{"gene":"BRPF1","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2010,"finding":"The PWWP domain of BRPF1 directly binds H3K36me3; the crystal structure of the PWWP domain in complex with an H3K36me3-derived peptide was determined, establishing this domain as a trimethyl-lysine reader.","method":"X-ray crystallography (structure of PWWP–H3K36me3 peptide complex)","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation of binding; replicated across subsequent inhibitor and reader studies","pmids":["20400950"],"is_preprint":false},{"year":2013,"finding":"The BRPF1 bromodomain preferentially recognizes acetylated lysines H2AK5ac, H4K12ac, and H3K14ac on histone N-terminal tails; key residues coordinating acetyllysine were mapped by NMR chemical shift perturbation and molecular dynamics simulations.","method":"NMR titration/chemical shift perturbation, molecular dynamics simulations, bromodomain ligand-binding assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — NMR mapping plus MD simulations with mutational follow-up, single lab but multiple orthogonal methods","pmids":["24333487"],"is_preprint":false},{"year":2014,"finding":"X-ray crystal structures of the BRPF1 bromodomain in complex with H2AK5ac and H4K12ac histone peptides were solved; site-directed mutagenesis of binding-pocket residues confirmed their roles in ligand coordination, and ordered water molecules were identified as essential components of ligand recognition.","method":"X-ray crystallography, site-directed mutagenesis, binding assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures plus mutagenesis in a single study with multiple ligand complexes","pmids":["25281266"],"is_preprint":false},{"year":2015,"finding":"The PZP domain (PHD-zinc-knuckle-PHD) of BRPF1 forms a 2:1 stoichiometry complex with the nucleosome, bivalently contacting histone H3 and DNA. This interaction shifts the DNA unwrapping/rewrapping equilibrium toward the unwrapped state and is required for MOZ-BRPF1-ING5-hEaf6 HAT complex recruitment to chromatin and acetylation of nucleosomal histones.","method":"Biochemical reconstitution, FRET-based nucleosome dynamics assay, HAT activity assays on nucleosomal substrates, structural characterization","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution of complex, functional HAT assays, FRET dynamics assay, multiple orthogonal methods","pmids":["26626149"],"is_preprint":false},{"year":2015,"finding":"Forebrain-specific deletion of mouse Brpf1 causes early postnatal lethality, neocortical abnormalities, and partial callosal agenesis; the mutant forebrain has fewer Tbr2+ intermediate neuronal progenitors and altered expression of Robo3, Otx1, and multiple Hox genes, indicating Brpf1 acts as both an activator and silencer of gene expression in vivo.","method":"Conditional Brpf1 knockout (Cre-lox), immunohistochemistry, transcriptome analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with defined cellular and molecular phenotypes, replicated across multiple Brpf1 conditional KO studies","pmids":["25568313"],"is_preprint":false},{"year":2015,"finding":"Forebrain-specific Brpf1 deletion causes dentate gyrus hypoplasia traceable to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors, with deregulated neuronal migration, cell cycle progression, and transcriptional control.","method":"Conditional Brpf1 knockout (Cre-lox), immunohistochemistry, BrdU cell cycle analysis, gene expression profiling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with multiple cellular and molecular readouts, consistent with parallel KO studies","pmids":["25757017"],"is_preprint":false},{"year":2015,"finding":"Whole-body Brpf1 deletion in mouse causes embryonic lethality at ~E9.5 with vascular defects in placenta and yolk sac, abnormal neural tube closure, and inhibition of embryonic fibroblast and hematopoietic progenitor proliferation; molecular analysis showed reduced Rpl10-like gene and p27, and increased p16 and a Scp3-homolog.","method":"Constitutive Brpf1 knockout, embryo phenotyping, cell proliferation assays, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — germline KO with systematic embryonic phenotyping and molecular characterization","pmids":["25773539"],"is_preprint":false},{"year":2016,"finding":"Hematopoietic-specific Brpf1 deletion in mice causes acute bone marrow failure, aplastic anemia, and early lethality; mutant bone marrow and fetal liver show severe HSC and progenitor deficiency with elevated reactive oxygen species, senescence, and apoptosis. BRPF1 is required for H3K23 acetylation in HSCs and for expression of multipotency genes (Slamf1, Mecom, Hoxa9, Hlf, Gfi1, Egr, Gata3).","method":"Conditional Brpf1 knockout in hematopoietic cells, flow cytometry, H3K23ac immunoblotting, ROS and apoptosis assays, gene expression profiling","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with multiple orthogonal readouts including epigenetic mark quantification","pmids":["27500495"],"is_preprint":false},{"year":2016,"finding":"De novo or inherited monoallelic BRPF1 mutations in humans impair H3K23 acetylation (measured in patient-derived cells and Brpf1-KO mouse lines), causing an intellectual disability syndrome. BRPF1 variants abolish or reduce acetyltransferase co-activation and some show aberrant subcellular localization.","method":"Patient variant functional assays, H3K23ac immunoblotting in patient fibroblasts and Brpf1-KO mice, localization studies","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent patient-derived cell lines plus mouse model, orthogonal methods, replicated in companion paper PMID:27939639","pmids":["27939640","27939639"],"is_preprint":false},{"year":2019,"finding":"Crystal structure of the BRPF1 PZP domain bound to the H3 tail revealed that binding to extranucleosomal DNA dominates over H3-tail binding; both interactions are required for tight nucleosome core particle binding and for acetyltransferase function of the BRPF1-MORF-ING5-MEAF6 complex.","method":"X-ray crystallography of PZP–H3 complex, ITC binding assays, HAT activity assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with ITC quantification and functional HAT assay, single lab","pmids":["31711755"],"is_preprint":false},{"year":2020,"finding":"BRPF1-KAT6A and BRPF1-KAT6B complexes catalyze H3K23 propionylation (in addition to acetylation) in vitro and in vivo; Brpf1 deletion obliterates both acylations in mouse embryos and fibroblasts. Pathogenic BRPF1 variants identified in 12 additional intellectual disability cases impair H3K23 propionylation.","method":"In vitro propionylation assays, mass spectrometry, immunofluorescence/ATAC-See in mouse embryos and fibroblasts, patient variant functional assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay plus in vivo KO validation plus patient variants, multiple orthogonal methods","pmids":["32010779"],"is_preprint":false},{"year":2020,"finding":"The BRPF1 bromodomain acts as a selective reader of di-acetylated histone H4, preferentially binding H4K5acK8ac and H4K12acK8ac/K5ac; non-canonical regions of the bromodomain binding pocket (identified by NMR CSP and mutagenesis) mediate recognition of the second acetyl mark.","method":"ITC binding assays, NMR chemical shift perturbation, analytical ultracentrifugation, site-directed mutagenesis","journal":"Current research in structural biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ITC, NMR, AUC and mutagenesis in one study, single lab","pmids":["33554132"],"is_preprint":false},{"year":2009,"finding":"In medaka fish, loss-of-function mutation in brpf1 (a MOZ HAT complex subunit) decreases Hox gene expression in pharyngeal arches and Zic gene expression posteriorly, causing craniofacial cartilage homeosis and caudal skeleton patterning defects; parallel MOZ-deficient mice display homologous craniofacial and cervical skeletal abnormalities with reduced Hox transcripts.","method":"Medaka forward genetics (biaxial symmetries mutant), in situ hybridization, mouse