage response (DDR) under normal growth conditions, activating ATM-CHK2 signaling, reducing CHK1, inducing replication stress (enhanced RPA32 phosphorylation), and reducing H4K16 acetylation, suggesting BRD8 is required for p400/Tip60 complex recruitment/stabilization at chromatin for DNA repair.","method":"siRNA knockdown, flow cytometry (cell cycle/apoptosis), Western blot (p21, CHK1/2, RPA32 phosphorylation, H4K16ac), DNA damage foci detection","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical readouts following KD, single lab, mechanistic pathway placement via epistasis","pmids":["30237520"],"is_preprint":false},{"year":2023,"finding":"BRD8 protein accumulates in colorectal cancer cells through inhibition of ubiquitin-dependent degradation via interaction with MRG domain binding protein. BRD8 transactivates genes independently of TIP60, regulates multiple subunits of the pre-replicative complex in concert with activator protein-1 (AP-1), and its bromodomain is indispensable for interaction with histone H4, transcriptional regulation, and its own protein stability. BRD8 depletion causes G1 cell cycle arrest.","method":"Transcriptome analysis, genome-wide BRD8 ChIP-seq, co-immunoprecipitation, bromodomain mutagenesis, siRNA knockdown, cell cycle analysis","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP-seq, transcriptomics, Co-IP, mutagenesis, KD phenotype) in a single mechanistic study","pmids":["37123243"],"is_preprint":false},{"year":2021,"finding":"A chemoproteomics approach using a functionalized BRD9 ligand affinity matrix identified BRD8 as a bromodomain-containing subunit of the NuA4 complex; selective and cellularly active first-in-class small molecule probes for BRD8 were developed using homology-model-guided design.","method":"Chemoproteomics (affinity matrix pulldown/MS), homology model-guided probe design, cellular activity assays","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical proteomics with MS confirmation of NuA4 complex interaction and validated cellularly active probes, single lab","pmids":["34515462"],"is_preprint":false},{"year":2020,"finding":"BRD8 knockdown reduces KAT5 (TIP60) protein levels and expression of KAT5-induced genes in HCC cells, placing BRD8 upstream of KAT5 in regulating HCC cell proliferation and apoptosis resistance. miR-876-3p directly targets BRD8 mRNA (confirmed by luciferase reporter assay), negatively regulating BRD8 expression.","method":"siRNA knockdown, overexpression, luciferase reporter assay, Western blot, RT-qPCR, cell viability and apoptosis assays","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD/OE with phenotypic readouts and luciferase validation of miRNA targeting, single lab, moderate mechanistic depth","pmids":["32860757"],"is_preprint":false},{"year":2021,"finding":"BRD8 occupies genome-wide sites in human lung epithelial cells, co-occupying regions with CTCF. BRD8 depletion increases secretion of beta-defensin 1 and multiple chemokines and reduces cell proliferation, implicating BRD8 in regulation of innate immune response genes and the cell cycle.","method":"ChIP-seq (genome-wide BRD8 occupancy), siRNA depletion, gene expression analysis, motif over-representation analysis, cytokine/peptide secretion assays","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with functional KD and multiple phenotypic readouts, single lab","pmids":["33476703"],"is_preprint":false},{"year":2024,"finding":"BRD8 reads histone acetylation to localize the histone acetyltransferase KAT5 genome-wide; BRD8 maintains open chromatin at somatic genes and histone acetylation at naive-specific genes in primed mouse epiblast stem cells, thereby impeding conversion to naive ESCs. Reduction of Brd8 reduces histone acetylation at naive-specific genes and permits faster acquisition of accessible chromatin at those loci during cell type conversion.","method":"ATAC-seq, ChIP-seq (histone acetylation), Brd8 knockdown/depletion, cell type conversion assays (EpiSC to naive ESC), chromatin accessibility analysis","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal epigenomic methods (ATAC-seq, ChIP-seq) combined with functional cell fate conversion assay and mechanistic model of BRD8 as KAT5 localizer","pmids":["39656858"],"is_preprint":false},{"year":2026,"finding":"BRD8, as an acetyl-lysine reader in the EP400 complex, mediates ER/HER2 signaling crosstalk in HR+/HER2+ breast cancer. BRD8 expression increases after anti-HER2 treatment; its depletion disrupts ER-HER2 interaction and enhances drug sensitivity. BRD8 regulates chromatin opening (H2AZac deposition via EP400) at ER, FOX, and ETS transcription factor motif-containing regions after anti-HER2 treatment, and is required for neratinib-induced ER activation.","method":"Single-cell transcriptomics, single-nucleus ATAC-seq, BRD8 depletion, co-immunoprecipitation (ER-HER2), H2AZac ChIP, drug sensitivity assays, clinical trial validation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (snATAC-seq, scRNA-seq, ChIP, Co-IP, functional