{"gene":"BPTF","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":2006,"finding":"The PHD finger of BPTF (bromodomain-proximal PHD finger) specifically recognizes histone H3 trimethylated at K4 (H3K4me3) through anti-parallel beta-sheet formation, with the side chains of H3R2 and K4me3 fitting into adjacent pre-formed surface pockets flanking an invariant tryptophan. Crystal and NMR structures of free and H3K4me3-bound PHD finger established the molecular basis for site-specific readout; mutagenesis identified key specificity-determining residues. BPTF PHD shows preference for K4me3 over K4me2 and discriminates against monomethylated and unmodified H3.","method":"X-ray crystallography, NMR spectroscopy, peptide binding assays, PHD finger point mutagenesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR structures, in vitro binding assays, and mutagenesis of specificity residues in a single rigorous study","pmids":["16728978"],"is_preprint":false},{"year":2001,"finding":"NURF301 (the Drosophila ortholog of BPTF) is the largest subunit of the NURF ISWI complex. Reconstitution of partial and full NURF complexes from recombinant proteins demonstrated that NURF301 and the ISWI ATPase are necessary and sufficient for accurate and efficient nucleosome sliding. An HMGA/HMGI(Y)-like domain of NURF301 facilitates sliding, indicating a role for DNA conformational changes. NURF301 also physically interacts with sequence-specific transcription factors, providing a basis for targeted recruitment.","method":"Recombinant protein reconstitution of NURF complexes, nucleosome sliding assays, protein interaction assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution from recombinant components plus functional nucleosome sliding assay, multiple orthogonal experiments","pmids":["11583616"],"is_preprint":false},{"year":2018,"finding":"In the full nucleosomal context, histone H3 tails interact robustly and dynamically with nucleosomal DNA, substantially reducing BPTF PHD finger association with H3K4me3. Altering H3 tail electrostatics via modification or mutation increases PHD finger accessibility. This demonstrates that post-translational modification crosstalk can regulate BPTF PHD binding by modulating nucleosome conformation.","method":"NMR spectroscopy, molecular dynamics (MD) simulations, nucleosome binding assays with modified H3 tails","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR and MD simulations with multiple H3 variants in a single rigorous study with functional conclusions","pmids":["29648537"],"is_preprint":false},{"year":2009,"finding":"Drosophila NURF301 (BPTF ortholog) is expressed as alternative splice isoforms encoding functionally distinct NURF complexes. Full-length NURF301 contains a C-terminal bromodomain and PHD finger that bind H3K4me3 and H4K16Ac respectively; a truncated isoform lacking these domains assembles a NURF complex deficient in H3K4me3 and H4K16Ac recognition. Mutants lacking C-terminal PHD finger and bromodomain show a spermatocyte arrest phenotype and fail to express spermatid differentiation genes, revealing that the histone-modification-reading isoform is specifically required for spermatogenesis.","method":"Genetic analysis of Drosophila NURF301 isoform mutants, microarray expression profiling, phenotypic characterization","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined genetic isoform mutants with specific cellular phenotype plus expression profiling and histone binding domain analysis","pmids":["19629165"],"is_preprint":false},{"year":2008,"finding":"Bptf-null mouse embryos fail to establish a functional distal visceral endoderm and are reabsorbed by E8.5, establishing an essential role for BPTF in early embryogenesis. Physical and functional links between the BPTF-containing NURF complex and Smad transcription factors were identified, suggesting BPTF co-regulates TGF-β/Smad pathway targets required for visceral endoderm establishment.","method":"Bptf knockout mice, histological analysis, lineage marker immunostaining, microarray, co-immunoprecipitation with Smad factors","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with specific developmental phenotype plus physical interaction with Smad factors in same study","pmids":["18974875"],"is_preprint":false},{"year":2008,"finding":"BPTF/FAC1 is essential in the extraembryonic trophoblast lineage for correct development of the ectoplacental cone; null embryos arrest at early gastrula stage (E6.5) with drastically reduced or absent ectoplacental cone, indicating BPTF is required for trophoblast differentiation.","method":"Loss-of-function allele knock-in mouse model, histological analysis, lineage marker staining","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with specific trophoblast/ectoplacental cone phenotypic readout","pmids":["18794365"],"is_preprint":false},{"year":2015,"finding":"BPTF physically interacts with the chromatin remodeling protein Bptf in zebrafish; Bptf functionally and physically interacts with phospho-Smad2 (activated by non-Nodal TGF-β signaling) to promote wnt8a expression required for neural posteriorization. Bptf and Smad2 directly bind to and activate the wnt8a promoter through recruiting the NURF remodeling complex. Knockdown of bptf increases nucleosome density at the wnt8a promoter.","method":"Zebrafish bptf morpholino knockdown, co-immunoprecipitation of Bptf and p-Smad2, ChIP at wnt8a promoter, nucleosome occupancy assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus nucleosome occupancy assay in a single study with genetic loss-of-function phenotype","pmids":["26041917"],"is_preprint":false},{"year":2016,"finding":"BPTF physically interacts with c-MYC and is required for full c-MYC transcriptional program activation. BPTF knockdown decreases c-MYC recruitment to DNA and reduces chromatin accessibility at c-MYC target loci. In Bptf-null MEFs, BPTF is necessary for c-MYC-driven proliferation, G1-S progression, and replication stress but not for c-MYC-driven apoptosis. Bptf inactivation in pre-neoplastic pancreatic acinar cells significantly delays tumor development in vivo.","method":"Co-immunoprecipitation (c-MYC and BPTF), ChIP (c-MYC at target genes), ATAC-seq/chromatin accessibility assays, Bptf-null MEFs, in vivo pancreatic cancer model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP, chromatin accessibility, clean KO MEFs with specific cell cycle phenotype, in vivo model in one study","pmids":["26729287"],"is_preprint":false},{"year":2006,"finding":"In C. elegans, the NURF301 ortholog NURF-1 acts together with ISWI (ISW-1) as a NURF-like complex to promote vulval cell fates and synMuv phenotype. isw-1 and nurf-1 mutations suppress the synMuv phenotype and the multivulva phenotype caused by Ras pathway overactivation, placing the NURF complex genetically downstream/parallel to Rb-like (lin-35) and Ras pathway in vulval fate determination.","method":"Genetic suppressor screen in C. elegans, double-mutant epistasis analysis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis in C. elegans with multiple double-mutant combinations; ortholog, not direct human BPTF experiments","pmids":["16774993"],"is_preprint":false},{"year":2000,"finding":"FAC1 (alias of BPTF) protein interacts with the Myc-associated zinc finger protein ZF87/MAZ as shown by yeast two-hybrid and in vitro pulldown with recombinant protein. The interaction domain was mapped to the NLS/NES region of FAC1. FAC1 reduces ZF87/MAZ-induced transcriptional activation of the SV40 promoter in a dose-dependent manner in NIH3T3 cells; a FAC1 deletion mutant lacking the ZF87/MAZ interaction domain does not alter ZF87/MAZ activation.","method":"Yeast two-hybrid screen, in vitro pulldown with recombinant proteins, deletion mutagenesis, co-transfection luciferase reporter assay","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro pulldown, deletion mutagenesis, and functional transcription reporter in single study","pmids":["10727212"],"is_preprint":false},{"year":1999,"finding":"FAC1 (alias of BPTF) DNA-binding activity is regulated by phosphorylation: phosphatase treatment of neuroblastoma nuclear extracts reduces FAC1 DNA-binding affinity, and inhibition of cellular serine/threonine phosphatases increases FAC1 DNA-binding activity.","method":"Electrophoretic mobility shift assay (EMSA/DNA-binding assay), phosphatase treatment of nuclear extracts, pharmacological phosphatase inhibition","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — two orthogonal biochemical approaches (phosphatase treatment + inhibitor) but single laboratory, no site identification","pmids":["10403843"],"is_preprint":false},{"year":2016,"finding":"MITF directly binds the BPTF promoter (demonstrated by ChIP) and transcriptionally activates BPTF expression (demonstrated by luciferase reporter assay). MITF overexpression upregulates BPTF and BPTF-regulated genes including BCL2; MITF silencing downregulates BPTF. Rescue of MITF silencing-induced growth suppression by BPTF cDNA overexpression demonstrates BPTF transduces MITF-driven prosurvival signals.","method":"ChIP of MITF at BPTF promoter, luciferase reporter assay, shRNA silencing, BPTF cDNA rescue experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus epistatic rescue in single study, single laboratory","pmids":["27185926"],"is_preprint":false},{"year":2017,"finding":"BPTF occupies heparanase (HPSE) regulatory elements and activates its expression, as established using gain/loss-of-function approaches. Increased heparanase activity reduces cell-surface heparan sulfate proteoglycans (HSPGs), which are NCR co-ligands, thereby suppressing NK cell cytolytic activity toward tumor cells. Blocking NCR1 in vivo rescues BPTF-KD tumor weights, confirming the pathway.","method":"BPTF gain- and loss-of-function in syngeneic mouse models, HPSE promoter occupancy (implied ChIP), NK cell cytolytic assays, NCR1 blocking in vivo","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with defined mechanistic pathway and in vivo epistasis with NCR1 blocking, single lab","pmids":["28969075"],"is_preprint":false},{"year":2016,"finding":"BPTF depletion in tumor cells enhances antigen processing by derepressing immunoproteasome subunits PSMB8 and PSMB9 and antigen transporter genes TAP1 and TAP2. ChIP/direct promoter occupancy experiments showed NURF directly regulates these gene loci. The PSMB8 inhibitor ONX-0914 reversed the enhanced CD8+ T-cell killing caused by BPTF ablation, confirming a role for the immunoproteasome.","method":"BPTF shRNA knockdown, ChIP of NURF at PSMB8/PSMB9/TAP1/TAP2 promoters, pharmacological epistasis with ONX-0914, CD8+ T-cell cytolytic assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus pharmacological epistasis plus functional immune assay, single laboratory","pmids":["27651309"],"is_preprint":false},{"year":2017,"finding":"BPTF PHD finger preferentially binds H3K4me3 and recruits the NURF complex to chromatin, and depletion of BPTF reduces chromatin accessibility at enhancer regions in mammary epithelial cells. BPTF is essential for mammary gland stem cell (MaSC) self-renewal and differentiation; BPTF depletion arrests cells at a stage associated with an inability to achieve the luminal cell fate.","method":"BPTF KO/KD in