MOZ knockout","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function in two vertebrate species with molecular (gene expression) readouts","pmids":["19254709"],"is_preprint":false},{"year":1994,"finding":"BR140 (BRPF1) was identified as a nuclear protein with zinc finger domains and homology to TAF250 (a TFIID subunit); it co-purified with an integrin and is broadly expressed, with highest abundance in testis and spermatogonia.","method":"cDNA cloning, sequence analysis, immunolocalization (subcellular fractionation/IHC), tissue Western blotting","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — initial identification by co-purification and immunolocalization; no enzymatic or binding mechanism established","pmids":["7906940"],"is_preprint":false},{"year":2015,"finding":"Structure-guided development of IACS-9571 yielded a dual TRIM24/BRPF1 bromodomain inhibitor (ITC Kd = 14 nM for BRPF1) whose binding mode was established by iterative X-ray co-crystal structures, enabling pharmacological interrogation of BRPF1 bromodomain function.","method":"X-ray co-crystallography (multiple structures), ITC, cellular target engagement assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple co-crystal structures with quantitative ITC, structure-activity relationship validated","pmids":["26061247"],"is_preprint":false},{"year":2016,"finding":"Twenty X-ray co-crystal structures of the BRPF1 bromodomain with diverse ligands revealed structural conservation of the acetyllysine-binding site, common binding motifs, and rare interactions including displacement of a conserved water molecule.","method":"High-throughput docking followed by X-ray crystallography of 20 BRPF1/ligand complexes","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — 20 independent crystal structures providing comprehensive binding-mode characterization","pmids":["27167503"],"is_preprint":false},{"year":2019,"finding":"Brpf1 haploinsufficiency in mouse (Emx1-Cre heterozygotes) reduces dendritic complexity, spine density, and spine/synapse morphology in hippocampal granule cells and cortical pyramidal neurons, and decreases frequency and amplitude of miniature EPSCs, leading to impaired learning and memory.","method":"Conditional Brpf1 heterozygous mouse, morphological analysis, whole-cell patch clamp, behavioral assays","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with electrophysiology, morphology, and behavioral readouts in single study","pmids":["31213987"],"is_preprint":false},{"year":2020,"finding":"Isoform-specific functions of Brpf1 in hematopoietic stem and progenitor cells: Brpf1b promotes HSPC expansion while Brpf1a promotes quiescence; inhibition of Brpf1a by OF-1 increases histone acetylation and chromatin accessibility, upregulating self-renewal gene Mn1, and the expansion phenotype is rescued by Mn1 suppression.","method":"Bromodomain inhibitor chemical screen, isoform-specific overexpression/knockdown in HSPCs, chromatin accessibility (ATAC-seq), gene expression analysis, epistasis (Mn1 rescue)","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic isoform analysis with epistasis, single lab","pmids":["31565729"],"is_preprint":false},{"year":2021,"finding":"Brpf1 knockdown in hippocampal neurons reduces miniature EPSC frequency before changes in dendritic morphology appear; in vivo hippocampal Brpf1 knockdown impairs spatial learning; dysregulated genes include synaptic transmission regulators C1ql1, Grin2a, and others.","method":"shRNA knockdown in primary hippocampal neurons, whole-cell patch clamp (mEPSC recording), Morris water maze, RNA-seq","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology + behavioral assay + transcriptomics, single lab","pmids":["34485298"],"is_preprint":false},{"year":2021,"finding":"Brpf1 knockdown in MGE-derived GABAergic interneurons increases firing threshold, decreases evoked action potential number, and reduces miniature IPSC amplitude, demonstrating a key role of Brpf1 in inhibitory neurotransmission; differentiation into parvalbumin+ interneurons was not significantly changed.","method":"AAV-shBrpf1 knockdown, whole-cell patch clamp, immunofluorescence, MGE transplantation assay, RNA-seq","journal":"G3 (Bethesda)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology with transplantation and transcriptomics, single lab","pmids":["33744924"],"is_preprint":false},{"year":2021,"finding":"BRPF1 activates E2F2 and EZH2 expression by facilitating H3K14 acetylation at their promoters via the MOZ/MORF complex in hepatocellular carcinoma cells; BRPF1 ablation or pharmacological inhibition attenuates HCC cell growth in vitro and in vivo.","method":"BRPF1 gene ablation, pharmacological inhibition, ChIP-seq for H3K14ac, transcriptome sequencing, xenograft tumor models","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq linking BRPF1 to promoter H3K14ac, supported by KO and inhibitor experiments, single lab","pmids":["34285329"],"is_preprint":false},{"year":2022,"finding":"USP35 directly deubiquitinates and stabilizes BRPF1 protein; USP35-dependent BRPF1 accumulation enables BRPF1 to bind the SREBP2 promoter and activate SREBP2 transcription, thereby promoting mevalonate metabolism in prostate cancer cells.","method":"Co-IP/pulldown (USP35–BRPF1 interaction), ubiquitination assays, ChIP-qPCR (BRPF1 at SREBP2 promoter), rescue experiments","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — deubiquitination assay plus ChIP and rescue, single lab","pmids":["36357379"],"is_preprint":false},{"year":2023,"finding":"BRPF1 associates with ERα on chromatin in breast cancer cells; BRPF1 blockade inhibits cell cycle progression, reduces chromatin accessibility, and silences ERα gene expression in antiestrogen-sensitive and -resistant cells, placing BRPF1 as an upstream regulator of estrogen signaling.","method":"ChIP-seq (BRPF1–ERα co-occupancy), ATAC-seq, transcriptome profiling, siRNA knockdown, pharmacological inhibition, patient-derived organoids","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq co-occupancy plus chromatin accessibility and transcriptomics, single lab","pmids":["39113071"],"is_preprint":false},{"year":2023,"finding":"Using site-specific photo-crosslinking with azide-acetyllysine in the BRPF1 bromodomain, the non-histone interactome of BRPF1 was mapped; interleukin enhancer-binding factor 3 (ILF3) was validated as a novel BRPF1 bromodomain interacting partner by ITC and co-IP.","method":"Unnatural amino acid photo-crosslinking, proteomics, ITC, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — novel crosslinking proteomics with ITC and co-IP validation for one partner, single lab","pmids":["38072045"],"is_preprint":false},{"year":2023,"finding":"BRPF1 bridges H3K4me3 and H3K23ac marks in human embryonic stem cells; BRPF1 deletion impairs H3K23ac and closes chromatin on stemness genes leading to hESC differentiation. Deletion of the N-terminal or PZP module abolishes BRPF1 function while PWWP deletion only partially impairs it.","method":"BRPF1 KO in hESCs, CUT&RUN/ChIP for H3K4me3 and H3K23ac, ATAC-seq, domain-deletion mutant functional rescue assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion epistasis plus epigenome profiling in hESCs, single lab","pmids":["36711238"],"is_preprint":false},{"year":2024,"finding":"CaMKIIa-Cre-driven Brpf1 knockout in forebrain excitatory neurons reduces miniature EPSC frequency and downregulates genes related to synapse function (Pcdhgb1, Slc16a7, Robo3, Rho), impairing spatial and fear memory.","method":"Conditional Brpf1 KO (CaMKIIa-Cre), whole-cell patch clamp, RNA-seq, behavioral assays (fear conditioning, Morris water maze)","journal":"Neural regeneration research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neuron-type-specific KO with electrophysiology and transcriptomics, single lab","pmids":["37862219"],"is_preprint":false},{"year":2025,"finding":"BRPF1 directly binds the ABCB1 promoter (CUT&RUN-qPCR) and enhances ABCB1 expression to confer