KD) in single study with clinical trial validation","pmids":["41886605"],"is_preprint":false},{"year":2025,"finding":"BRD8 knockdown suppresses TGF-β1 upregulation, which in turn reduces M2-like tumor-associated macrophage (TAM2) polarization and decreases migration and invasion of colorectal cancer cells, placing BRD8 upstream of TGF-β1 in regulating the tumor immune microenvironment.","method":"siRNA knockdown, RT-qPCR, Western blot, flow cytometry (macrophage polarization), transwell migration/invasion assays, IHC/immunofluorescence","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect mechanistic link (BRD8→TGF-β1→TAM2), limited orthogonal validation of direct mechanism","pmids":["40720004"],"is_preprint":false}],"current_model":"BRD8 is a bromodomain-containing subunit of the NuA4/EP400-TIP60 histone acetyltransferase complex that reads acetylated lysine residues on histones H4 and H2AZ to recruit and stabilize KAT5 (TIP60) at chromatin, thereby regulating H2AZ incorporation, histone acetylation, and chromatin accessibility at target gene loci; through this mechanism BRD8 maintains repressive chromatin at p53 target genes (suppressing p53-mediated tumor suppression), activates PPARγ and pre-replicative complex gene programs, sustains genome stability via the ATM-CHK2 DDR pathway, controls cell cycle progression in a TIP60-independent manner via AP-1, and mediates ER/HER2 signaling crosstalk through EP400-dependent H2AZ acetylation deposition."},"narrative":{"mechanistic_narrative":"BRD8 is a bromodomain-containing acetyl-lysine reader subunit of the NuA4/EP400-TIP60 (KAT5) histone acetyltransferase complex that uses its bromodomain to engage acetylated histone H4 and direct the incorporation of histone variant H2A.Z into chromatin, thereby governing histone acetylation, chromatin accessibility, and target-gene expression [PMID:36544023, PMID:23064015, PMID:37123243, PMID:39656858]. By localizing and stabilizing KAT5 at chromatin genome-wide, BRD8 controls the acetylation state of specific gene programs: it maintains H2A.Z-dependent repressive chromatin at p53 target loci to suppress p53 transactivation and sustain proliferation, such that bromodomain targeting or depletion displaces H2A.Z, opens chromatin, activates p53 and p21, and enforces G1/S arrest and apoptosis [PMID:36544023, PMID:30237520]. BRD8 depletion concomitantly reduces KAT5 protein levels and KAT5-dependent gene expression, lowers H4K16 acetylation, and triggers replication stress and ATM-CHK2 DNA damage signaling, indicating a requirement for BRD8 in p400/TIP60 recruitment supporting genome stability [PMID:30237520, PMID:32860757]. BRD8 also drives developmental and lineage programs—promoting PPARγ-dependent adipogenesis through H2A.Z deposition [PMID:23064015] and maintaining open chromatin at somatic genes to impede the conversion of primed epiblast stem cells to the naive state [PMID:39656858]—and acts in transcription at additional loci, co-occupying genomic sites with CTCF and regulating innate immune response and cell cycle genes [PMID:33476703]. Beyond its canonical complex role, BRD8 transactivates pre-replicative complex genes together with AP-1 independently of TIP60, and its own protein stability is bromodomain-dependent and protected from ubiquitin-mediated degradation via interaction with an MRG domain binding protein [PMID:37123243]. In cancer, BRD8 mediates ER/HER2 signaling crosstalk by directing EP400-dependent H2A.Z acetylation at ER, FOX, and ETS motif regions and is required for neratinib-induced ER activation in HR+/HER2+ breast cancer [PMID:41886605].","teleology":[{"year":2009,"claim":"Established BRD8 as a functional accessory subunit of the human NuA4-HAT (TRRAP/TIP60) complex with a role in drug resistance, linking it for the first time to a defined chromatin-modifying machinery and a cancer phenotype.","evidence":"siRNA knockdown and stable overexpression in HeLa/colorectal cancer lines with viability and spindle-poison sensitivity readouts","pmids":["19787264"],"confidence":"Medium","gaps":["Did not define the molecular activity of BRD8 within the complex","No direct demonstration of bromodomain function or histone reading","Mechanism of taxol/MG132 sensitization unresolved"]},{"year":2012,"claim":"Showed BRD8 within the p400 complex directs histone variant H2A.Z incorporation to activate a defined gene program, establishing its role in chromatin-templated transcriptional activation during differentiation.","evidence":"shRNA knockdown and ChIP with adipogenesis/lipid accumulation assays in 3T3-L1 preadipocytes","pmids":["23064015"],"confidence":"High","gaps":["Did not test whether the bromodomain mediates chromatin targeting","Mechanism connecting H2A.Z deposition to PPARγ accumulation not resolved","Restricted to adipogenic context"]},{"year":2018,"claim":"Placed BRD8 upstream of both the p53 pathway and the DNA damage response, revealing that loss of BRD8 derepresses p53 and induces replication stress with ATM-CHK2 