mammary epithelial cells, ATAC-seq genome-wide chromatin accessibility, functional MaSC self-renewal assays","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ATAC-seq plus loss-of-function with specific cellular differentiation phenotype, single laboratory","pmids":["28579392"],"is_preprint":false},{"year":2018,"finding":"BPTF is required for the maintenance of hematopoietic stem/progenitor cell (HSPC) population size and long-term HSC function. Hematopoietic-specific knockout of Bptf causes bone marrow failure and anemia. Genome-wide transcriptome profiling showed BPTF loss causes downregulation of HSC stemness transcription factors (Meis1, Pbx1, Mn1, Lmo2) and BPTF potentiates chromatin accessibility of these genes.","method":"Conditional Bptf knockout mice, bone marrow transplantation reconstitution assay, RNA-seq, ATAC-seq at stemness gene loci","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific HSC phenotype plus transcriptome and chromatin accessibility profiling, single laboratory","pmids":["29456179"],"is_preprint":false},{"year":2016,"finding":"BPTF is critical for T cell homeostasis in a cell-intrinsic manner. Treg cell-specific BPTF deletion leads to reduced Foxp3 expression, increased lymphocyte infiltration in non-lymphoid organs, and a systemic autoimmune syndrome.","method":"Conditional Bptf knockout from late DN3/DN4 T cells, Treg-specific Bptf deletion, flow cytometry, histological analysis of organ infiltration","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with specific Foxp3/Treg phenotype, single laboratory","pmids":["27799308"],"is_preprint":false},{"year":2019,"finding":"BPTF cooperates with p50 subunit of NF-κB to regulate COX-2 promoter activity and COX-2 expression in lung cancer cells. BPTF was identified as a COX-2 promoter-binding protein; knockdown of BPTF abrogated p50 binding to the COX-2 promoter; inhibition of p50 activity blocked BPTF-dependent COX-2 expression and cell proliferation.","method":"Biotin-streptavidin-agarose DNA pulldown of COX-2 promoter, mass spectrometry identification, ChIP, co-immunoprecipitation of BPTF and p50, confocal immunofluorescence, BPTF siRNA knockdown","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DNA pulldown, ChIP, Co-IP with multiple orthogonal methods in single study, single laboratory","pmids":["31934287"],"is_preprint":false},{"year":2018,"finding":"BPTF promotes HCC growth by transcriptionally regulating hTERT expression. Knockdown of BPTF suppressed hTERT expression, reduced cancer stem cell marker expression, and inhibited tumor growth in xenograft models.","method":"BPTF shRNA knockdown, ChIP (implied for BPTF at hTERT promoter), xenograft mouse model, Western blot for CSC markers","journal":"Redox biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, loss-of-function with phenotype but mechanistic link to hTERT relies on knockdown correlation rather than direct ChIP validation clearly described","pmids":["30419422"],"is_preprint":false},{"year":2015,"finding":"The BPTF bromodomain was identified as a druggable target; AU1 was identified as the first small molecule selective for BPTF bromodomain over Brd4 (Kd = 2.8 μM by 19F NMR). No binding was detected with Brd4. AU1 is active in a cell-based reporter assay.","method":"Protein-observed 19F NMR dual screening, fluorescence anisotropy, cell-based reporter assay","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro binding assay (19F NMR) with orthogonal biophysical validation and cell-based functional confirmation","pmids":["26158404"],"is_preprint":false},{"year":2017,"finding":"H2A.Z diacetylated at K4 and K11 directly interacts with the BPTF bromodomain with Kd ~780 μM, as established by PrOF NMR and photo-cross-linking. Specificity for the K4/K11 diacetylation pattern over other combinations was demonstrated biophysically.","method":"Protein-observed 19F NMR (PrOF NMR), 1H NMR CPMG experiments, photo-cross-linking, fluorescence anisotropy","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple biophysical methods in a single study confirming weak but specific direct interaction; functional consequences not tested","pmids":["28771339"],"is_preprint":false},{"year":2022,"finding":"BPTF binds the Cdc25A promoter (−178/+107 region) and transcriptionally activates Cdc25A to accelerate colorectal cancer cell cycle progression. BPTF itself is transcriptionally regulated by c-Myc. Established by RNA-seq, DNA-pulldown, ChIP, and luciferase reporter assay; Cdc25A overexpression partially reversed BPTF-silencing-induced growth inhibition (epistasis).","method":"RNA-seq, DNA pulldown, ChIP at Cdc25A promoter, luciferase reporter assay, siRNA/shRNA knockdown, rescue with Cdc25A overexpression","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus epistatic rescue in single laboratory with multiple orthogonal methods","pmids":["35932692"],"is_preprint":false},{"year":2022,"finding":"BPTF is required for c-MYC recruitment to the promoter of ABC-transporters (MDR genes) in pancreatic cancer. BPTF silencing reduces IC50 of gemcitabine in vitro, and its depletion increases intracellular gemcitabine accumulation and DNA damage. ChIP confirmed reduced c-MYC occupancy at ABC-transporter promoters upon BPTF knockdown.","method":"BPTF siRNA/shRNA knockdown, ChIP (c-MYC at ABC-transporter promoters), gemcitabine sensitivity assays, DNA damage assays, xenograft models","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional drug sensitivity plus in vivo model, single laboratory","pmids":["35326669"],"is_preprint":false},{"year":2020,"finding":"Bptf deletion in aggressive B-cell lymphoma (Eμ-Myc mouse model) delays lymphomagenesis; tumors arising in a Bptf heterozygous background display decreased c-MYC levels, reduced c-MYC pathway activity, and increased NF-κB pathway activation. This defines BPTF as genetically required for c-MYC-driven B-cell lymphomagenesis.","method":"Eμ-Myc transgenic mouse with Bptf heterozygous deletion, tumor analysis, gene expression profiling, IHC for c-MYC/NF-κB pathway","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis in in vivo lymphoma model with molecular pathway analysis, single laboratory","pmids":["32451433"],"is_preprint":false},{"year":2025,"finding":"BPTF forms a protein complex with androgen receptor (AR) and FOXA1 in prostate cancer. BPTF increases chromatin accessibility via SMARCA1 (catalytic NURF subunit) to facilitate AR binding at promoters, enhancers, and super-enhancers. FOXA1 recruits the BPTF-AR complex to chromatin, while BPTF stabilizes the AR-FOXA1 interaction. BPTF interacts with AR through its bromodomain; a bromodomain inhibitor disrupts this interaction and impairs AR signaling.","method":"Co-immunoprecipitation (BPTF, AR, FOXA1), ChIP-seq (BPTF, AR), ATAC-seq (chromatin accessibility), RNA-seq, BPTF bromodomain inhibitor treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with three partners, ChIP-seq, ATAC-seq, functional inhibitor validation in single rigorous study","pmids":["41381516"],"is_preprint":false},{"year":2025,"finding":"BPTF PHD finger reads H3K4me3 to protect hepatocellular carcinoma (HCC) cells from NK cell recognition. PROTAC-mediated selective degradation of BPTF directly increases the abundance of natural cytotoxicity receptor ligands on HCC cells, enhancing NK cell cytotoxicity against HCC both in vitro and in vivo.","method":"PROTAC degrader, NK cell cytotoxicity assays, surface NCR ligand analysis, in vivo HCC models","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein degradation with direct functional readout (NK ligand surface abundance, cytotoxicity) in vitro and in vivo, single laboratory","pmids":["39935175"],"is_preprint":false},{"year":2025,"finding":"BPTF bromodomain directly binds acetylated H2A.Z in a pocket-specific and affinity-dependent manner in vitro (photo-crosslinking with recombinant bromodomain) and enriches endogenous BPTF from nuclear lysates of A549 cells, confirming the interaction occurs in a cellular context, albeit less efficiently than with canonical H4K16ac.","method":"Photoaffinity probes with diazirine and biotin tag, SDS-PAGE photo-crosslinking, nuclear lysate pull-down, bottom-up proteomics for H2A.Z acetylation patterns","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstituted direct photo-crosslinking in vitro plus validation in nuclear lysate, single laboratory","pmids":["40864556"],"is_preprint":false},{"year":2024,"finding":"BPTF cooperates with MYCN and MYC in neuroblastoma; immunoprecipitation/mass spectrometry showed BPTF interacts with MYCN and core regulatory circuitry (CRC) transcription factors. Genome-wide distribution analysis revealed BPTF co-localizes with MYCN/MYC at promoters of cell cycle genes and with CRC factors at super-enhancers to regulate cell identity.","method":"Immunoprecipitation/mass spectrometry, ChIP-seq (BPTF, MYCN, CRC TFs), bulk RNA-seq, single-cell sequencing, tissue microarrays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP/MS plus ChIP-seq with multiple orthogonal approaches; preprint, single laboratory","pmids":["38405949"],"is_preprint":true},{"year":2024,"finding":"NUP98-BPTF fusion protein promotes oncogenic transformation by transcriptionally upregulating PIM1 proto-oncogene via binding to its promoter, leading to activation of MYC and mTORC1 signaling. PIM1 knockdown or mTORC1 inhibition suppressed NUP98-BPTF-induced NIH3T3 transformation. NUP98-BPTF also inactivates the pro-apoptotic protein BAD to enhance leukemia cell survival.","method":"Doxycycline-inducible NUP98-BPTF expression, NIH3T3 transformation assay, ChIP at PIM1 promoter, PIM1 shRNA knockdown, pharmacological mTORC1 inhibition, Jurkat T-ALL survival assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus multiple epistasis experiments (KD + pharmacological inhibition) in single laboratory","pmids":["38940430"],"is_preprint":false},{"year":2025,"finding":"BPTF regulates trophoblast EMT by directly binding the Slug gene promoter and activating Slug transcription. BPTF knockdown prevented EMT and attenuated trophoblast invasion; Slug and BPTF protein levels were both decreased in villous cytotrophoblasts of recurrent miscarriage patients.","method":"ChIP (BPTF at Slug promoter), BPTF knockdown, EMT assays, invasion assays, immunostaining of patient villi","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP experiment plus loss-of-function phenotype, single laboratory, limited mechanistic depth","pmids":["38521110"],"is_preprint":false},{"year":2022,"finding":"NURF301 (Drosophila BPTF ortholog) co-localizes genome-wide with gypsy insulator proteins CP190 and Su(Hw) and promotes chromatin association of these insulator proteins at gypsy insulator binding sites, as shown by ChIP-seq. NURF301 physically interacts with gypsy insulator proteins and promotes nucleosome repositioning at insulator sites, contributing to 3D nuclear organization of gypsy insulator binding sites.","method":"RNAi screen, ChIP-seq (NURF301, Su(Hw), CP190), physical interaction assays (pulldown/IP with insulator proteins), Oligopaint FISH with immunofluorescence for 3D localization, nucleosome positioning assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq plus physical interaction plus 3D localization data in