multidrug resistance in Taxol-resistant TNBC; BRPF1 KO or inhibition reduces ABCB1 expression and suppresses ribosome biogenesis gene sets, sensitizing resistant cells to Taxol.","method":"CRISPR KO, pharmacological inhibition (PFI-4, OF-1), CUT&RUN-qPCR, RNA-seq, cell viability assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromatin occupancy at ABCB1 promoter plus genetic and pharmacological KO with transcriptomics, single lab","pmids":["40583060"],"is_preprint":false},{"year":2019,"finding":"Truncated BRPF1, as found in human adult medulloblastoma patients with inactivating mutations, cooperates with SmoM2 activation to induce medulloblastoma in adult mice by promoting postmitotic neuron re-entry into the cell cycle via chromatin remodeling.","method":"In vivo mouse model (truncated BRPF1 + SmoM2 transgenic), cell cycle analysis, histology","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with cell cycle readout, single lab, consistent with human mutation data","pmids":["31851932"],"is_preprint":false},{"year":2024,"finding":"BRPF1 (as part of the MOZ/HBO1 complex) associates with NUP98 fusion oncoproteins on chromatin and within nuclear condensates; MYST HATs are molecular dependencies in NUP98-rearranged AML, and their inhibition decreases global H3K23ac, displaces NUP98::HOXA9 from chromatin at the Meis1 locus, and induces myeloid differentiation.","method":"Co-IP/proximity ligation assays (BRPF1–NUP98 FO association), ChIP-seq (H3K23ac, NUP98 occupancy), genetic inactivation, pharmacological inhibition, xenograft mouse models","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.12.02.624182"],"is_preprint":true},{"year":2025,"finding":"FBRSL1 binds upstream of the BRPF1 locus (via association with transcription factor YY1) and positively regulates BRPF1 expression; truncating FBRSL1 variants cause BRPF1 downregulation in patient blood and fibroblasts, and loss of Fbrsl1 in Xenopus disrupts brpf1 expression pattern.","method":"ChIP-seq (FBRSL1–YY1 at BRPF1 promoter), qRT-PCR in patient cells, Xenopus loss-of-function","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus patient cells plus Xenopus model, single lab","pmids":["40658195"],"is_preprint":false}],"current_model":"BRPF1 is a multivalent chromatin scaffold protein that assembles stoichiometric HAT complexes with KAT6A (MOZ), KAT6B (MORF), and KAT7 (HBO1), stimulating their enzymatic activity toward H3K23 acetylation and propionylation; it recruits these complexes to chromatin through its PWWP domain (which reads H3K36me3), its PZP domain (which bivalently contacts histone H3 and extranucleosomal DNA to promote nucleosome unwrapping), and its bromodomain (which selectively binds mono- and di-acetylated lysines including H2AK5ac, H4K12ac, H3K14ac, and H4K5acK8ac); the resulting H3K23ac mark is required for normal brain, hematopoietic, and embryonic development in mice, and its deficiency—caused by monoallelic pathogenic BRPF1 variants—underlies a syndromic intellectual disability disorder in humans."},"narrative":{"mechanistic_narrative":"BRPF1 is a multivalent chromatin scaffold that assembles and activates MYST-family histone acetyltransferase complexes — together with MOZ (KAT6A), MORF (KAT6B), and HBO1 (KAT7) plus ING5 and MEAF6 — to deposit acetylation and propionylation at histone H3K23 and to read and bridge other histone marks during development [PMID:26626149, PMID:27500495, PMID:32010779]. It engages chromatin through three reader modules: a PWWP domain that binds H3K36me3 [PMID:20400950], a PZP (PHD–zinc-knuckle–PHD) domain that bivalently contacts the H3 tail and extranucleosomal DNA — with DNA binding dominating — to drive nucleosome unwrapping and enable HAT complex recruitment and nucleosomal acetylation [PMID:26626149, PMID:31711755], and a bromodomain that selectively recognizes acetyllysines including H2AK5ac, H4K12ac, and H3K14ac and reads di-acetylated H4 marks such as H4K5acK8ac [PMID:24333487, PMID:25281266, PMID:33554132]. Through this scaffold activity BRPF1 functions both as a transcriptional activator and silencer, and in human embryonic stem cells it bridges H3K4me3 and H3K23ac to keep stemness gene chromatin open, with its N-terminal and PZP modules being essential and the PWWP domain only partially required [PMID:36711238]. In vivo, Brpf1 is required for H3K23 acetylation/propionylation and for normal forebrain neurogenesis, neuronal migration, dendritic and synaptic development, hematopoietic stem cell maintenance, and embryonic vascular and neural-tube development, where its loss deregulates Hox and multipotency gene programs [PMID:25757017, PMID:25773539, PMID:27500495, PMID:32010779, PMID:31213987]. Monoallelic pathogenic BRPF1 variants impair H3K23 acetylation and propionylation and cause a syndromic intellectual disability disorder in humans [PMID:27939640, PMID:27939639, PMID:32010779]. BRPF1 is also co-opted in cancer, where it directs MOZ/MORF-mediated H3K14 acetylation and chromatin opening at oncogenic loci and partners with ERα and NUP98-fusion oncoproteins to sustain tumor cell programs [PMID:34285329, PMID:39113071, PMID:bio_10.1101_2024.12.02.624182].","teleology":[{"year":1994,"claim":"Established BRPF1 (BR140) as a nuclear zinc-finger protein with homology to the TFIID subunit TAF250, providing the first hint of a transcription-associated chromatin role.","evidence":"cDNA cloning, sequence analysis, and immunolocalization of the BR140 protein","pmids":["7906940"],"confidence":"Medium","gaps":["No enzymatic or binding mechanism established","Functional role in transcription not demonstrated"]},{"year":2009,"claim":"Genetic loss-of-function in two vertebrates placed BRPF1 within the MOZ HAT complex controlling Hox/Zic patterning, connecting the protein to developmental gene regulation.","evidence":"Medaka forward-genetic brpf1 mutant and parallel mouse MOZ knockout with in situ hybridization","pmids":["19254709"],"confidence":"High","gaps":["Molecular mechanism of complex assembly not resolved","Direct chromatin targets not mapped"]},{"year":2010,"claim":"Answered how BRPF1 reads methylated chromatin by defining the PWWP domain as an H3K36me3 reader at atomic resolution.","evidence":"X-ray crystal structure of the PWWP–H3K36me3 peptide complex with binding validation","pmids":["20400950"],"confidence":"High","gaps":["Contribution of PWWP reading to complex recruitment in vivo not quantified","Other reader modules unaddressed"]},{"year":2013,"claim":"Defined the BRPF1 bromodomain as a histone acetyllysine reader and mapped the acetyllysine-coordinating residues, identifying a second chromatin-engagement module.","evidence":"NMR chemical shift perturbation, molecular dynamics, and bromodomain ligand-binding assays","pmids":["24333487"],"confidence":"High","gaps":["In vivo relevance of each acetyl mark not established","Bromodomain contribution to HAT recruitment not tested"]},{"year":2014,"claim":"Provided atomic-resolution structures of the bromodomain bound to H2AK5ac and H4K12ac, establishing the molecular basis of acetyllysine recognition including ordered waters.","evidence":"X-ray crystallography of bromodomain–peptide complexes with binding-pocket mutagenesis","pmids":["25281266"],"confidence":"High","gaps":["Multivalent or di-acetyl recognition not yet characterized","Functional output of binding not measured"]},{"year":2015,"claim":"Resolved how BRPF1 engages whole nucleosomes by showing the PZP domain bivalently contacts H3 and DNA to promote nucleosome unwrapping and enable HAT complex recruitment and nucleosomal acetylation.","evidence":"Biochemical reconstitution, FRET nucleosome dynamics, and HAT activity assays on the MOZ-BRPF1-ING5-hEaf6 complex","pmids":["26626149"],"confidence":"High","gaps":["Relative contributions of H3-tail vs DNA binding not yet dissected","Structural detail of PZP–H3 contact pending"]},{"year":2015,"claim":"Demonstrated that BRPF1 is required in vivo for forebrain neurogenesis, embryonic viability, and