activation, implicating it in p400/TIP60-dependent genome maintenance.","evidence":"siRNA knockdown with flow cytometry, Western blots for p21/CHK1-2/RPA32-P/H4K16ac in cell lines","pmids":["30237520"],"confidence":"Medium","gaps":["Epistatic placement does not establish direct chromatin recruitment mechanism","Whether DDR activation is p53-dependent or parallel unresolved","No genome-wide occupancy data"]},{"year":2020,"claim":"Demonstrated BRD8 acts upstream of KAT5 protein stability and KAT5-target gene expression and is itself controlled by miR-876-3p, defining a regulatory hierarchy and an upstream regulator in hepatocellular carcinoma.","evidence":"siRNA/overexpression, luciferase reporter validation of miRNA targeting, Western blot and viability/apoptosis assays in HCC cells","pmids":["32860757"],"confidence":"Medium","gaps":["Mechanism by which BRD8 stabilizes KAT5 protein not defined","No direct chromatin co-occupancy data","Single cancer type"]},{"year":2021,"claim":"Mapped genome-wide BRD8 occupancy showing co-localization with CTCF and a functional role in innate immune and cell cycle gene regulation, broadening its transcriptional targets beyond differentiation.","evidence":"ChIP-seq, siRNA depletion, motif analysis, and cytokine/peptide secretion assays in human lung epithelial cells","pmids":["33476703"],"confidence":"Medium","gaps":["Functional significance of CTCF co-occupancy not mechanistically dissected","Direct vs indirect regulation of immune genes unclear"]},{"year":2021,"claim":"Confirmed BRD8 as a bromodomain subunit of NuA4 by chemoproteomics and delivered first-in-class selective small-molecule probes, enabling pharmacological interrogation of its bromodomain.","evidence":"Chemoproteomic affinity-matrix pulldown/MS and homology-model-guided probe design with cellular activity assays","pmids":["34515462"],"confidence":"Medium","gaps":["Endogenous acetyl-lysine ligand specificity not defined here","No structural model of bromodomain-histone engagement"]},{"year":2022,"claim":"Defined the disease-relevant mechanism: BRD8 maintains H2A.Z at p53 target loci to enforce repressive chromatin in TP53-wild-type GBM, and bromodomain targeting reactivates p53 and arrests proliferation, validating the bromodomain as a therapeutic target.","evidence":"ChIP, chromatin accessibility, bromodomain targeting with functional readout, loss-of-function in patient-derived GBM models","pmids":["36544023"],"confidence":"High","gaps":["Whether p53 repression generalizes beyond GBM not established here","Direct acetyl-mark read by the bromodomain at these loci not resolved"]},{"year":2023,"claim":"Revealed TIP60-independent functions of BRD8: bromodomain-dependent H4 binding required for its own protein stability and transactivation, AP-1-coordinated regulation of pre-replicative complex genes, and stabilization via an MRG domain binding protein against ubiquitin-dependent degradation.","evidence":"Transcriptomics, genome-wide BRD8 ChIP-seq, Co-IP, bromodomain mutagenesis, and cell-cycle analysis in colorectal cancer cells","pmids":["37123243"],"confidence":"High","gaps":["Identity/mechanism of the deubiquitinating or stabilizing pathway incompletely defined","How AP-1 cooperation is achieved at the molecular level unresolved"]},{"year":2024,"claim":"Established BRD8 as a histone-acetylation reader that localizes KAT5 genome-wide, demonstrating in epiblast stem cells that it sustains open chromatin and acetylation to gate cell-fate transitions.","evidence":"ATAC-seq, histone-acetylation ChIP-seq, Brd8 depletion, and EpiSC-to-naive ESC conversion assays","pmids":["39656858"],"confidence":"High","gaps":["Precise acetyl-lysine marks read at each locus class not fully enumerated","Generalizability of the KAT5-localizer role across cell types"]},{"year":2026,"claim":"Extended BRD8's reader function to oncogenic signaling crosstalk, showing it directs EP400-dependent H2A.Z acetylation at ER/FOX/ETS regions to couple ER and HER2 signaling and confer drug resistance in HR+/HER2+ breast cancer.","evidence":"scRNA-seq, snATAC-seq, BRD8 depletion, ER-HER2 Co-IP, H2AZac ChIP, drug-sensitivity assays with clinical-trial validation","pmids":["41886605"],"confidence":"High","gaps":["Direct molecular basis of the ER-HER2 interaction disruption upon BRD8 loss not fully resolved","Whether the bromodomain is required for this specific function not isolated"]},{"year":null,"claim":"How BRD8's bromodomain specificity (which acetyl-lysine marks on H4/H2A.Z it reads) and its switch between TIP60/KAT5-dependent and TIP60-independent functions are mechanistically partitioned across contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of bromodomain-acetyl-histone complex in the timeline","Determinants selecting between KAT5-dependent and AP-1-dependent transcriptional programs unknown","Mechanism coupling chromatin reading to KAT5 protein stabilization undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,4,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,6,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,7,8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,1,8]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,7,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,9]}],"complexes":["NuA4/TIP60 histone acetyltransferase complex","EP400/p400 complex"],"partners":["KAT5","EP400","TRRAP","AP-1","CTCF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H0E9","full_name":"Bromodomain-containing protein 8","aliases":["Skeletal muscle abundant protein","Skeletal muscle abundant protein 2","Thyroid hormone receptor coactivating protein of 120 kDa","TrCP120","p120"],"length_aa":1235,"mass_kda":135.3,"function":"May act as a coactivator during transcriptional activation by hormone-activated nuclear receptors (NR). Isoform 2 stimulates transcriptional activation by AR/DHTR, ESR1/NR3A1, RXRA/NR2B1 and THRB/ERBA2. At least isoform 1 and isoform 2 are components of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H0E9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/BRD8","classification":"Common Essential","n_dependent_lines":583,"n_total_lines":1208,"dependency_fraction":0.4826158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TRRAP","stoichiometry":4.0},{"gene":"ACTB","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BRD8","total_profiled":1310},"omim":[{"mim_id":"602848","title":"BROMODOMAIN-CONTAINING PROTEIN 8; BRD8","url":"https://www.omim.org/entry/602848"},{"mim_id":"601409","title":"LYSINE ACETYLTRANSFERASE 5; KAT5","url":"https://www.omim.org/entry/601409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BRD8"},"hgnc":{"alias_symbol":["SMAP","p120"],"prev_symbol":[]},"alphafold":{"accession":"Q9H0E9","domains":[{"cath_id":"-","chopping":"22-76_92-134","consensus_level":"high","plddt":90.9782,"start":22,"end":134},{"cath_id":"1.20.920.10","chopping":"1123-1217","consensus_level":"medium","plddt":85.9386,"start":1123,"end":1217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0E9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0E9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0E9-F1-predicted_aligned_error_v6.png","plddt_mean":52.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BRD8","jax_strain_url":"https://www.jax.org/strain/search?query=BRD8"},"sequence":{"accession":"Q9H0E9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0E9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0E9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0E9"}},"corpus_meta":[{"pmid":"36544023","id":"PMC_36544023","title":"BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/36544023","citation_count":64,"is_preprint":false},{"pmid":"28758277","id":"PMC_28758277","title":"Fusion of the genes BRD8 and PHF1 in endometrial stromal sarcoma.","date":"2017","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28758277","citation_count":44,"is_preprint":false},{"pmid":"19787264","id":"PMC_19787264","title":"BRD8 is a potential chemosensitizing target for spindle poisons in colorectal cancer therapy.","date":"2009","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19787264","citation_count":30,"is_preprint":false},{"pmid":"23064015","id":"PMC_23064015","title":"The p400/Brd8 chromatin remodeling complex promotes adipogenesis by incorporating histone variant H2A.Z at PPARγ target genes.","date":"2012","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23064015","citation_count":24,"is_preprint":false},{"pmid":"30237520","id":"PMC_30237520","title":"Cellular Depletion of BRD8 Causes p53-Dependent Apoptosis and Induces a DNA Damage Response in Non-Stressed Cells.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30237520","citation_count":17,"is_preprint":false},{"pmid":"32860757","id":"PMC_32860757","title":"BRD8, which is negatively regulated by miR-876-3p, promotes the proliferation and apoptosis resistance of hepatocellular carcinoma cells via KAT5.","date":"2020","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/32860757","citation_count":16,"is_preprint":false},{"pmid":"33476703","id":"PMC_33476703","title":"The Bromodomain Containing 8 (BRD8) transcriptional network in human lung epithelial cells.","date":"2021","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/33476703","citation_count":11,"is_preprint":false},{"pmid":"37123243","id":"PMC_37123243","title":"Bromodomain protein BRD8 regulates cell cycle progression in colorectal cancer cells through a TIP60-independent regulation of the pre-RC complex.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37123243","citation_count":10,"is_preprint":false},{"pmid":"34515462","id":"PMC_34515462","title":"Chemoproteomics Enabled Discovery of Selective Probes for NuA4 Factor BRD8.","date":"2021","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/34515462","citation_count":8,"is_preprint":false},{"pmid":"38965933","id":"PMC_38965933","title":"Understanding the role of BRD8 in human carcinogenesis.","date":"2024","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/38965933","citation_count":5,"is_preprint":false},{"pmid":"33975123","id":"PMC_33975123","title":"Ossifying low grade endometrial stromal sarcoma with PHF1-BRD8 fusion.","date":"2021","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33975123","citation_count":4,"is_preprint":false},{"pmid":"39656858","id":"PMC_39656858","title":"BRD8 Guards the Pluripotent State by Sensing and Maintaining Histone Acetylation.