single study; Drosophila ortholog","pmids":["35819192"],"is_preprint":false},{"year":2021,"finding":"METTL14-mediated m6A modification negatively regulates BPTF mRNA stability, such that METTL14 deficiency leads to BPTF accumulation. Accumulated BPTF remodels the enhancer landscape in renal cell carcinoma, constituting super-enhancers that activate downstream oncogenic targets including ENO2 and SRC, leading to glycolytic reprogramming.","method":"MeRIP-seq, RNA-seq, ChIP-seq, ATAC-seq, BPTF knockdown, METTL14 knockout, organoid and xenograft models, BPTF inhibitor AU1 treatment","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus ChIP-seq plus ATAC-seq with multiple loss-of-function approaches and functional validation in organoids and xenografts, single laboratory","pmids":["33664855"],"is_preprint":false},{"year":2025,"finding":"Loss of BPTF in mammary tumors results in elevated ERα levels linked with decreased TGF-β activity, leading to tamoxifen-sensitive estrogen-responsive tumors with limited lung metastasis. Loss of ERα is sufficient to restore TGF-β activity and metastatic potential in BPTF-KO tumors, establishing an epistatic relationship between BPTF, TGF-β, and ERα in tumor progression.","method":"Conditional BPTF knockout mammary tumor model, ERα/TGF-β functional analysis, ERα loss-of-function rescue experiment, lung metastasis assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with specific phenotype and epistatic rescue with ERα loss, single laboratory","pmids":["41093864"],"is_preprint":false},{"year":2025,"finding":"BPTF operates at gene promoters and is most effective at facilitating transcription and chromatin accessibility at genes marked by Set1-dependent H3K4me3 peaks (broader peaks) but not MLL1/2-dependent H3K4me3. Loss-of-function phenotype of bptf knockdown in planarian stem cells mimics that of Set1 knockdown, establishing a functional epistatic relationship between BPTF and Set1-H3K4me3 in vivo.","method":"BPTF RNAi knockdown in planarian stem cells, ATAC-seq, RNA-seq, Set1 vs MLL1/2 ChIP-seq peak comparison, genetic epistasis (bptf vs set1 knockdown phenotype)","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ATAC-seq plus RNA-seq plus genetic epistasis in a planarian in vivo system; ortholog, single laboratory","pmids":["40069606"],"is_preprint":false},{"year":2025,"finding":"Molecular dynamics simulations show that BPTF PHD finger binding to H3K4me3 displaces the H3 tail from nucleosomal DNA, increasing H3 tail flexibility and promoting compensatory binding of the H4 tail to nucleosomal DNA. This redistribution weakens overall DNA-histone hydrogen bonding, suggesting BPTF engagement induces localized nucleosome destabilization. BPTF adopts a compacted conformation upon nucleosome engagement.","method":"Molecular dynamics simulations of BPTF PHD finger and bromodomain bound to H3 peptide or full nucleosome","journal":"Biophysical journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational simulation only, no experimental validation; mechanistically informative but not experimentally confirmed","pmids":["40616262"],"is_preprint":false},{"year":2021,"finding":"Cocrystal structures of the BPTF bromodomain with small molecule inhibitors (BZ1 series pyridazinones) were determined, identifying an acidic triad in the binding pocket that guides inhibitor design. BZ1 showed Kd = 6.3 nM and >350-fold selectivity over BET bromodomains.","method":"X-ray co-crystallography of BPTF bromodomain:inhibitor complexes, ITC, SPR binding assays","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cocrystal structures validated with orthogonal biophysical binding assays, defines binding pocket architecture","pmids":["34515477"],"is_preprint":false},{"year":2021,"finding":"Cocrystal structures of the BPTF bromodomain with small molecule inhibitors DC-BPi-07 and DC-BPi-11 were determined, demonstrating the rational basis for high-affinity (>100-fold selective over other BRD targets) inhibition at the atomic level.","method":"X-ray cocrystallography, biochemical IC50 assays, selectivity profiling","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cocrystal structures of two inhibitors with functional binding data, single laboratory","pmids":["34375106"],"is_preprint":false},{"year":2020,"finding":"First published cocrystal structures of the BPTF bromodomain with small molecule inhibitors were reported, providing structural validation for ligand binding modes and guiding medicinal chemistry.","method":"X-ray crystallography of BPTF bromodomain:ligand complexes, PrOF NMR, SPR, AlphaScreen","journal":"Organic & biomolecular chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures cross-validated with three complementary biophysical assays","pmids":["32588860"],"is_preprint":false},{"year":2025,"finding":"Nucleosome Mass Spectrometry (Nuc-MS) directly revealed that the BPTF PHD-bromodomain tandem reader requires coincident H3K4me3, K9ac, K14ac, and K18ac for effective nucleosome engagement, demonstrating that multivalent combinatorial histone PTM reading is required for productive BPTF-nucleosome interaction.","method":"Native top-down nucleosome mass spectrometry (Nuc-MS) disassembly of CAP:nucleosome complexes, histone proteoform identification","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — novel direct readout method on native nucleosomes; single laboratory, preprint, no mutagenesis validation","pmids":["bio_10.1101_2025.05.01.651740"],"is_preprint":true}],"current_model":"BPTF is the largest subunit of the NURF ATP-dependent chromatin remodeling complex, where its C-terminal PHD finger specifically reads H3K4me3 (and requires additional histone acetylation marks for full nucleosome engagement) to recruit the NURF complex to target loci, while its bromodomain engages acetylated histones including H4K16ac and H2A.Z; together with ISWI/SMARCA1, BPTF drives nucleosome sliding to increase chromatin accessibility, and it acts as a transcriptional coactivator by physically interacting with sequence-specific factors including c-MYC, MYCN, Smad2, NF-κB p50, AR, FOXA1, and ZF87/MAZ to regulate gene expression programs essential for stem cell self-renewal, embryonic development, immune cell homeostasis, and oncogenesis."},"narrative":{"mechanistic_narrative":"BPTF is the largest subunit of the NURF ATP-dependent chromatin-remodeling complex and functions as a histone-modification reader that couples recognition of chromatin marks to nucleosome sliding and targeted transcriptional activation [PMID:11583616, PMID:16728978]. Its C-terminal PHD finger specifically reads H3K4me3 through anti-parallel beta-sheet engagement of the H3 tail, discriminating against lower methylation states [PMID:16728978], while its bromodomain engages acetylated histones including diacetylated H2A.Z [PMID:28771339, PMID:40864556]; productive nucleosome engagement requires multivalent reading of coincident H3K4me3 and histone acetylation, and is modulated by H3-tail/DNA electrostatics within the nucleosome [PMID:bio_10.1101_2025.05.01.651740, PMID:29648537]. Through the NURF ISWI/SMARCA1 ATPase, BPTF drives nucleosome repositioning to increase chromatin accessibility at promoters and enhancers [PMID:11583616, PMID:41381516], with strongest activity at broad Set1-dependent H3K4me3 loci [PMID:40069606]. BPTF acts as a transcriptional coactivator by physically partnering with sequence-specific factors—Smad2, c-MYC/MYCN, AR-FOXA1, NF-κB p50, and ZF87/MAZ—to direct context-specific gene programs governing visceral endoderm and trophoblast development, stem-cell self-renewal, immune-cell homeostasis, and oncogenesis [PMID:18974875, PMID:26729287, PMID:41381516, PMID:31934287, PMID:38405949]. Genetic ablation of Bptf is embryonic-lethal, disrupting distal visceral endoderm and ectoplacental cone formation, and conditional loss impairs hematopoietic and mammary stem-cell maintenance and Treg-dependent immune tolerance [PMID:18974875, PMID:18794365, PMID:29456179, PMID:28579392, PMID:27799308]. In cancer, BPTF is required for c-MYC-driven proliferation and lymphomagenesis, AR signaling in prostate cancer, and immune evasion via repression of antigen-processing and NCR-ligand pathways, and its bromodomain and PHD finger are druggable by selective small molecules and PROTAC degraders [PMID:26729287, PMID:32451433, PMID:41381516, PMID:27651309, PMID:39935175, PMID:34515477].","teleology":[{"year":1999,"claim":"Established that BPTF/FAC1 DNA-binding activity is dynamically regulated, indicating its chromatin engagement is signal-responsive rather than constitutive.","evidence":"EMSA with phosphatase treatment and phosphatase inhibition of neuroblastoma nuclear extracts","pmids":["10403843"],"confidence":"Medium","gaps":["No phosphorylation site identified","Kinase/phosphatase not defined","Link to NURF function untested"]},{"year":2000,"claim":"Identified the first sequence-specific transcription factor partner of BPTF, framing it as a modulator of factor-driven transcription.","evidence":"Yeast two-hybrid, in vitro pulldown, deletion mapping, and reporter assay with ZF87/MAZ","pmids":["10727212"],"confidence":"Medium","gaps":["Interaction not validated in chromatin context","No genome-wide targets defined","Relationship to NURF complex unclear at the time"]},{"year":2001,"claim":"Defined the ortholog NURF301 as the largest NURF subunit and showed it plus the ISWI ATPase suffice for nucleosome sliding, establishing the core remodeling mechanism and a basis for factor-targeted recruitment.","evidence":"Recombinant reconstitution of NURF complexes and nucleosome sliding assays in Drosophila","pmids":["11583616"],"confidence":"High","gaps":["Drosophila ortholog, not human BPTF","Recruitment to specific loci not demonstrated","Histone-mark dependence not yet mapped"]},{"year":2006,"claim":"Solved the molecular basis of how BPTF reads chromatin, showing the PHD finger specifically recognizes H3K4me3, linking an activating histone mark to NURF recruitment.","evidence":"X-ray crystallography, NMR, peptide binding and PHD point mutagenesis","pmids":["16728978"],"confidence":"High","gaps":["Binding shown on peptides, not nucleosomes","Functional consequence of recruitment not tested here","Role of bromodomain not addressed"]},{"year":2006,"claim":"Placed the NURF complex genetically within developmental signaling, linking it to Rb/Ras-controlled cell-fate decisions.","evidence":"Genetic suppressor screen and epistasis analysis in C. elegans (NURF-1/ISW-1)","pmids":["16774993"],"confidence":"Medium","gaps":["Ortholog, not human BPTF","Direct target genes not identified","Molecular mechanism inferred genetically"]},{"year":2008,"claim":"Demonstrated that BPTF is essential for early mammalian development and acts through TGF-β/Smad transcription factors, connecting chromatin remodeling to a developmental signaling pathway.","evidence":"Bptf knockout mice, histology, lineage markers, microarray, Smad co-IP; separate KO showing trophoblast/ectoplacental cone requirement","pmids":["18974875","18794365"],"confidence":"High","gaps":["Direct Smad-target genes at chromatin not fully mapped","Tissue-specific versus global requirement not resolved","Smad interaction surface on BPTF undefined"]},{"year":2009,"claim":"Showed