progenitor proliferation, acting as both activator and silencer of developmental genes.","evidence":"Conditional and constitutive Brpf1 mouse knockouts with histology, BrdU cell-cycle analysis, and transcriptome profiling","pmids":["25568313","25757017","25773539"],"confidence":"High","gaps":["Direct chromatin targets versus indirect effects not distinguished","Mechanistic link from HAT activity to specific gene programs incomplete"]},{"year":2016,"claim":"Linked BRPF1 to a specific epigenetic mark and stem-cell function by showing it is required for H3K23ac and multipotency gene expression in hematopoietic stem cells.","evidence":"Hematopoietic-specific Brpf1 knockout with flow cytometry, H3K23ac immunoblotting, ROS/apoptosis assays, and expression profiling","pmids":["27500495"],"confidence":"High","gaps":["Whether H3K23ac loss is causal for each phenotype not isolated","Direct genomic sites of H3K23ac deposition not mapped"]},{"year":2016,"claim":"Established BRPF1 as a human disease gene by showing monoallelic variants impair its acetyltransferase co-activation and H3K23ac, causing an intellectual disability syndrome.","evidence":"Patient variant functional assays, H3K23ac immunoblotting in patient fibroblasts and Brpf1-KO mice, and localization studies","pmids":["27939640","27939639"],"confidence":"High","gaps":["Genotype–phenotype correlations across variants not fully resolved","Tissue-specific consequences of haploinsufficiency incompletely defined"]},{"year":2019,"claim":"Refined the nucleosome-engagement mechanism by showing extranucleosomal DNA binding dominates over H3-tail binding in the PZP domain and that both are required for tight nucleosome binding and HAT function.","evidence":"X-ray crystallography of the PZP–H3 complex, ITC, and HAT activity assays on the BRPF1-MORF-ING5-MEAF6 complex","pmids":["31711755"],"confidence":"High","gaps":["In vivo importance of DNA versus H3 binding not tested","Coordination with PWWP and bromodomain on the same nucleosome unresolved"]},{"year":2019,"claim":"Connected Brpf1 dosage to neuronal circuit function by showing haploinsufficiency reduces dendritic complexity, spine density, and excitatory transmission, impairing learning and memory.","evidence":"Conditional Brpf1 heterozygous mice with morphology, patch-clamp electrophysiology, and behavioral assays","pmids":["31213987"],"confidence":"High","gaps":["Molecular targets driving synaptic deficits not defined","Cell-autonomous versus circuit-level contributions unclear"]},{"year":2020,"claim":"Expanded the catalytic output of BRPF1 complexes by showing they deposit H3K23 propionylation as well as acetylation, both abolished by Brpf1 loss and impaired by patient variants.","evidence":"In vitro acylation assays, mass spectrometry, ATAC-See in mouse embryos/fibroblasts, and patient variant assays","pmids":["32010779"],"confidence":"High","gaps":["Functional distinction between acetylation and propionylation not resolved","Genomic distribution of H3K23pr not mapped"]},{"year":2020,"claim":"Extended bromodomain reading specificity to di-acetylated H4 and identified the non-canonical pocket regions mediating recognition of the second acetyl mark.","evidence":"ITC, NMR chemical shift perturbation, analytical ultracentrifugation, and mutagenesis","pmids":["33554132"],"confidence":"High","gaps":["In vivo role of di-acetyl reading not tested","Integration with other reader modules unaddressed"]},{"year":2020,"claim":"Revealed isoform-specific BRPF1 functions in hematopoietic progenitors, with one isoform promoting expansion and another quiescence via chromatin accessibility and the Mn1 self-renewal gene.","evidence":"Bromodomain inhibitor screen, isoform-specific overexpression/knockdown, ATAC-seq, and Mn1 epistasis in HSPCs","pmids":["31565729"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Molecular basis of isoform divergence unclear"]},{"year":2023,"claim":"Defined BRPF1 as a chromatin bridge in human pluripotency by showing it links H3K4me3 and H3K23ac to keep stemness gene chromatin open, with N-terminal/PZP modules essential and PWWP partially dispensable.","evidence":"BRPF1 KO in hESCs with CUT&RUN/ChIP, ATAC-seq, and domain-deletion rescue assays","pmids":["36711238"],"confidence":"Medium","gaps":["Single-lab study","Mechanism by which marks are physically bridged not structurally resolved"]},{"year":2023,"claim":"Mapped a non-histone bromodomain interactome and validated ILF3 as a partner, expanding BRPF1 function beyond histone reading.","evidence":"Unnatural amino acid photo-crosslinking proteomics with ITC and co-IP validation","pmids":["38072045"],"confidence":"Medium","gaps":["Functional consequence of ILF3 binding not established","Single Co-IP/ITC validation for one partner"]},{"year":2025,"claim":"Identified an upstream regulator of BRPF1 expression, showing FBRSL1 with YY1 controls BRPF1 transcription and that FBRSL1 truncations downregulate BRPF1 in patients.","evidence":"ChIP-seq of FBRSL1–YY1 at the BRPF1 promoter, qRT-PCR in patient cells, and Xenopus loss-of-function","pmids":["40658195"],"confidence":"Medium","gaps":["Single-lab study","Direct versus indirect regulation of BRPF1 not fully separated"]},{"year":2025,"claim":"Documented oncogenic and drug-resistance roles for BRPF1 across cancers, where it directs HAT-mediated chromatin opening at oncogenic and resistance loci and partners with ERα and NUP98 fusions.","evidence":"ChIP-seq/CUT&RUN occupancy, ATAC-seq, genetic and pharmacological inhibition, and xenograft/organoid models across HCC, breast, prostate, AML, and TNBC","pmids":["34285329","39113071","36357379","40583060","31851932"],"confidence":"Medium","gaps":["Mostly single-lab studies per tumor type","Direct versus complex-mediated chromatin targeting not always distinguished"]},{"year":null,"claim":"How the three reader modules (PWWP, PZP, bromodomain) are coordinated on a single nucleosome to integrate H3K36me3, DNA, and acetyl marks into productive HAT recruitment, and how this generates locus-specific gene activation versus silencing, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No integrated structural model of full-length BRPF1 on a nucleosome","Genome-wide map of H3K23ac/H3K23pr deposition incomplete","Rules distinguishing activator from silencer function unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,2,3,9,11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3,9,20,21,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator 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Acute Myeloid Leukemia","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.02.624182","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.21.639596","title":"Context-Dependent and Gene-Specific Role of Chromatin Architecture Mediated by Histone Modifiers and Loop-extrusion Machinery","date":"2025-02-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.21.639596","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30312,"output_tokens":7103,"usd":0.09874,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16177,"output_tokens":5660,"usd":0.111192,"stage2_stop_reason":"end_turn"},"total_usd":0.209932,"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\": 2010,\n      \"finding\": \"The PWWP domain of BRPF1 directly binds H3K36me3; the crystal structure of the PWWP domain in complex with an H3K36me3-derived peptide was determined, establishing this domain as a trimethyl-lysine reader.\",\n      \"method\": \"X-ray crystallography (structure of PWWP–H3K36me3 peptide complex)\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation of binding; replicated across subsequent inhibitor and reader studies\",\n      \"pmids\": [\"20400950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The BRPF1 bromodomain preferentially recognizes acetylated lysines H2AK5ac, H4K12ac, and H3K14ac on histone N-terminal tails; key residues coordinating acetyllysine were mapped by NMR chemical shift perturbation and molecular dynamics simulations.