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39656858","citation_count":3,"is_preprint":false},{"pmid":"38401187","id":"PMC_38401187","title":"Targeting bromodomian-containing protein 8 (BRD8): An advanced tool to interrogate BRD8.","date":"2024","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38401187","citation_count":2,"is_preprint":false},{"pmid":"40720004","id":"PMC_40720004","title":"BRD8 inhibits colorectal cancer progression through TGF-β1-mediated tumor-associated macrophage recruitment.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40720004","citation_count":1,"is_preprint":false},{"pmid":"41886605","id":"PMC_41886605","title":"Integrated Multi-omic Profiling Identifies BRD8/EP400 as a Pivotal Chromatin Module Mediating Anti-HER2 Response in HR+/HER2+ Breast Cancer.","date":"2026","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41886605","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8800,"output_tokens":3118,"usd":0.036585,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10543,"output_tokens":4320,"usd":0.080357,"stage2_stop_reason":"end_turn"},"total_usd":0.116942,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"BRD8 maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex, creating a repressive chromatin state that prevents p53 transactivation and sustains proliferation in TP53-wild-type GBM. Targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility, and engages p53 transactivation, enforcing cell cycle arrest.\",\n      \"method\": \"ChIP, chromatin accessibility assays, bromodomain inhibition/targeting, loss-of-function in patient-derived GBM models, gene expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, chromatin accessibility, bromodomain targeting with functional readout) in a focused mechanistic study replicated in patient-derived models\",\n      \"pmids\": [\"36544023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BRD8, as a subunit of the p400 complex, promotes adipogenesis by targeting and incorporating histone variant H2A.Z into transcriptional regulatory regions of PPARγ target genes; shRNA knockdown of Brd8 blocks H2A.Z incorporation, PPARγ accumulation, p400 and RNA Pol II recruitment, and abrogates fat cell differentiation.\",\n      \"method\": \"shRNA knockdown, chromatin immunoprecipitation (ChIP), lipid accumulation assays in 3T3-L1 preadipocytes\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal ChIP and functional KD with specific phenotypic readout (adipogenesis failure), multiple orthogonal methods in single lab\",\n      \"pmids\": [\"23064015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"BRD8 is an accessory subunit of the human NuA4-HAT (TRRAP/TIP60) complex and confers resistance to spindle poisons; siRNA knockdown of BRD8 induces cell death/growth delay in colorectal cancer lines and sensitizes surviving cells to spindle poisons and proteasome inhibitor MG132, while overexpression of at least one BRD8 isoform confers growth advantage and taxol resistance.\",\n      \"method\": \"siRNA knockdown, stable overexpression in HeLa cells, cell viability assays, expression cloning\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with defined phenotypic readout (drug sensitivity), single lab, two complementary approaches\",\n      \"pmids\": [\"19787264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Knockdown of BRD8 activates the p53 transcriptional pathway, upregulating p21 and pro-apoptotic genes, inducing G1/S arrest and apoptosis. BRD8 depletion also triggers the DNA damage response (DDR) under normal growth conditions, activating ATM-CHK2 signaling, reducing CHK1, inducing replication stress (enhanced RPA32 phosphorylation), and reducing H4K16 acetylation, suggesting BRD8 is required for p400/Tip60 complex recruitment/stabilization at chromatin for DNA repair.\",\n      \"method\": \"siRNA knockdown, flow cytometry (cell cycle/apoptosis), Western blot (p21, CHK1/2, RPA32 phosphorylation, H4K16ac), DNA damage foci detection\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical readouts following KD, single lab, mechanistic pathway placement via epistasis\",\n      \"pmids\": [\"30237520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRD8 protein accumulates in colorectal cancer cells through inhibition of ubiquitin-dependent degradation via interaction with MRG domain binding protein. BRD8 transactivates genes independently of TIP60, regulates multiple subunits of the pre-replicative complex in concert with activator protein-1 (AP-1), and its bromodomain is indispensable for interaction with histone H4, transcriptional regulation, and its own protein stability. BRD8 depletion causes G1 cell cycle arrest.