that the histone-reading C-terminal module (PHD+bromodomain) is functionally required in vivo, separating reader-dependent from reader-independent NURF activities.","evidence":"Drosophila NURF301 isoform mutants with spermatocyte arrest and expression profiling","pmids":["19629165"],"confidence":"High","gaps":["Drosophila ortholog","Direct mark-dependence of target genes not shown","Mammalian isoform relevance untested"]},{"year":2015,"claim":"Linked BPTF-Smad2 cooperation to a specific target gene program, demonstrating that BPTF recruitment lowers nucleosome density to activate transcription.","evidence":"Zebrafish bptf knockdown, Bptf/p-Smad2 co-IP, ChIP and nucleosome occupancy at wnt8a","pmids":["26041917"],"confidence":"High","gaps":["Ortholog system","Generality beyond wnt8a not established","Direct PHD/mark requirement at promoter not tested"]},{"year":2015,"claim":"Validated the BPTF bromodomain as a selective druggable target, opening chemical-biology approaches to NURF function.","evidence":"19F NMR screening, fluorescence anisotropy and cell-based reporter for inhibitor AU1","pmids":["26158404"],"confidence":"Medium","gaps":["Modest affinity (Kd 2.8 μM)","On-target cellular specificity limited","Endogenous bromodomain ligand not defined here"]},{"year":2016,"claim":"Established BPTF as a required cofactor for the c-MYC oncogenic program, linking NURF-driven chromatin accessibility to MYC recruitment and proliferation.","evidence":"Reciprocal Co-IP, c-MYC ChIP, ATAC-seq, Bptf-null MEFs, in vivo pancreatic model","pmids":["26729287"],"confidence":"High","gaps":["Whether MYC requires the PHD/bromodomain reader function untested here","Selective effect on proliferation vs apoptosis arm mechanism unclear","Direct BPTF-MYC interface undefined"]},{"year":2016,"claim":"Extended the coactivator role to additional transcription factors and immune homeostasis, showing BPTF maintains MITF survival signaling and Treg-dependent tolerance.","evidence":"MITF ChIP/reporter and BPTF rescue in melanoma; Treg- and T-cell-specific Bptf conditional knockouts","pmids":["27185926","27799308"],"confidence":"Medium","gaps":["Direct BPTF target genes in Tregs not mapped","MITF-BPTF axis is a regulatory feedback, mechanism upstream of chromatin unclear","Foxp3 regulation by BPTF not shown to be direct"]},{"year":2017,"claim":"Defined BPTF as a driver of tumor immune evasion through transcriptional control of antigen processing and NK-ligand pathways, with epistatic in vivo validation.","evidence":"BPTF gain/loss with HPSE regulation and NCR1 blocking; ChIP at PSMB8/9 and TAP1/2 with ONX-0914 epistasis; ATAC-seq and self-renewal assays in mammary epithelium","pmids":["28969075","27651309","28579392"],"confidence":"Medium","gaps":["Whether BPTF directly represses or indirectly modulates these loci varies by study","Mark dependence of immune-gene regulation untested","Single-laboratory findings per target"]},{"year":2018,"claim":"Demonstrated cell-intrinsic requirement of BPTF for adult stem-cell maintenance, connecting NURF-driven accessibility to stemness transcription factor programs.","evidence":"Conditional Bptf knockout in hematopoiesis with transplantation, RNA-seq and ATAC-seq at stemness loci; HCC hTERT regulation","pmids":["29456179","30419422"],"confidence":"Medium","gaps":["Direct versus indirect regulation of stemness TFs not fully resolved","hTERT regulation relies on knockdown correlation","Reader-domain dependence not tested"]},{"year":2018,"claim":"Refined the reader mechanism by showing the nucleosomal context, not the isolated peptide, governs PHD engagement via H3-tail/DNA electrostatics.","evidence":"NMR, MD simulations and nucleosome binding with modified/mutant H3 tails","pmids":["29648537"],"confidence":"High","gaps":["PTM crosstalk partners in vivo not enumerated","Effect on remodeling output not measured","Single-study biophysics"]},{"year":2019,"claim":"Broadened the partner repertoire to NF-κB p50, showing BPTF is required for p50 promoter binding and inflammatory gene activation.","evidence":"DNA pulldown/MS, ChIP, BPTF/p50 Co-IP and knockdown at COX-2 promoter in lung cancer","pmids":["31934287"],"confidence":"Medium","gaps":["Single locus (COX-2) focus","Direct interaction surface undefined","Generality to other NF-κB targets untested"]},{"year":2020,"claim":"Provided genetic in vivo proof that BPTF is required for c-MYC-driven lymphomagenesis and modulates the MYC/NF-κB balance.","evidence":"Eμ-Myc mouse with Bptf heterozygous deletion, tumor profiling and pathway IHC; first BPTF bromodomain cocrystal structures reported","pmids":["32451433","32588860"],"confidence":"Medium","gaps":["Mechanism of NF-κB elevation upon BPTF loss unclear","Heterozygous (not null) tumor analysis","Structural ligand binding modes not yet linked to cellular efficacy"]},{"year":2021,"claim":"Delivered atomic-resolution inhibitor structures enabling potent, selective BPTF bromodomain chemistry, and connected BPTF to an m6A-regulated oncogenic enhancer program.","evidence":"Cocrystal structures with BZ1, DC-BPi series (ITC/SPR/IC50); MeRIP/ChIP/ATAC-seq with METTL14 axis in renal carcinoma","pmids":["34515477","34375106","33664855"],"confidence":"High","gaps":["In vivo efficacy of structurally-defined inhibitors not established here","How BPTF builds super-enhancers mechanistically unresolved","ENO2/SRC regulation directness not fully shown"]},{"year":2022,"claim":"Defined BPTF as a node in chemoresistance and cell-cycle control via c-MYC and Cdc25A, with epistatic rescue establishing causality.","evidence":"ChIP at Cdc25A and ABC-transporter promoters, gemcitabine sensitivity, rescue experiments and xenografts in colorectal and pancreatic cancer; NURF301-insulator ChIP-seq in Drosophila","pmids":["35932692","35326669","35819192"],"confidence":"Medium","gaps":["Whether reader domains are required for these target genes untested","Insulator role demonstrated only in Drosophila","Single-laboratory findings"]},{"year":2024,"claim":"Mapped BPTF cooperation with MYCN and core regulatory circuitry transcription factors at promoters and super-enhancers, and characterized a NUP98-BPTF oncogenic fusion mechanism.","evidence":"IP/MS and ChIP-seq in neuroblastoma (preprint); inducible NUP98-BPTF transformation with ChIP at PIM1 and pathway epistasis","pmids":["38405949","38940430"],"confidence":"Medium","gaps":["Neuroblastoma data in preprint, single laboratory","Fusion mechanism may diverge from wild-type BPTF function","Direct binding interfaces undefined"]},{"year":2025,"claim":"Resolved the reader logic as multivalent combinatorial PTM recognition and extended BPTF function to AR-FOXA1 prostate signaling, NK-mediated tumor immunity, mammary metastasis, and Set1-H3K4me3-dependent transcription.","evidence":"Nuc-MS combinatorial PTM mapping (preprint); AR-FOXA1 Co-IP/ChIP-seq/ATAC-seq with bromodomain inhibitor; PROTAC degradation and NK cytotoxicity in HCC; conditional KO mammary tumor epistasis; planarian bptf/Set1 epistasis; H2A.Z bromodomain photo-crosslinking","pmids":["41381516","39935175","41093864","40069606","40864556"],"confidence":"High","gaps":["Nuc-MS combinatorial requirement lacks mutagenesis validation (preprint)","Tissue-specific partner selection rules unresolved","Mechanism linking BPTF loss to ERα elevation incompletely defined"]},{"year":null,"claim":"How BPTF integrates its histone-reader specificity with selection of specific transcription-factor partners to produce context-dependent gene programs across development, immunity, and distinct cancers remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of how the PHD/bromodomain reader output dictates which sequence-specific partner is engaged at a given locus","Whether reader-domain inhibitors phenocopy genetic loss across contexts untested","Structural basis of BPTF interaction with transcription factor partners undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,2,20,26,38]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,7,17,24,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,7,24]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[10,21,17]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,24]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17,24,7]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2,38]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,7,17,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5,6,14,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,12,16,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,23,24,28,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,24]}],"complexes":["NURF"],"partners":["SMARCA1","MYC","MYCN","SMAD2","AR","FOXA1","NFKB1","MAZ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12830","full_name":"Nucleosome-remodeling factor subunit BPTF","aliases":["Bromodomain and PHD finger-containing transcription factor","Fetal Alz-50 clone 1 protein","Fetal Alzheimer antigen"],"length_aa":3046,"mass_kda":338.3,"function":"Regulatory subunit of the ATP-dependent NURF-1 and NURF-5 ISWI chromatin remodeling complexes, which form ordered nucleosome arrays on chromatin and facilitate access to DNA during DNA-templated processes such as DNA replication, transcription, and repair (PubMed:14609955, PubMed:28801535). The NURF-1 ISWI chromatin remodeling complex has a lower ATP hydrolysis rate than the NURF-5 ISWI chromatin remodeling complex (PubMed:28801535). Within the NURF-1 ISWI chromatin-remodeling complex, binds to the promoters of En1 and En2 to positively regulate their expression and promote brain development (PubMed:14609955). Histone-binding protein which binds to H3 tails trimethylated on 'Lys-4' (H3K4me3), which mark transcription start sites of active genes (PubMed:16728976, PubMed:16728978). Binds to histone H3 tails dimethylated on 'Lys-4' (H3K4Me2) to a lesser extent (PubMed:16728976, PubMed:16728978, PubMed:18042461). May also regulate transcription through direct binding to DNA or transcription factors (PubMed:10575013)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q12830/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/BPTF","classification":"Common Essential","n_dependent_lines":853,"n_total_lines":1208,"dependency_fraction":0.7061258278145696},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SMARCA1","stoichiometry":4.0},{"gene":"SMARCA5","stoichiometry":4.0},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/BPTF","total_profiled":1310},"omim":[{"mim_id":"617755","title":"NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND DISTAL LIMB ANOMALIES; NEDDFL","url":"https://www.omim.org/entry/617755"},{"mim_id":"617215","title":"BPTF-ASSOCIATED CHROMATIN COMPLEX COMPONENT 1; BACC1","url":"https://www.omim.org/entry/617215"},{"mim_id":"602810","title":"HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER A; HIST1H3A","url":"https://www.omim.org/entry/602810"},{"mim_id":"601819","title":"BROMODOMAIN PHD FINGER TRANSCRIPTION FACTOR; BPTF","url":"https://www.omim.org/entry/601819"},{"mim_id":"300012","title":"SWI/SNF-RELATED, MATRIX-ASSOCIATED, ACTIN-DEPENDENT REGULATOR OF CHROMATIN, SUBFAMILY A, MEMBER 1; SMARCA1","url":"https://www.omim.org/entry/300012"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/BPTF"},"hgnc":{"alias_symbol":["FAC1","NURF301"],"prev_symbol":["FALZ"]},"alphafold":{"accession":"Q12830","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12830","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BPTF","jax_strain_url":"https://www.jax.org/strain/search?query=BPTF"},"sequence":{"accession":"Q12830","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12830.