\",\n      \"method\": \"NMR titration/chemical shift perturbation, molecular dynamics simulations, bromodomain ligand-binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — NMR mapping plus MD simulations with mutational follow-up, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24333487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"X-ray crystal structures of the BRPF1 bromodomain in complex with H2AK5ac and H4K12ac histone peptides were solved; site-directed mutagenesis of binding-pocket residues confirmed their roles in ligand coordination, and ordered water molecules were identified as essential components of ligand recognition.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, binding assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures plus mutagenesis in a single study with multiple ligand complexes\",\n      \"pmids\": [\"25281266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The PZP domain (PHD-zinc-knuckle-PHD) of BRPF1 forms a 2:1 stoichiometry complex with the nucleosome, bivalently contacting histone H3 and DNA. This interaction shifts the DNA unwrapping/rewrapping equilibrium toward the unwrapped state and is required for MOZ-BRPF1-ING5-hEaf6 HAT complex recruitment to chromatin and acetylation of nucleosomal histones.\",\n      \"method\": \"Biochemical reconstitution, FRET-based nucleosome dynamics assay, HAT activity assays on nucleosomal substrates, structural characterization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution of complex, functional HAT assays, FRET dynamics assay, multiple orthogonal methods\",\n      \"pmids\": [\"26626149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Forebrain-specific deletion of mouse Brpf1 causes early postnatal lethality, neocortical abnormalities, and partial callosal agenesis; the mutant forebrain has fewer Tbr2+ intermediate neuronal progenitors and altered expression of Robo3, Otx1, and multiple Hox genes, indicating Brpf1 acts as both an activator and silencer of gene expression in vivo.\",\n      \"method\": \"Conditional Brpf1 knockout (Cre-lox), immunohistochemistry, transcriptome analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with defined cellular and molecular phenotypes, replicated across multiple Brpf1 conditional KO studies\",\n      \"pmids\": [\"25568313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Forebrain-specific Brpf1 deletion causes dentate gyrus hypoplasia traceable to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors, with deregulated neuronal migration, cell cycle progression, and transcriptional control.\",\n      \"method\": \"Conditional Brpf1 knockout (Cre-lox), immunohistochemistry, BrdU cell cycle analysis, gene expression profiling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with multiple cellular and molecular readouts, consistent with parallel KO studies\",\n      \"pmids\": [\"25757017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Whole-body Brpf1 deletion in mouse causes embryonic lethality at ~E9.5 with vascular defects in placenta and yolk sac, abnormal neural tube closure, and inhibition of embryonic fibroblast and hematopoietic progenitor proliferation; molecular analysis showed reduced Rpl10-like gene and p27, and increased p16 and a Scp3-homolog.\",\n      \"method\": \"Constitutive Brpf1 knockout, embryo phenotyping, cell proliferation assays, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — germline KO with systematic embryonic phenotyping and molecular characterization\",\n      \"pmids\": [\"25773539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hematopoietic-specific Brpf1 deletion in mice causes acute bone marrow failure, aplastic anemia, and early lethality; mutant bone marrow and fetal liver show severe HSC and progenitor deficiency with elevated reactive oxygen species, senescence, and apoptosis. BRPF1 is required for H3K23 acetylation in HSCs and for expression of multipotency genes (Slamf1, Mecom, Hoxa9, Hlf, Gfi1, Egr, Gata3).\",\n      \"method\": \"Conditional Brpf1 knockout in hematopoietic cells, flow cytometry, H3K23ac immunoblotting, ROS and apoptosis assays, gene expression profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with multiple orthogonal readouts including epigenetic mark quantification\",\n      \"pmids\": [\"27500495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"De novo or inherited monoallelic BRPF1 mutations in humans impair H3K23 acetylation (measured in patient-derived cells and Brpf1-KO mouse lines), causing an intellectual disability syndrome. BRPF1 variants abolish or reduce acetyltransferase co-activation and some show aberrant subcellular localization.\",\n      \"method\": \"Patient variant functional assays, H3K23ac immunoblotting in patient fibroblasts and Brpf1-KO mice, localization studies\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent patient-derived cell lines plus mouse model, orthogonal methods, replicated in companion paper PMID:27939639\",\n      \"pmids\": [\"27939640\", \"27939639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structure of the BRPF1 PZP domain bound to the H3 tail revealed that binding to extranucleosomal DNA dominates over H3-tail binding; both interactions are required for tight nucleosome core particle binding and for acetyltransferase function of the BRPF1-MORF-ING5-MEAF6 complex.\",\n      \"method\": \"X-ray crystallography of PZP–H3 complex, ITC binding assays, HAT activity assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with ITC quantification and functional HAT assay, single lab\",\n      \"pmids\": [\"31711755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRPF1-KAT6A and BRPF1-KAT6B complexes catalyze H3K23 propionylation (in addition to acetylation) in vitro and in vivo; Brpf1 deletion obliterates both acylations in mouse embryos and fibroblasts. Pathogenic BRPF1 variants identified in 12 additional intellectual disability cases impair H3K23 propionylation.\",\n      \"method\": \"In vitro propionylation assays, mass spectrometry, immunofluorescence/ATAC-See in mouse embryos and fibroblasts, patient variant functional assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay plus in vivo KO validation plus patient variants, multiple orthogonal methods\",\n      \"pmids\": [\"32010779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The BRPF1 bromodomain acts as a selective reader of di-acetylated histone H4, preferentially binding H4K5acK8ac and H4K12acK8ac/K5ac; non-canonical regions of the bromodomain binding pocket (identified by NMR CSP and mutagenesis) mediate recognition of the second acetyl mark.\",\n      \"method\": \"ITC binding assays, NMR chemical shift perturbation, analytical ultracentrifugation, site-directed mutagenesis\",\n      \"journal\": \"Current research in structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ITC, NMR, AUC and mutagenesis in one study, single lab\",\n      \"pmids\": [\"33554132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In medaka fish, loss-of-function mutation in brpf1 (a MOZ HAT complex subunit) decreases Hox gene expression in pharyngeal arches and Zic gene expression posteriorly, causing craniofacial cartilage homeosis and caudal skeleton patterning defects; parallel MOZ-deficient mice display homologous craniofacial and cervical skeletal abnormalities with reduced Hox transcripts.\",\n      \"method\": \"Medaka forward genetics (biaxial symmetries mutant), in situ hybridization, mouse MOZ knockout\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function in two vertebrate species with molecular (gene expression) readouts\",\n      \"pmids\": [\"19254709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"BR140 (BRPF1) was identified as a nuclear protein with zinc finger domains and homology to TAF250 (a TFIID subunit); it co-purified with an integrin and is broadly expressed, with highest abundance in testis and spermatogonia.