\",\n      \"method\": \"Transcriptome analysis, genome-wide BRD8 ChIP-seq, co-immunoprecipitation, bromodomain mutagenesis, siRNA knockdown, cell cycle analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP-seq, transcriptomics, Co-IP, mutagenesis, KD phenotype) in a single mechanistic study\",\n      \"pmids\": [\"37123243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A chemoproteomics approach using a functionalized BRD9 ligand affinity matrix identified BRD8 as a bromodomain-containing subunit of the NuA4 complex; selective and cellularly active first-in-class small molecule probes for BRD8 were developed using homology-model-guided design.\",\n      \"method\": \"Chemoproteomics (affinity matrix pulldown/MS), homology model-guided probe design, cellular activity assays\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical proteomics with MS confirmation of NuA4 complex interaction and validated cellularly active probes, single lab\",\n      \"pmids\": [\"34515462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRD8 knockdown reduces KAT5 (TIP60) protein levels and expression of KAT5-induced genes in HCC cells, placing BRD8 upstream of KAT5 in regulating HCC cell proliferation and apoptosis resistance. miR-876-3p directly targets BRD8 mRNA (confirmed by luciferase reporter assay), negatively regulating BRD8 expression.\",\n      \"method\": \"siRNA knockdown, overexpression, luciferase reporter assay, Western blot, RT-qPCR, cell viability and apoptosis assays\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD/OE with phenotypic readouts and luciferase validation of miRNA targeting, single lab, moderate mechanistic depth\",\n      \"pmids\": [\"32860757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BRD8 occupies genome-wide sites in human lung epithelial cells, co-occupying regions with CTCF. BRD8 depletion increases secretion of beta-defensin 1 and multiple chemokines and reduces cell proliferation, implicating BRD8 in regulation of innate immune response genes and the cell cycle.\",\n      \"method\": \"ChIP-seq (genome-wide BRD8 occupancy), siRNA depletion, gene expression analysis, motif over-representation analysis, cytokine/peptide secretion assays\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with functional KD and multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"33476703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRD8 reads histone acetylation to localize the histone acetyltransferase KAT5 genome-wide; BRD8 maintains open chromatin at somatic genes and histone acetylation at naive-specific genes in primed mouse epiblast stem cells, thereby impeding conversion to naive ESCs. Reduction of Brd8 reduces histone acetylation at naive-specific genes and permits faster acquisition of accessible chromatin at those loci during cell type conversion.\",\n      \"method\": \"ATAC-seq, ChIP-seq (histone acetylation), Brd8 knockdown/depletion, cell type conversion assays (EpiSC to naive ESC), chromatin accessibility analysis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal epigenomic methods (ATAC-seq, ChIP-seq) combined with functional cell fate conversion assay and mechanistic model of BRD8 as KAT5 localizer\",\n      \"pmids\": [\"39656858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"BRD8, as an acetyl-lysine reader in the EP400 complex, mediates ER/HER2 signaling crosstalk in HR+/HER2+ breast cancer. BRD8 expression increases after anti-HER2 treatment; its depletion disrupts ER-HER2 interaction and enhances drug sensitivity. BRD8 regulates chromatin opening (H2AZac deposition via EP400) at ER, FOX, and ETS transcription factor motif-containing regions after anti-HER2 treatment, and is required for neratinib-induced ER activation.\",\n      \"method\": \"Single-cell transcriptomics, single-nucleus ATAC-seq, BRD8 depletion, co-immunoprecipitation (ER-HER2), H2AZac ChIP, drug sensitivity assays, clinical trial validation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (snATAC-seq, scRNA-seq, ChIP, Co-IP, functional KD) in single study with clinical trial validation\",\n      \"pmids\": [\"41886605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BRD8 knockdown suppresses TGF-β1 upregulation, which in turn reduces M2-like tumor-associated macrophage (TAM2) polarization and decreases migration and invasion of colorectal cancer cells, placing BRD8 upstream of TGF-β1 in regulating the tumor immune microenvironment.