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12830/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12830"}},"corpus_meta":[{"pmid":"16728978","id":"PMC_16728978","title":"Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of 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Crystal and NMR structures of free and H3K4me3-bound PHD finger established the molecular basis for site-specific readout; mutagenesis identified key specificity-determining residues. BPTF PHD shows preference for K4me3 over K4me2 and discriminates against monomethylated and unmodified H3.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, peptide binding assays, PHD finger point mutagenesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR structures, in vitro binding assays, and mutagenesis of specificity residues in a single rigorous study\",\n      \"pmids\": [\"16728978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NURF301 (the Drosophila ortholog of BPTF) is the largest subunit of the NURF ISWI complex. Reconstitution of partial and full NURF complexes from recombinant proteins demonstrated that NURF301 and the ISWI ATPase are necessary and sufficient for accurate and efficient nucleosome sliding. An HMGA/HMGI(Y)-like domain of NURF301 facilitates sliding, indicating a role for DNA conformational changes. NURF301 also physically interacts with sequence-specific transcription factors, providing a basis for targeted recruitment.\",\n      \"method\": \"Recombinant protein reconstitution of NURF complexes, nucleosome sliding assays, protein interaction assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution from recombinant components plus functional nucleosome sliding assay, multiple orthogonal experiments\",\n      \"pmids\": [\"11583616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In the full nucleosomal context, histone H3 tails interact robustly and dynamically with nucleosomal DNA, substantially reducing BPTF PHD finger association with H3K4me3. Altering H3 tail electrostatics via modification or mutation increases PHD finger accessibility. This demonstrates that post-translational modification crosstalk can regulate BPTF PHD binding by modulating nucleosome conformation.\",\n      \"method\": \"NMR spectroscopy, molecular dynamics (MD) simulations, nucleosome binding assays with modified H3 tails\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR and MD simulations with multiple H3 variants in a single rigorous study with functional conclusions\",\n      \"pmids\": [\"29648537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Drosophila NURF301 (BPTF ortholog) is expressed as alternative splice isoforms encoding functionally distinct NURF complexes. Full-length NURF301 contains a C-terminal bromodomain and PHD finger that bind H3K4me3 and H4K16Ac respectively; a truncated isoform lacking these domains assembles a NURF complex deficient in H3K4me3 and H4K16Ac recognition. Mutants lacking C-terminal PHD finger and bromodomain show a spermatocyte arrest phenotype and fail to express spermatid differentiation genes, revealing that the histone-modification-reading isoform is specifically required for spermatogenesis.\",\n      \"method\": \"Genetic analysis of Drosophila NURF301 isoform mutants, microarray expression profiling, phenotypic characterization\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic isoform mutants with specific cellular phenotype plus expression profiling and histone binding domain analysis\",\n      \"pmids\": [\"19629165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Bptf-null mouse embryos fail to establish a functional distal visceral endoderm and are reabsorbed by E8.5, establishing an essential role for BPTF in early embryogenesis. Physical and functional links between the BPTF-containing NURF complex and Smad transcription factors were identified, suggesting BPTF co-regulates TGF-β/Smad pathway targets required for visceral endoderm establishment.\",\n      \"method\": \"Bptf knockout mice, histological analysis, lineage marker immunostaining, microarray, co-immunoprecipitation with Smad factors\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with specific developmental phenotype plus physical interaction with Smad factors in same study\",\n      \"pmids\": [\"18974875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BPTF/FAC1 is essential in the extraembryonic trophoblast lineage for correct development of the ectoplacental cone; null embryos arrest at early gastrula stage (E6.5) with drastically reduced or absent ectoplacental cone, indicating BPTF is required for trophoblast differentiation.\",\n      \"method\": \"Loss-of-function allele knock-in mouse model, histological analysis, lineage marker staining\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with specific trophoblast/ectoplacental cone phenotypic readout\",\n      \"pmids\": [\"18794365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BPTF physically interacts with the chromatin remodeling protein Bptf in zebrafish; Bptf functionally and physically interacts with phospho-Smad2 (activated by non-Nodal TGF-β signaling) to promote wnt8a expression required for neural posteriorization. Bptf and Smad2 directly bind to and activate the wnt8a promoter through recruiting the NURF remodeling complex. Knockdown of bptf increases nucleosome density at the wnt8a promoter.\",\n      \"method\": \"Zebrafish bptf morpholino knockdown, co-immunoprecipitation of Bptf and p-Smad2, ChIP at wnt8a promoter, nucleosome occupancy assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus nucleosome occupancy assay in a single study with genetic loss-of-function phenotype\",\n      \"pmids\": [\"26041917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BPTF physically interacts with c-MYC and is required for full c-MYC transcriptional program activation. BPTF knockdown decreases c-MYC recruitment to DNA and reduces chromatin accessibility at c-MYC target loci. In Bptf-null MEFs, BPTF is necessary for c-MYC-driven proliferation, G1-S progression, and replication stress but not for c-MYC-driven apoptosis. Bptf inactivation in pre-neoplastic pancreatic acinar cells significantly delays tumor development in vivo.\",\n      \"method\": \"Co-immunoprecipitation (c-MYC and BPTF), ChIP (c-MYC at target genes), ATAC-seq/chromatin accessibility assays, Bptf-null MEFs, in vivo pancreatic cancer model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP, chromatin accessibility, clean KO MEFs with specific cell cycle phenotype, in vivo model in one study\",\n      \"pmids\": [\"26729287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In C. elegans, the NURF301 ortholog NURF-1 acts together with ISWI (ISW-1) as a NURF-like complex to promote vulval cell fates and synMuv phenotype. isw-1 and nurf-1 mutations suppress the synMuv phenotype and the multivulva phenotype caused by Ras pathway overactivation, placing the NURF complex genetically downstream/parallel to Rb-like (lin-35) and Ras pathway in vulval fate determination.\",\n      \"method\": \"Genetic suppressor screen in C. elegans, double-mutant epistasis analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis in C. elegans with multiple double-mutant combinations; ortholog, not direct human BPTF experiments\",\n      \"pmids\": [\"16774993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"FAC1 (alias of BPTF) protein interacts with the Myc-associated zinc finger protein ZF87/MAZ as shown by yeast two-hybrid and in vitro pulldown with recombinant protein. The interaction domain was mapped to the NLS/NES region of FAC1. FAC1 reduces ZF87/MAZ-induced transcriptional activation of the SV40 promoter in a dose-dependent manner in NIH3T3 cells; a FAC1 deletion mutant lacking the ZF87/MAZ interaction domain does not alter ZF87/MAZ activation.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro pulldown with recombinant proteins, deletion mutagenesis, co-transfection luciferase reporter assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by in vitro pulldown, deletion mutagenesis, and functional transcription reporter in single study\",\n      \"pmids\": [\"10727212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"FAC1 (alias of BPTF) DNA-binding activity is regulated by phosphorylation: phosphatase treatment of neuroblastoma nuclear extracts reduces FAC1 DNA-binding affinity, and inhibition of cellular serine/threonine phosphatases increases FAC1 DNA-binding activity.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA/DNA-binding assay), phosphatase treatment of nuclear extracts, pharmacological phosphatase inhibition\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — two orthogonal biochemical approaches (phosphatase treatment + inhibitor) but single laboratory, no site identification\",\n      \"pmids\": [\"10403843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MITF directly binds the BPTF promoter (demonstrated by ChIP) and transcriptionally activates BPTF expression (demonstrated by luciferase reporter assay). MITF overexpression upregulates BPTF and BPTF-regulated genes including BCL2; MITF silencing downregulates BPTF. Rescue of MITF silencing-induced growth suppression by BPTF cDNA overexpression demonstrates BPTF transduces MITF-driven prosurvival signals.\",\n      \"method\": \"ChIP of MITF at BPTF promoter, luciferase reporter assay, shRNA silencing, BPTF cDNA rescue experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus epistatic rescue in single study, single laboratory\",\n      \"pmids\": [\"27185926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BPTF occupies heparanase (HPSE) regulatory elements and activates its expression, as established using gain/loss-of-function approaches. Increased heparanase activity reduces cell-surface heparan sulfate proteoglycans (HSPGs), which are NCR co-ligands, thereby suppressing NK cell cytolytic activity toward tumor cells. Blocking NCR1 in vivo rescues BPTF-KD tumor weights, confirming the pathway.\",\n      \"method\": \"BPTF gain- and loss-of-function in syngeneic mouse models, HPSE promoter occupancy (implied ChIP), NK cell cytolytic assays, NCR1 blocking in vivo\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with defined mechanistic pathway and in vivo epistasis with NCR1 blocking, single lab\",\n      \"pmids\": [\"28969075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BPTF depletion in tumor cells enhances antigen processing by derepressing immunoproteasome subunits PSMB8 and PSMB9 and antigen transporter genes TAP1 and TAP2. ChIP/direct promoter occupancy experiments showed NURF directly regulates these gene loci. The PSMB8 inhibitor ONX-0914 reversed the enhanced CD8+ T-cell killing caused by BPTF ablation, confirming a role for the immunoproteasome.