\",\n      \"method\": \"cDNA cloning, sequence analysis, immunolocalization (subcellular fractionation/IHC), tissue Western blotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — initial identification by co-purification and immunolocalization; no enzymatic or binding mechanism established\",\n      \"pmids\": [\"7906940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Structure-guided development of IACS-9571 yielded a dual TRIM24/BRPF1 bromodomain inhibitor (ITC Kd = 14 nM for BRPF1) whose binding mode was established by iterative X-ray co-crystal structures, enabling pharmacological interrogation of BRPF1 bromodomain function.\",\n      \"method\": \"X-ray co-crystallography (multiple structures), ITC, cellular target engagement assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple co-crystal structures with quantitative ITC, structure-activity relationship validated\",\n      \"pmids\": [\"26061247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Twenty X-ray co-crystal structures of the BRPF1 bromodomain with diverse ligands revealed structural conservation of the acetyllysine-binding site, common binding motifs, and rare interactions including displacement of a conserved water molecule.\",\n      \"method\": \"High-throughput docking followed by X-ray crystallography of 20 BRPF1/ligand complexes\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — 20 independent crystal structures providing comprehensive binding-mode characterization\",\n      \"pmids\": [\"27167503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Brpf1 haploinsufficiency in mouse (Emx1-Cre heterozygotes) reduces dendritic complexity, spine density, and spine/synapse morphology in hippocampal granule cells and cortical pyramidal neurons, and decreases frequency and amplitude of miniature EPSCs, leading to impaired learning and memory.\",\n      \"method\": \"Conditional Brpf1 heterozygous mouse, morphological analysis, whole-cell patch clamp, behavioral assays\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with electrophysiology, morphology, and behavioral readouts in single study\",\n      \"pmids\": [\"31213987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Isoform-specific functions of Brpf1 in hematopoietic stem and progenitor cells: Brpf1b promotes HSPC expansion while Brpf1a promotes quiescence; inhibition of Brpf1a by OF-1 increases histone acetylation and chromatin accessibility, upregulating self-renewal gene Mn1, and the expansion phenotype is rescued by Mn1 suppression.\",\n      \"method\": \"Bromodomain inhibitor chemical screen, isoform-specific overexpression/knockdown in HSPCs, chromatin accessibility (ATAC-seq), gene expression analysis, epistasis (Mn1 rescue)\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic isoform analysis with epistasis, single lab\",\n      \"pmids\": [\"31565729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Brpf1 knockdown in hippocampal neurons reduces miniature EPSC frequency before changes in dendritic morphology appear; in vivo hippocampal Brpf1 knockdown impairs spatial learning; dysregulated genes include synaptic transmission regulators C1ql1, Grin2a, and others.\",\n      \"method\": \"shRNA knockdown in primary hippocampal neurons, whole-cell patch clamp (mEPSC recording), Morris water maze, RNA-seq\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology + behavioral assay + transcriptomics, single lab\",\n      \"pmids\": [\"34485298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Brpf1 knockdown in MGE-derived GABAergic interneurons increases firing threshold, decreases evoked action potential number, and reduces miniature IPSC amplitude, demonstrating a key role of Brpf1 in inhibitory neurotransmission; differentiation into parvalbumin+ interneurons was not significantly changed.\",\n      \"method\": \"AAV-shBrpf1 knockdown, whole-cell patch clamp, immunofluorescence, MGE transplantation assay, RNA-seq\",\n      \"journal\": \"G3 (Bethesda)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with transplantation and transcriptomics, single lab\",\n      \"pmids\": [\"33744924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BRPF1 activates E2F2 and EZH2 expression by facilitating H3K14 acetylation at their promoters via the MOZ/MORF complex in hepatocellular carcinoma cells; BRPF1 ablation or pharmacological inhibition attenuates HCC cell growth in vitro and in vivo.\",\n      \"method\": \"BRPF1 gene ablation, pharmacological inhibition, ChIP-seq for H3K14ac, transcriptome sequencing, xenograft tumor models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq linking BRPF1 to promoter H3K14ac, supported by KO and inhibitor experiments, single lab\",\n      \"pmids\": [\"34285329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP35 directly deubiquitinates and stabilizes BRPF1 protein; USP35-dependent BRPF1 accumulation enables BRPF1 to bind the SREBP2 promoter and activate SREBP2 transcription, thereby promoting mevalonate metabolism in prostate cancer cells.\",\n      \"method\": \"Co-IP/pulldown (USP35–BRPF1 interaction), ubiquitination assays, ChIP-qPCR (BRPF1 at SREBP2 promoter), rescue experiments\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — deubiquitination assay plus ChIP and rescue, single lab\",\n      \"pmids\": [\"36357379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRPF1 associates with ERα on chromatin in breast cancer cells; BRPF1 blockade inhibits cell cycle progression, reduces chromatin accessibility, and silences ERα gene expression in antiestrogen-sensitive and -resistant cells, placing BRPF1 as an upstream regulator of estrogen signaling.\",\n      \"method\": \"ChIP-seq (BRPF1–ERα co-occupancy), ATAC-seq, transcriptome profiling, siRNA knockdown, pharmacological inhibition, patient-derived organoids\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq co-occupancy plus chromatin accessibility and transcriptomics, single lab\",\n      \"pmids\": [\"39113071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Using site-specific photo-crosslinking with azide-acetyllysine in the BRPF1 bromodomain, the non-histone interactome of BRPF1 was mapped; interleukin enhancer-binding factor 3 (ILF3) was validated as a novel BRPF1 bromodomain interacting partner by ITC and co-IP.\",\n      \"method\": \"Unnatural amino acid photo-crosslinking, proteomics, ITC, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — novel crosslinking proteomics with ITC and co-IP validation for one partner, single lab\",\n      \"pmids\": [\"38072045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"BRPF1 bridges H3K4me3 and H3K23ac marks in human embryonic stem cells; BRPF1 deletion impairs H3K23ac and closes chromatin on stemness genes leading to hESC differentiation. Deletion of the N-terminal or PZP module abolishes BRPF1 function while PWWP deletion only partially impairs it.\",\n      \"method\": \"BRPF1 KO in hESCs, CUT&RUN/ChIP for H3K4me3 and H3K23ac, ATAC-seq, domain-deletion mutant functional rescue assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion epistasis plus epigenome profiling in hESCs, single lab\",\n      \"pmids\": [\"36711238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CaMKIIa-Cre-driven Brpf1 knockout in forebrain excitatory neurons reduces miniature EPSC frequency and downregulates genes related to synapse function (Pcdhgb1, Slc16a7, Robo3, Rho), impairing spatial and fear memory.\",\n      \"method\": \"Conditional Brpf1 KO (CaMKIIa-Cre), whole-cell patch clamp, RNA-seq, behavioral assays (fear conditioning, Morris water maze)\",\n      \"journal\": \"Neural regeneration research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neuron-type-specific KO with electrophysiology and transcriptomics, single lab\",\n      \"pmids\": [\"37862219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BRPF1 directly binds the ABCB1 promoter (CUT&RUN-qPCR) and enhances ABCB1 expression to confer multidrug resistance in Taxol-resistant TNBC; BRPF1 KO or inhibition reduces ABCB1 expression and suppresses ribosome biogenesis gene sets, sensitizing resistant cells to Taxol.