\",\n      \"method\": \"siRNA knockdown, RT-qPCR, Western blot, flow cytometry (macrophage polarization), transwell migration/invasion assays, IHC/immunofluorescence\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect mechanistic link (BRD8→TGF-β1→TAM2), limited orthogonal validation of direct mechanism\",\n      \"pmids\": [\"40720004\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRD8 is a bromodomain-containing subunit of the NuA4/EP400-TIP60 histone acetyltransferase complex that reads acetylated lysine residues on histones H4 and H2AZ to recruit and stabilize KAT5 (TIP60) at chromatin, thereby regulating H2AZ incorporation, histone acetylation, and chromatin accessibility at target gene loci; through this mechanism BRD8 maintains repressive chromatin at p53 target genes (suppressing p53-mediated tumor suppression), activates PPARγ and pre-replicative complex gene programs, sustains genome stability via the ATM-CHK2 DDR pathway, controls cell cycle progression in a TIP60-independent manner via AP-1, and mediates ER/HER2 signaling crosstalk through EP400-dependent H2AZ acetylation deposition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"BRD8 is a bromodomain-containing acetyl-lysine reader subunit of the NuA4/EP400-TIP60 (KAT5) histone acetyltransferase complex that uses its bromodomain to engage acetylated histone H4 and direct the incorporation of histone variant H2A.Z into chromatin, thereby governing histone acetylation, chromatin accessibility, and target-gene expression [#0, #1, #4, #8]. By localizing and stabilizing KAT5 at chromatin genome-wide, BRD8 controls the acetylation state of specific gene programs: it maintains H2A.Z-dependent repressive chromatin at p53 target loci to suppress p53 transactivation and sustain proliferation, such that bromodomain targeting or depletion displaces H2A.Z, opens chromatin, activates p53 and p21, and enforces G1/S arrest and apoptosis [#0, #3]. BRD8 depletion concomitantly reduces KAT5 protein levels and KAT5-dependent gene expression, lowers H4K16 acetylation, and triggers replication stress and ATM-CHK2 DNA damage signaling, indicating a requirement for BRD8 in p400/TIP60 recruitment supporting genome stability [#3, #6]. BRD8 also drives developmental and lineage programs—promoting PPARγ-dependent adipogenesis through H2A.Z deposition [#1] and maintaining open chromatin at somatic genes to impede the conversion of primed epiblast stem cells to the naive state [#8]—and acts in transcription at additional loci, co-occupying genomic sites with CTCF and regulating innate immune response and cell cycle genes [#7]. Beyond its canonical complex role, BRD8 transactivates pre-replicative complex genes together with AP-1 independently of TIP60, and its own protein stability is bromodomain-dependent and protected from ubiquitin-mediated degradation via interaction with an MRG domain binding protein [#4]. In cancer, BRD8 mediates ER/HER2 signaling crosstalk by directing EP400-dependent H2A.Z acetylation at ER, FOX, and ETS motif regions and is required for neratinib-induced ER activation in HR+/HER2+ breast cancer [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established BRD8 as a functional accessory subunit of the human NuA4-HAT (TRRAP/TIP60) complex with a role in drug resistance, linking it for the first time to a defined chromatin-modifying machinery and a cancer phenotype.\",\n      \"evidence\": \"siRNA knockdown and stable overexpression in HeLa/colorectal cancer lines with viability and spindle-poison sensitivity readouts\",\n      \"pmids\": [\"19787264\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not define the molecular activity of BRD8 within the complex\", \"No direct demonstration of bromodomain function or histone reading\", \"Mechanism of taxol/MG132 sensitization unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed BRD8 within the p400 complex directs histone variant H2A.Z incorporation to activate a defined gene program, establishing its role in chromatin-templated transcriptional activation during differentiation.\",\n      \"evidence\": \"shRNA knockdown and ChIP with adipogenesis/lipid accumulation assays in 3T3-L1 preadipocytes\",\n      \"pmids\": [\"23064015\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not test whether the bromodomain mediates chromatin targeting\", \"Mechanism connecting H2A.Z deposition to PPARγ accumulation not resolved\", \"Restricted to adipogenic context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed BRD8 upstream of both the p53 pathway and the DNA damage response, revealing that loss of BRD8 derepresses p53 and induces replication stress with ATM-CHK2 activation, implicating it in p400/TIP60-dependent genome maintenance.\",\n      \"evidence\": \"siRNA knockdown with flow cytometry, Western blots for p21/CHK1-2/RPA32-P/H4K16ac in cell lines\",\n      \"pmids\": [\"30237520\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Epistatic placement does not establish direct chromatin recruitment mechanism\", \"Whether DDR activation is p53-dependent or parallel unresolved\", \"No genome-wide occupancy data\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated BRD8 acts upstream of KAT5 protein stability and KAT5-target gene expression and is itself controlled by miR-876-3p, defining a regulatory hierarchy and an upstream regulator in hepatocellular carcinoma.