\",\n      \"method\": \"BPTF shRNA knockdown, ChIP of NURF at PSMB8/PSMB9/TAP1/TAP2 promoters, pharmacological epistasis with ONX-0914, CD8+ T-cell cytolytic assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus pharmacological epistasis plus functional immune assay, single laboratory\",\n      \"pmids\": [\"27651309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BPTF PHD finger preferentially binds H3K4me3 and recruits the NURF complex to chromatin, and depletion of BPTF reduces chromatin accessibility at enhancer regions in mammary epithelial cells. BPTF is essential for mammary gland stem cell (MaSC) self-renewal and differentiation; BPTF depletion arrests cells at a stage associated with an inability to achieve the luminal cell fate.\",\n      \"method\": \"BPTF KO/KD in mammary epithelial cells, ATAC-seq genome-wide chromatin accessibility, functional MaSC self-renewal assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ATAC-seq plus loss-of-function with specific cellular differentiation phenotype, single laboratory\",\n      \"pmids\": [\"28579392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BPTF is required for the maintenance of hematopoietic stem/progenitor cell (HSPC) population size and long-term HSC function. Hematopoietic-specific knockout of Bptf causes bone marrow failure and anemia. Genome-wide transcriptome profiling showed BPTF loss causes downregulation of HSC stemness transcription factors (Meis1, Pbx1, Mn1, Lmo2) and BPTF potentiates chromatin accessibility of these genes.\",\n      \"method\": \"Conditional Bptf knockout mice, bone marrow transplantation reconstitution assay, RNA-seq, ATAC-seq at stemness gene loci\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific HSC phenotype plus transcriptome and chromatin accessibility profiling, single laboratory\",\n      \"pmids\": [\"29456179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BPTF is critical for T cell homeostasis in a cell-intrinsic manner. Treg cell-specific BPTF deletion leads to reduced Foxp3 expression, increased lymphocyte infiltration in non-lymphoid organs, and a systemic autoimmune syndrome.\",\n      \"method\": \"Conditional Bptf knockout from late DN3/DN4 T cells, Treg-specific Bptf deletion, flow cytometry, histological analysis of organ infiltration\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with specific Foxp3/Treg phenotype, single laboratory\",\n      \"pmids\": [\"27799308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BPTF cooperates with p50 subunit of NF-κB to regulate COX-2 promoter activity and COX-2 expression in lung cancer cells. BPTF was identified as a COX-2 promoter-binding protein; knockdown of BPTF abrogated p50 binding to the COX-2 promoter; inhibition of p50 activity blocked BPTF-dependent COX-2 expression and cell proliferation.\",\n      \"method\": \"Biotin-streptavidin-agarose DNA pulldown of COX-2 promoter, mass spectrometry identification, ChIP, co-immunoprecipitation of BPTF and p50, confocal immunofluorescence, BPTF siRNA knockdown\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DNA pulldown, ChIP, Co-IP with multiple orthogonal methods in single study, single laboratory\",\n      \"pmids\": [\"31934287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BPTF promotes HCC growth by transcriptionally regulating hTERT expression. Knockdown of BPTF suppressed hTERT expression, reduced cancer stem cell marker expression, and inhibited tumor growth in xenograft models.\",\n      \"method\": \"BPTF shRNA knockdown, ChIP (implied for BPTF at hTERT promoter), xenograft mouse model, Western blot for CSC markers\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, loss-of-function with phenotype but mechanistic link to hTERT relies on knockdown correlation rather than direct ChIP validation clearly described\",\n      \"pmids\": [\"30419422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The BPTF bromodomain was identified as a druggable target; AU1 was identified as the first small molecule selective for BPTF bromodomain over Brd4 (Kd = 2.8 μM by 19F NMR). No binding was detected with Brd4. AU1 is active in a cell-based reporter assay.\",\n      \"method\": \"Protein-observed 19F NMR dual screening, fluorescence anisotropy, cell-based reporter assay\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro binding assay (19F NMR) with orthogonal biophysical validation and cell-based functional confirmation\",\n      \"pmids\": [\"26158404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"H2A.Z diacetylated at K4 and K11 directly interacts with the BPTF bromodomain with Kd ~780 μM, as established by PrOF NMR and photo-cross-linking. Specificity for the K4/K11 diacetylation pattern over other combinations was demonstrated biophysically.\",\n      \"method\": \"Protein-observed 19F NMR (PrOF NMR), 1H NMR CPMG experiments, photo-cross-linking, fluorescence anisotropy\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple biophysical methods in a single study confirming weak but specific direct interaction; functional consequences not tested\",\n      \"pmids\": [\"28771339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BPTF binds the Cdc25A promoter (−178/+107 region) and transcriptionally activates Cdc25A to accelerate colorectal cancer cell cycle progression. BPTF itself is transcriptionally regulated by c-Myc. Established by RNA-seq, DNA-pulldown, ChIP, and luciferase reporter assay; Cdc25A overexpression partially reversed BPTF-silencing-induced growth inhibition (epistasis).\",\n      \"method\": \"RNA-seq, DNA pulldown, ChIP at Cdc25A promoter, luciferase reporter assay, siRNA/shRNA knockdown, rescue with Cdc25A overexpression\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus epistatic rescue in single laboratory with multiple orthogonal methods\",\n      \"pmids\": [\"35932692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BPTF is required for c-MYC recruitment to the promoter of ABC-transporters (MDR genes) in pancreatic cancer. BPTF silencing reduces IC50 of gemcitabine in vitro, and its depletion increases intracellular gemcitabine accumulation and DNA damage. ChIP confirmed reduced c-MYC occupancy at ABC-transporter promoters upon BPTF knockdown.\",\n      \"method\": \"BPTF siRNA/shRNA knockdown, ChIP (c-MYC at ABC-transporter promoters), gemcitabine sensitivity assays, DNA damage assays, xenograft models\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional drug sensitivity plus in vivo model, single laboratory\",\n      \"pmids\": [\"35326669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Bptf deletion in aggressive B-cell lymphoma (Eμ-Myc mouse model) delays lymphomagenesis; tumors arising in a Bptf heterozygous background display decreased c-MYC levels, reduced c-MYC pathway activity, and increased NF-κB pathway activation. This defines BPTF as genetically required for c-MYC-driven B-cell lymphomagenesis.\",\n      \"method\": \"Eμ-Myc transgenic mouse with Bptf heterozygous deletion, tumor analysis, gene expression profiling, IHC for c-MYC/NF-κB pathway\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis in in vivo lymphoma model with molecular pathway analysis, single laboratory\",\n      \"pmids\": [\"32451433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BPTF forms a protein complex with androgen receptor (AR) and FOXA1 in prostate cancer. BPTF increases chromatin accessibility via SMARCA1 (catalytic NURF subunit) to facilitate AR binding at promoters, enhancers, and super-enhancers. FOXA1 recruits the BPTF-AR complex to chromatin, while BPTF stabilizes the AR-FOXA1 interaction. BPTF interacts with AR through its bromodomain; a bromodomain inhibitor disrupts this interaction and impairs AR signaling.\",\n      \"method\": \"Co-immunoprecipitation (BPTF, AR, FOXA1), ChIP-seq (BPTF, AR), ATAC-seq (chromatin accessibility), RNA-seq, BPTF bromodomain inhibitor treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with three partners, ChIP-seq, ATAC-seq, functional inhibitor validation in single rigorous study\",\n      \"pmids\": [\"41381516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BPTF PHD finger reads H3K4me3 to protect hepatocellular carcinoma (HCC) cells from NK cell recognition. PROTAC-mediated selective degradation of BPTF directly increases the abundance of natural cytotoxicity receptor ligands on HCC cells, enhancing NK cell cytotoxicity against HCC both in vitro and in vivo.\",\n      \"method\": \"PROTAC degrader, NK cell cytotoxicity assays, surface NCR ligand analysis, in vivo HCC models\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein degradation with direct functional readout (NK ligand surface abundance, cytotoxicity) in vitro and in vivo, single laboratory\",\n      \"pmids\": [\"39935175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BPTF bromodomain directly binds acetylated H2A.Z in a pocket-specific and affinity-dependent manner in vitro (photo-crosslinking with recombinant bromodomain) and enriches endogenous BPTF from nuclear lysates of A549 cells, confirming the interaction occurs in a cellular context, albeit less efficiently than with canonical H4K16ac.\",\n      \"method\": \"Photoaffinity probes with diazirine and biotin tag, SDS-PAGE photo-crosslinking, nuclear lysate pull-down, bottom-up proteomics for H2A.Z acetylation patterns\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted direct photo-crosslinking in vitro plus validation in nuclear lysate, single laboratory\",\n      \"pmids\": [\"40864556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BPTF cooperates with MYCN and MYC in neuroblastoma; immunoprecipitation/mass spectrometry showed BPTF interacts with MYCN and core regulatory circuitry (CRC) transcription factors. Genome-wide distribution analysis revealed BPTF co-localizes with MYCN/MYC at promoters of cell cycle genes and with CRC factors at super-enhancers to regulate cell identity.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry, ChIP-seq (BPTF, MYCN, CRC TFs), bulk RNA-seq, single-cell sequencing, tissue microarrays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP/MS plus ChIP-seq with multiple orthogonal approaches; preprint, single laboratory\",\n      \"pmids\": [\"38405949\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUP98-BPTF fusion protein promotes oncogenic transformation by transcriptionally upregulating PIM1 proto-oncogene via binding to its promoter, leading to activation of MYC and mTORC1 signaling. PIM1 knockdown or mTORC1 inhibition suppressed NUP98-BPTF-induced NIH3T3 transformation. NUP98-BPTF also inactivates the pro-apoptotic protein BAD to enhance leukemia cell survival.\",\n      \"method\": \"Doxycycline-inducible NUP98-BPTF expression, NIH3T3 transformation assay, ChIP at PIM1 promoter, PIM1 shRNA knockdown, pharmacological mTORC1 inhibition, Jurkat T-ALL survival assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus multiple epistasis experiments (KD + pharmacological inhibition) in single laboratory\",\n      \"pmids\": [\"38940430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BPTF regulates trophoblast EMT by directly binding the Slug gene promoter and activating Slug transcription. BPTF knockdown prevented EMT and attenuated trophoblast invasion; Slug and BPTF protein levels were both decreased in villous cytotrophoblasts of recurrent miscarriage patients.