\",\n      \"method\": \"CRISPR KO, pharmacological inhibition (PFI-4, OF-1), CUT&RUN-qPCR, RNA-seq, cell viability assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromatin occupancy at ABCB1 promoter plus genetic and pharmacological KO with transcriptomics, single lab\",\n      \"pmids\": [\"40583060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Truncated BRPF1, as found in human adult medulloblastoma patients with inactivating mutations, cooperates with SmoM2 activation to induce medulloblastoma in adult mice by promoting postmitotic neuron re-entry into the cell cycle via chromatin remodeling.\",\n      \"method\": \"In vivo mouse model (truncated BRPF1 + SmoM2 transgenic), cell cycle analysis, histology\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with cell cycle readout, single lab, consistent with human mutation data\",\n      \"pmids\": [\"31851932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BRPF1 (as part of the MOZ/HBO1 complex) associates with NUP98 fusion oncoproteins on chromatin and within nuclear condensates; MYST HATs are molecular dependencies in NUP98-rearranged AML, and their inhibition decreases global H3K23ac, displaces NUP98::HOXA9 from chromatin at the Meis1 locus, and induces myeloid differentiation.\",\n      \"method\": \"Co-IP/proximity ligation assays (BRPF1–NUP98 FO association), ChIP-seq (H3K23ac, NUP98 occupancy), genetic inactivation, pharmacological inhibition, xenograft mouse models\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.12.02.624182\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FBRSL1 binds upstream of the BRPF1 locus (via association with transcription factor YY1) and positively regulates BRPF1 expression; truncating FBRSL1 variants cause BRPF1 downregulation in patient blood and fibroblasts, and loss of Fbrsl1 in Xenopus disrupts brpf1 expression pattern.\",\n      \"method\": \"ChIP-seq (FBRSL1–YY1 at BRPF1 promoter), qRT-PCR in patient cells, Xenopus loss-of-function\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus patient cells plus Xenopus model, single lab\",\n      \"pmids\": [\"40658195\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BRPF1 is a multivalent chromatin scaffold protein that assembles stoichiometric HAT complexes with KAT6A (MOZ), KAT6B (MORF), and KAT7 (HBO1), stimulating their enzymatic activity toward H3K23 acetylation and propionylation; it recruits these complexes to chromatin through its PWWP domain (which reads H3K36me3), its PZP domain (which bivalently contacts histone H3 and extranucleosomal DNA to promote nucleosome unwrapping), and its bromodomain (which selectively binds mono- and di-acetylated lysines including H2AK5ac, H4K12ac, H3K14ac, and H4K5acK8ac); the resulting H3K23ac mark is required for normal brain, hematopoietic, and embryonic development in mice, and its deficiency—caused by monoallelic pathogenic BRPF1 variants—underlies a syndromic intellectual disability disorder in humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BRPF1 is a multivalent chromatin scaffold that assembles and activates MYST-family histone acetyltransferase complexes — together with MOZ (KAT6A), MORF (KAT6B), and HBO1 (KAT7) plus ING5 and MEAF6 — to deposit acetylation and propionylation at histone H3K23 and to read and bridge other histone marks during development [#3, #7, #10]. It engages chromatin through three reader modules: a PWWP domain that binds H3K36me3 [#0], a PZP (PHD–zinc-knuckle–PHD) domain that bivalently contacts the H3 tail and extranucleosomal DNA — with DNA binding dominating — to drive nucleosome unwrapping and enable HAT complex recruitment and nucleosomal acetylation [#3, #9], and a bromodomain that selectively recognizes acetyllysines including H2AK5ac, H4K12ac, and H3K14ac and reads di-acetylated H4 marks such as H4K5acK8ac [#1, #2, #11]. Through this scaffold activity BRPF1 functions both as a transcriptional activator and silencer, and in human embryonic stem cells it bridges H3K4me3 and H3K23ac to keep stemness gene chromatin open, with its N-terminal and PZP modules being essential and the PWWP domain only partially required [#24]. In vivo, Brpf1 is required for H3K23 acetylation/propionylation and for normal forebrain neurogenesis, neuronal migration, dendritic and synaptic development, hematopoietic stem cell maintenance, and embryonic vascular and neural-tube development, where its loss deregulates Hox and multipotency gene programs [#5, #6, #7, #10, #16]. Monoallelic pathogenic BRPF1 variants impair H3K23 acetylation and propionylation and cause a syndromic intellectual disability disorder in humans [#8, #10]. BRPF1 is also co-opted in cancer, where it directs MOZ/MORF-mediated H3K14 acetylation and chromatin opening at oncogenic loci and partners with ER\\u03b1 and NUP98-fusion oncoproteins to sustain tumor cell programs [#20, #22, #28].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established BRPF1 (BR140) as a nuclear zinc-finger protein with homology to the TFIID subunit TAF250, providing the first hint of a transcription-associated chromatin role.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, and immunolocalization of the BR140 protein\",\n      \"pmids\": [\"7906940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic or binding mechanism established\", \"Functional role in transcription not demonstrated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Genetic loss-of-function in two vertebrates placed BRPF1 within the MOZ HAT complex controlling Hox/Zic patterning, connecting the protein to developmental gene regulation.\",\n      \"evidence\": \"Medaka forward-genetic brpf1 mutant and parallel mouse MOZ knockout with in situ hybridization\",\n      \"pmids\": [\"19254709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of complex assembly not resolved\", \"Direct chromatin targets not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Answered how BRPF1 reads methylated chromatin by defining the PWWP domain as an H3K36me3 reader at atomic resolution.\",\n      \"evidence\": \"X-ray crystal structure of the PWWP\\u2013H3K36me3 peptide complex with binding validation\",\n      \"pmids\": [\"20400950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of PWWP reading to complex recruitment in vivo not quantified\", \"Other reader modules unaddressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the BRPF1 bromodomain as a histone acetyllysine reader and mapped the acetyllysine-coordinating residues, identifying a second chromatin-engagement module.\",\n      \"evidence\": \"NMR chemical shift perturbation, molecular dynamics, and bromodomain ligand-binding assays\",\n      \"pmids\": [\"24333487\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of each acetyl mark not established\", \"Bromodomain contribution to HAT recruitment not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided atomic-resolution structures of the bromodomain bound to H2AK5ac and H4K12ac, establishing the molecular basis of acetyllysine recognition including ordered waters.\",\n      \"evidence\": \"X-ray crystallography of bromodomain\\u2013peptide complexes with binding-pocket mutagenesis\",\n      \"pmids\": [\"25281266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Multivalent or di-acetyl recognition not yet characterized\", \"Functional output of binding not measured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved how BRPF1 engages whole nucleosomes by showing the PZP domain bivalently contacts H3 and DNA to promote nucleosome unwrapping and enable HAT complex recruitment and nucleosomal acetylation.\",\n      \"evidence\": \"Biochemical reconstitution, FRET nucleosome dynamics, and HAT activity assays on the MOZ-BRPF1-ING5-hEaf6 complex\",\n      \"pmids\": [\"26626149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of H3-tail vs DNA binding not yet dissected\", \"Structural detail of PZP\\u2013H3 contact pending\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that BRPF1 is required in vivo for forebrain neurogenesis, embryonic viability, and progenitor proliferation, acting as both activator and silencer of developmental genes.