\",\n      \"evidence\": \"siRNA/overexpression, luciferase reporter validation of miRNA targeting, Western blot and viability/apoptosis assays in HCC cells\",\n      \"pmids\": [\"32860757\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which BRD8 stabilizes KAT5 protein not defined\", \"No direct chromatin co-occupancy data\", \"Single cancer type\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped genome-wide BRD8 occupancy showing co-localization with CTCF and a functional role in innate immune and cell cycle gene regulation, broadening its transcriptional targets beyond differentiation.\",\n      \"evidence\": \"ChIP-seq, siRNA depletion, motif analysis, and cytokine/peptide secretion assays in human lung epithelial cells\",\n      \"pmids\": [\"33476703\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Functional significance of CTCF co-occupancy not mechanistically dissected\", \"Direct vs indirect regulation of immune genes unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed BRD8 as a bromodomain subunit of NuA4 by chemoproteomics and delivered first-in-class selective small-molecule probes, enabling pharmacological interrogation of its bromodomain.\",\n      \"evidence\": \"Chemoproteomic affinity-matrix pulldown/MS and homology-model-guided probe design with cellular activity assays\",\n      \"pmids\": [\"34515462\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Endogenous acetyl-lysine ligand specificity not defined here\", \"No structural model of bromodomain-histone engagement\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the disease-relevant mechanism: BRD8 maintains H2A.Z at p53 target loci to enforce repressive chromatin in TP53-wild-type GBM, and bromodomain targeting reactivates p53 and arrests proliferation, validating the bromodomain as a therapeutic target.\",\n      \"evidence\": \"ChIP, chromatin accessibility, bromodomain targeting with functional readout, loss-of-function in patient-derived GBM models\",\n      \"pmids\": [\"36544023\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether p53 repression generalizes beyond GBM not established here\", \"Direct acetyl-mark read by the bromodomain at these loci not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed TIP60-independent functions of BRD8: bromodomain-dependent H4 binding required for its own protein stability and transactivation, AP-1-coordinated regulation of pre-replicative complex genes, and stabilization via an MRG domain binding protein against ubiquitin-dependent degradation.\",\n      \"evidence\": \"Transcriptomics, genome-wide BRD8 ChIP-seq, Co-IP, bromodomain mutagenesis, and cell-cycle analysis in colorectal cancer cells\",\n      \"pmids\": [\"37123243\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Identity/mechanism of the deubiquitinating or stabilizing pathway incompletely defined\", \"How AP-1 cooperation is achieved at the molecular level unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established BRD8 as a histone-acetylation reader that localizes KAT5 genome-wide, demonstrating in epiblast stem cells that it sustains open chromatin and acetylation to gate cell-fate transitions.\",\n      \"evidence\": \"ATAC-seq, histone-acetylation ChIP-seq, Brd8 depletion, and EpiSC-to-naive ESC conversion assays\",\n      \"pmids\": [\"39656858\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Precise acetyl-lysine marks read at each locus class not fully enumerated\", \"Generalizability of the KAT5-localizer role across cell types\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended BRD8's reader function to oncogenic signaling crosstalk, showing it directs EP400-dependent H2A.Z acetylation at ER/FOX/ETS regions to couple ER and HER2 signaling and confer drug resistance in HR+/HER2+ breast cancer.\",\n      \"evidence\": \"scRNA-seq, snATAC-seq, BRD8 depletion, ER-HER2 Co-IP, H2AZac ChIP, drug-sensitivity assays with clinical-trial validation\",\n      \"pmids\": [\"41886605\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular basis of the ER-HER2 interaction disruption upon BRD8 loss not fully resolved\", \"Whether the bromodomain is required for this specific function not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BRD8's bromodomain specificity (which acetyl-lysine marks on H4/H2A.Z it reads) and its switch between TIP60/KAT5-dependent and TIP60-independent functions are mechanistically partitioned across contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No structural model of bromodomain-acetyl-histone complex in the timeline\", \"Determinants selecting between KAT5-dependent and AP-1-dependent transcriptional programs unknown\", \"Mechanism coupling chromatin reading to KAT5 protein stabilization undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 7, 8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 1, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"complexes\": [\n      \"NuA4/TIP60 histone acetyltransferase complex\",\n      \"EP400/p400 complex\"\n    ],\n    \"partners\": [\n      \"KAT5\",\n      \"EP400\",\n      \"TRRAP\",\n      \"AP-1\",\n      \"CTCF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}