\",\n      \"method\": \"ChIP (BPTF at Slug promoter), BPTF knockdown, EMT assays, invasion assays, immunostaining of patient villi\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP experiment plus loss-of-function phenotype, single laboratory, limited mechanistic depth\",\n      \"pmids\": [\"38521110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NURF301 (Drosophila BPTF ortholog) co-localizes genome-wide with gypsy insulator proteins CP190 and Su(Hw) and promotes chromatin association of these insulator proteins at gypsy insulator binding sites, as shown by ChIP-seq. NURF301 physically interacts with gypsy insulator proteins and promotes nucleosome repositioning at insulator sites, contributing to 3D nuclear organization of gypsy insulator binding sites.\",\n      \"method\": \"RNAi screen, ChIP-seq (NURF301, Su(Hw), CP190), physical interaction assays (pulldown/IP with insulator proteins), Oligopaint FISH with immunofluorescence for 3D localization, nucleosome positioning assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq plus physical interaction plus 3D localization data in single study; Drosophila ortholog\",\n      \"pmids\": [\"35819192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"METTL14-mediated m6A modification negatively regulates BPTF mRNA stability, such that METTL14 deficiency leads to BPTF accumulation. Accumulated BPTF remodels the enhancer landscape in renal cell carcinoma, constituting super-enhancers that activate downstream oncogenic targets including ENO2 and SRC, leading to glycolytic reprogramming.\",\n      \"method\": \"MeRIP-seq, RNA-seq, ChIP-seq, ATAC-seq, BPTF knockdown, METTL14 knockout, organoid and xenograft models, BPTF inhibitor AU1 treatment\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus ChIP-seq plus ATAC-seq with multiple loss-of-function approaches and functional validation in organoids and xenografts, single laboratory\",\n      \"pmids\": [\"33664855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of BPTF in mammary tumors results in elevated ERα levels linked with decreased TGF-β activity, leading to tamoxifen-sensitive estrogen-responsive tumors with limited lung metastasis. Loss of ERα is sufficient to restore TGF-β activity and metastatic potential in BPTF-KO tumors, establishing an epistatic relationship between BPTF, TGF-β, and ERα in tumor progression.\",\n      \"method\": \"Conditional BPTF knockout mammary tumor model, ERα/TGF-β functional analysis, ERα loss-of-function rescue experiment, lung metastasis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with specific phenotype and epistatic rescue with ERα loss, single laboratory\",\n      \"pmids\": [\"41093864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BPTF operates at gene promoters and is most effective at facilitating transcription and chromatin accessibility at genes marked by Set1-dependent H3K4me3 peaks (broader peaks) but not MLL1/2-dependent H3K4me3. Loss-of-function phenotype of bptf knockdown in planarian stem cells mimics that of Set1 knockdown, establishing a functional epistatic relationship between BPTF and Set1-H3K4me3 in vivo.\",\n      \"method\": \"BPTF RNAi knockdown in planarian stem cells, ATAC-seq, RNA-seq, Set1 vs MLL1/2 ChIP-seq peak comparison, genetic epistasis (bptf vs set1 knockdown phenotype)\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ATAC-seq plus RNA-seq plus genetic epistasis in a planarian in vivo system; ortholog, single laboratory\",\n      \"pmids\": [\"40069606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Molecular dynamics simulations show that BPTF PHD finger binding to H3K4me3 displaces the H3 tail from nucleosomal DNA, increasing H3 tail flexibility and promoting compensatory binding of the H4 tail to nucleosomal DNA. This redistribution weakens overall DNA-histone hydrogen bonding, suggesting BPTF engagement induces localized nucleosome destabilization. BPTF adopts a compacted conformation upon nucleosome engagement.\",\n      \"method\": \"Molecular dynamics simulations of BPTF PHD finger and bromodomain bound to H3 peptide or full nucleosome\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational simulation only, no experimental validation; mechanistically informative but not experimentally confirmed\",\n      \"pmids\": [\"40616262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cocrystal structures of the BPTF bromodomain with small molecule inhibitors (BZ1 series pyridazinones) were determined, identifying an acidic triad in the binding pocket that guides inhibitor design. BZ1 showed Kd = 6.3 nM and >350-fold selectivity over BET bromodomains.\",\n      \"method\": \"X-ray co-crystallography of BPTF bromodomain:inhibitor complexes, ITC, SPR binding assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cocrystal structures validated with orthogonal biophysical binding assays, defines binding pocket architecture\",\n      \"pmids\": [\"34515477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cocrystal structures of the BPTF bromodomain with small molecule inhibitors DC-BPi-07 and DC-BPi-11 were determined, demonstrating the rational basis for high-affinity (>100-fold selective over other BRD targets) inhibition at the atomic level.\",\n      \"method\": \"X-ray cocrystallography, biochemical IC50 assays, selectivity profiling\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cocrystal structures of two inhibitors with functional binding data, single laboratory\",\n      \"pmids\": [\"34375106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"First published cocrystal structures of the BPTF bromodomain with small molecule inhibitors were reported, providing structural validation for ligand binding modes and guiding medicinal chemistry.\",\n      \"method\": \"X-ray crystallography of BPTF bromodomain:ligand complexes, PrOF NMR, SPR, AlphaScreen\",\n      \"journal\": \"Organic & biomolecular chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures cross-validated with three complementary biophysical assays\",\n      \"pmids\": [\"32588860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nucleosome Mass Spectrometry (Nuc-MS) directly revealed that the BPTF PHD-bromodomain tandem reader requires coincident H3K4me3, K9ac, K14ac, and K18ac for effective nucleosome engagement, demonstrating that multivalent combinatorial histone PTM reading is required for productive BPTF-nucleosome interaction.\",\n      \"method\": \"Native top-down nucleosome mass spectrometry (Nuc-MS) disassembly of CAP:nucleosome complexes, histone proteoform identification\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — novel direct readout method on native nucleosomes; single laboratory, preprint, no mutagenesis validation\",\n      \"pmids\": [\"bio_10.1101_2025.05.01.651740\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"BPTF is the largest subunit of the NURF ATP-dependent chromatin remodeling complex, where its C-terminal PHD finger specifically reads H3K4me3 (and requires additional histone acetylation marks for full nucleosome engagement) to recruit the NURF complex to target loci, while its bromodomain engages acetylated histones including H4K16ac and H2A.Z; together with ISWI/SMARCA1, BPTF drives nucleosome sliding to increase chromatin accessibility, and it acts as a transcriptional coactivator by physically interacting with sequence-specific factors including c-MYC, MYCN, Smad2, NF-κB p50, AR, FOXA1, and ZF87/MAZ to regulate gene expression programs essential for stem cell self-renewal, embryonic development, immune cell homeostasis, and oncogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BPTF is the largest subunit of the NURF ATP-dependent chromatin-remodeling complex and functions as a histone-modification reader that couples recognition of chromatin marks to nucleosome sliding and targeted transcriptional activation [#1, #0]. Its C-terminal PHD finger specifically reads H3K4me3 through anti-parallel beta-sheet engagement of the H3 tail, discriminating against lower methylation states [#0], while its bromodomain engages acetylated histones including diacetylated H2A.Z [#20, #26]; productive nucleosome engagement requires multivalent reading of coincident H3K4me3 and histone acetylation, and is modulated by H3-tail/DNA electrostatics within the nucleosome [#38, #2]. Through the NURF ISWI/SMARCA1 ATPase, BPTF drives nucleosome repositioning to increase chromatin accessibility at promoters and enhancers [#1, #24], with strongest activity at broad Set1-dependent H3K4me3 loci [#33]. BPTF acts as a transcriptional coactivator by physically partnering with sequence-specific factors—Smad2, c-MYC/MYCN, AR-FOXA1, NF-\\u03baB p50, and ZF87/MAZ—to direct context-specific gene programs governing visceral endoderm and trophoblast development, stem-cell self-renewal, immune-cell homeostasis, and oncogenesis [#4, #7, #24, #17, #27]. Genetic ablation of Bptf is embryonic-lethal, disrupting distal visceral endoderm and ectoplacental cone formation, and conditional loss impairs hematopoietic and mammary stem-cell maintenance and Treg-dependent immune tolerance [#4, #5, #15, #14, #16]. In cancer, BPTF is required for c-MYC-driven proliferation and lymphomagenesis, AR signaling in prostate cancer, and immune evasion via repression of antigen-processing and NCR-ligand pathways, and its bromodomain and PHD finger are druggable by selective small molecules and PROTAC degraders [#7, #23, #24, #13, #25, #35].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that BPTF/FAC1 DNA-binding activity is dynamically regulated, indicating its chromatin engagement is signal-responsive rather than constitutive.\",\n      \"evidence\": \"EMSA with phosphatase treatment and phosphatase inhibition of neuroblastoma nuclear extracts\",\n      \"pmids\": [\"10403843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No phosphorylation site identified\", \"Kinase/phosphatase not defined\", \"Link to NURF function untested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified the first sequence-specific transcription factor partner of BPTF, framing it as a modulator of factor-driven transcription.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pulldown, deletion mapping, and reporter assay with ZF87/MAZ\",\n      \"pmids\": [\"10727212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction not validated in chromatin context\", \"No genome-wide targets defined\", \"Relationship to NURF complex unclear at the time\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the ortholog NURF301 as the largest NURF subunit and showed it plus the ISWI ATPase suffice for nucleosome sliding, establishing the core remodeling mechanism and a basis for factor-targeted recruitment.\",\n      \"evidence\": \"Recombinant reconstitution of NURF complexes and nucleosome sliding assays in Drosophila\",\n      \"pmids\": [\"11583616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Drosophila ortholog, not human BPTF\", \"Recruitment to specific loci not demonstrated\", \"Histone-mark dependence not yet mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Solved the molecular basis of how BPTF reads chromatin, showing the PHD finger specifically recognizes H3K4me3, linking an activating histone mark to NURF recruitment.