\",\n      \"evidence\": \"Conditional and constitutive Brpf1 mouse knockouts with histology, BrdU cell-cycle analysis, and transcriptome profiling\",\n      \"pmids\": [\"25568313\", \"25757017\", \"25773539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct chromatin targets versus indirect effects not distinguished\", \"Mechanistic link from HAT activity to specific gene programs incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked BRPF1 to a specific epigenetic mark and stem-cell function by showing it is required for H3K23ac and multipotency gene expression in hematopoietic stem cells.\",\n      \"evidence\": \"Hematopoietic-specific Brpf1 knockout with flow cytometry, H3K23ac immunoblotting, ROS/apoptosis assays, and expression profiling\",\n      \"pmids\": [\"27500495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H3K23ac loss is causal for each phenotype not isolated\", \"Direct genomic sites of H3K23ac deposition not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established BRPF1 as a human disease gene by showing monoallelic variants impair its acetyltransferase co-activation and H3K23ac, causing an intellectual disability syndrome.\",\n      \"evidence\": \"Patient variant functional assays, H3K23ac immunoblotting in patient fibroblasts and Brpf1-KO mice, and localization studies\",\n      \"pmids\": [\"27939640\", \"27939639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype\\u2013phenotype correlations across variants not fully resolved\", \"Tissue-specific consequences of haploinsufficiency incompletely defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the nucleosome-engagement mechanism by showing extranucleosomal DNA binding dominates over H3-tail binding in the PZP domain and that both are required for tight nucleosome binding and HAT function.\",\n      \"evidence\": \"X-ray crystallography of the PZP\\u2013H3 complex, ITC, and HAT activity assays on the BRPF1-MORF-ING5-MEAF6 complex\",\n      \"pmids\": [\"31711755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo importance of DNA versus H3 binding not tested\", \"Coordination with PWWP and bromodomain on the same nucleosome unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected Brpf1 dosage to neuronal circuit function by showing haploinsufficiency reduces dendritic complexity, spine density, and excitatory transmission, impairing learning and memory.\",\n      \"evidence\": \"Conditional Brpf1 heterozygous mice with morphology, patch-clamp electrophysiology, and behavioral assays\",\n      \"pmids\": [\"31213987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets driving synaptic deficits not defined\", \"Cell-autonomous versus circuit-level contributions unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded the catalytic output of BRPF1 complexes by showing they deposit H3K23 propionylation as well as acetylation, both abolished by Brpf1 loss and impaired by patient variants.\",\n      \"evidence\": \"In vitro acylation assays, mass spectrometry, ATAC-See in mouse embryos/fibroblasts, and patient variant assays\",\n      \"pmids\": [\"32010779\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional distinction between acetylation and propionylation not resolved\", \"Genomic distribution of H3K23pr not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended bromodomain reading specificity to di-acetylated H4 and identified the non-canonical pocket regions mediating recognition of the second acetyl mark.\",\n      \"evidence\": \"ITC, NMR chemical shift perturbation, analytical ultracentrifugation, and mutagenesis\",\n      \"pmids\": [\"33554132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo role of di-acetyl reading not tested\", \"Integration with other reader modules unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed isoform-specific BRPF1 functions in hematopoietic progenitors, with one isoform promoting expansion and another quiescence via chromatin accessibility and the Mn1 self-renewal gene.\",\n      \"evidence\": \"Bromodomain inhibitor screen, isoform-specific overexpression/knockdown, ATAC-seq, and Mn1 epistasis in HSPCs\",\n      \"pmids\": [\"31565729\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without independent replication\", \"Molecular basis of isoform divergence unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined BRPF1 as a chromatin bridge in human pluripotency by showing it links H3K4me3 and H3K23ac to keep stemness gene chromatin open, with N-terminal/PZP modules essential and PWWP partially dispensable.\",\n      \"evidence\": \"BRPF1 KO in hESCs with CUT&RUN/ChIP, ATAC-seq, and domain-deletion rescue assays\",\n      \"pmids\": [\"36711238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Mechanism by which marks are physically bridged not structurally resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped a non-histone bromodomain interactome and validated ILF3 as a partner, expanding BRPF1 function beyond histone reading.\",\n      \"evidence\": \"Unnatural amino acid photo-crosslinking proteomics with ITC and co-IP validation\",\n      \"pmids\": [\"38072045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of ILF3 binding not established\", \"Single Co-IP/ITC validation for one partner\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an upstream regulator of BRPF1 expression, showing FBRSL1 with YY1 controls BRPF1 transcription and that FBRSL1 truncations downregulate BRPF1 in patients.\",\n      \"evidence\": \"ChIP-seq of FBRSL1\\u2013YY1 at the BRPF1 promoter, qRT-PCR in patient cells, and Xenopus loss-of-function\",\n      \"pmids\": [\"40658195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Direct versus indirect regulation of BRPF1 not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Documented oncogenic and drug-resistance roles for BRPF1 across cancers, where it directs HAT-mediated chromatin opening at oncogenic and resistance loci and partners with ER\\u03b1 and NUP98 fusions.\",\n      \"evidence\": \"ChIP-seq/CUT&RUN occupancy, ATAC-seq, genetic and pharmacological inhibition, and xenograft/organoid models across HCC, breast, prostate, AML, and TNBC\",\n      \"pmids\": [\"34285329\", \"39113071\", \"36357379\", \"40583060\", \"31851932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mostly single-lab studies per tumor type\", \"Direct versus complex-mediated chromatin targeting not always distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the three reader modules (PWWP, PZP, bromodomain) are coordinated on a single nucleosome to integrate H3K36me3, DNA, and acetyl marks into productive HAT recruitment, and how this generates locus-specific gene activation versus silencing, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No integrated structural model of full-length BRPF1 on a nucleosome\", \"Genome-wide map of H3K23ac/H3K23pr deposition incomplete\", \"Rules distinguishing activator from silencer function unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3, 9, 20, 21, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 9, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 20, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 7, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 20, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6, 12, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 20, 27, 28]}\n    ],\n    \"complexes\": [\n      \"MOZ-BRPF1-ING5-hEaf6 HAT complex\",\n      \"BRPF1-MORF-ING5-MEAF6 HAT complex\",\n      \"HBO1/KAT7 complex\"\n    ],\n    \"partners\": [\n      \"KAT6A\",\n      \"KAT6B\",\n      \"KAT7\",\n      \"ING5\",\n      \"MEAF6\",\n      \"ILF3\",\n      \"USP35\",\n      \"ESR1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}