\",\n      \"evidence\": \"X-ray crystallography, NMR, peptide binding and PHD point mutagenesis\",\n      \"pmids\": [\"16728978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding shown on peptides, not nucleosomes\", \"Functional consequence of recruitment not tested here\", \"Role of bromodomain not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed the NURF complex genetically within developmental signaling, linking it to Rb/Ras-controlled cell-fate decisions.\",\n      \"evidence\": \"Genetic suppressor screen and epistasis analysis in C. elegans (NURF-1/ISW-1)\",\n      \"pmids\": [\"16774993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog, not human BPTF\", \"Direct target genes not identified\", \"Molecular mechanism inferred genetically\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that BPTF is essential for early mammalian development and acts through TGF-\\u03b2/Smad transcription factors, connecting chromatin remodeling to a developmental signaling pathway.\",\n      \"evidence\": \"Bptf knockout mice, histology, lineage markers, microarray, Smad co-IP; separate KO showing trophoblast/ectoplacental cone requirement\",\n      \"pmids\": [\"18974875\", \"18794365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Smad-target genes at chromatin not fully mapped\", \"Tissue-specific versus global requirement not resolved\", \"Smad interaction surface on BPTF undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that the histone-reading C-terminal module (PHD+bromodomain) is functionally required in vivo, separating reader-dependent from reader-independent NURF activities.\",\n      \"evidence\": \"Drosophila NURF301 isoform mutants with spermatocyte arrest and expression profiling\",\n      \"pmids\": [\"19629165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Drosophila ortholog\", \"Direct mark-dependence of target genes not shown\", \"Mammalian isoform relevance untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked BPTF-Smad2 cooperation to a specific target gene program, demonstrating that BPTF recruitment lowers nucleosome density to activate transcription.\",\n      \"evidence\": \"Zebrafish bptf knockdown, Bptf/p-Smad2 co-IP, ChIP and nucleosome occupancy at wnt8a\",\n      \"pmids\": [\"26041917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ortholog system\", \"Generality beyond wnt8a not established\", \"Direct PHD/mark requirement at promoter not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Validated the BPTF bromodomain as a selective druggable target, opening chemical-biology approaches to NURF function.\",\n      \"evidence\": \"19F NMR screening, fluorescence anisotropy and cell-based reporter for inhibitor AU1\",\n      \"pmids\": [\"26158404\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Modest affinity (Kd 2.8 \\u03bcM)\", \"On-target cellular specificity limited\", \"Endogenous bromodomain ligand not defined here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established BPTF as a required cofactor for the c-MYC oncogenic program, linking NURF-driven chromatin accessibility to MYC recruitment and proliferation.\",\n      \"evidence\": \"Reciprocal Co-IP, c-MYC ChIP, ATAC-seq, Bptf-null MEFs, in vivo pancreatic model\",\n      \"pmids\": [\"26729287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYC requires the PHD/bromodomain reader function untested here\", \"Selective effect on proliferation vs apoptosis arm mechanism unclear\", \"Direct BPTF-MYC interface undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the coactivator role to additional transcription factors and immune homeostasis, showing BPTF maintains MITF survival signaling and Treg-dependent tolerance.\",\n      \"evidence\": \"MITF ChIP/reporter and BPTF rescue in melanoma; Treg- and T-cell-specific Bptf conditional knockouts\",\n      \"pmids\": [\"27185926\", \"27799308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct BPTF target genes in Tregs not mapped\", \"MITF-BPTF axis is a regulatory feedback, mechanism upstream of chromatin unclear\", \"Foxp3 regulation by BPTF not shown to be direct\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined BPTF as a driver of tumor immune evasion through transcriptional control of antigen processing and NK-ligand pathways, with epistatic in vivo validation.\",\n      \"evidence\": \"BPTF gain/loss with HPSE regulation and NCR1 blocking; ChIP at PSMB8/9 and TAP1/2 with ONX-0914 epistasis; ATAC-seq and self-renewal assays in mammary epithelium\",\n      \"pmids\": [\"28969075\", \"27651309\", \"28579392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether BPTF directly represses or indirectly modulates these loci varies by study\", \"Mark dependence of immune-gene regulation untested\", \"Single-laboratory findings per target\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated cell-intrinsic requirement of BPTF for adult stem-cell maintenance, connecting NURF-driven accessibility to stemness transcription factor programs.\",\n      \"evidence\": \"Conditional Bptf knockout in hematopoiesis with transplantation, RNA-seq and ATAC-seq at stemness loci; HCC hTERT regulation\",\n      \"pmids\": [\"29456179\", \"30419422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect regulation of stemness TFs not fully resolved\", \"hTERT regulation relies on knockdown correlation\", \"Reader-domain dependence not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Refined the reader mechanism by showing the nucleosomal context, not the isolated peptide, governs PHD engagement via H3-tail/DNA electrostatics.\",\n      \"evidence\": \"NMR, MD simulations and nucleosome binding with modified/mutant H3 tails\",\n      \"pmids\": [\"29648537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PTM crosstalk partners in vivo not enumerated\", \"Effect on remodeling output not measured\", \"Single-study biophysics\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened the partner repertoire to NF-\\u03baB p50, showing BPTF is required for p50 promoter binding and inflammatory gene activation.\",\n      \"evidence\": \"DNA pulldown/MS, ChIP, BPTF/p50 Co-IP and knockdown at COX-2 promoter in lung cancer\",\n      \"pmids\": [\"31934287\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single locus (COX-2) focus\", \"Direct interaction surface undefined\", \"Generality to other NF-\\u03baB targets untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided genetic in vivo proof that BPTF is required for c-MYC-driven lymphomagenesis and modulates the MYC/NF-\\u03baB balance.\",\n      \"evidence\": \"E\\u03bc-Myc mouse with Bptf heterozygous deletion, tumor profiling and pathway IHC; first BPTF bromodomain cocrystal structures reported\",\n      \"pmids\": [\"32451433\", \"32588860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of NF-\\u03baB elevation upon BPTF loss unclear\", \"Heterozygous (not null) tumor analysis\", \"Structural ligand binding modes not yet linked to cellular efficacy\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Delivered atomic-resolution inhibitor structures enabling potent, selective BPTF bromodomain chemistry, and connected BPTF to an m6A-regulated oncogenic enhancer program.\",\n      \"evidence\": \"Cocrystal structures with BZ1, DC-BPi series (ITC/SPR/IC50); MeRIP/ChIP/ATAC-seq with METTL14 axis in renal carcinoma\",\n      \"pmids\": [\"34515477\", \"34375106\", \"33664855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy of structurally-defined inhibitors not established here\", \"How BPTF builds super-enhancers mechanistically unresolved\", \"ENO2/SRC regulation directness not fully shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined BPTF as a node in chemoresistance and cell-cycle control via c-MYC and Cdc25A, with epistatic rescue establishing causality.\",\n      \"evidence\": \"ChIP at Cdc25A and ABC-transporter promoters, gemcitabine sensitivity, rescue experiments and xenografts in colorectal and pancreatic cancer; NURF301-insulator ChIP-seq in Drosophila\",\n      \"pmids\": [\"35932692\", \"35326669\", \"35819192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether reader domains are required for these target genes untested\", \"Insulator role demonstrated only in Drosophila\", \"Single-laboratory findings\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped BPTF cooperation with MYCN and core regulatory circuitry transcription factors at promoters and super-enhancers, and characterized a NUP98-BPTF oncogenic fusion mechanism.\",\n      \"evidence\": \"IP/MS and ChIP-seq in neuroblastoma (preprint); inducible NUP98-BPTF transformation with ChIP at PIM1 and pathway epistasis\",\n      \"pmids\": [\"38405949\", \"38940430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuroblastoma data in preprint, single laboratory\", \"Fusion mechanism may diverge from wild-type BPTF function\", \"Direct binding interfaces undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the reader logic as multivalent combinatorial PTM recognition and extended BPTF function to AR-FOXA1 prostate signaling, NK-mediated tumor immunity, mammary metastasis, and Set1-H3K4me3-dependent transcription.\",\n      \"evidence\": \"Nuc-MS combinatorial PTM mapping (preprint); AR-FOXA1 Co-IP/ChIP-seq/ATAC-seq with bromodomain inhibitor; PROTAC degradation and NK cytotoxicity in HCC; conditional KO mammary tumor epistasis; planarian bptf/Set1 epistasis; H2A.Z bromodomain photo-crosslinking\",\n      \"pmids\": [\"41381516\", \"39935175\", \"41093864\", \"40069606\", \"40864556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuc-MS combinatorial requirement lacks mutagenesis validation (preprint)\", \"Tissue-specific partner selection rules unresolved\", \"Mechanism linking BPTF loss to ER\\u03b1 elevation incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BPTF integrates its histone-reader specificity with selection of specific transcription-factor partners to produce context-dependent gene programs across development, immunity, and distinct cancers remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of how the PHD/bromodomain reader output dictates which sequence-specific partner is engaged at a given locus\", \"Whether reader-domain inhibitors phenocopy genetic loss across contexts untested\", \"Structural basis of BPTF interaction with transcription factor partners undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 2, 20, 26, 38]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 7, 17, 24, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 7, 24]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [10, 21, 17]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17, 24, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2, 38]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 7, 17, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 6, 14, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 12, 16, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 23, 24, 28, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 24]}\n    ],\n    \"complexes\": [\"NURF\"],\n    \"partners\": [\"SMARCA1\", \"MYC\", \"MYCN\", \"SMAD2\", \"AR\", \"FOXA1\", \"NFKB1\", \"MAZ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}