{"gene":"CREBBP","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2011,"finding":"CREBBP mutations in relapsed ALL cluster in the histone acetyltransferase (HAT) domain, resulting in truncated alleles or deleterious substitutions that impair histone acetylation and transcriptional regulation of CREBBP target genes, including glucocorticoid-responsive genes.","method":"Resequencing of 300 genes in matched diagnosis/relapse ALL samples, functional assays of HAT activity and glucocorticoid target gene expression in mutant cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — large cohort sequencing plus functional validation of HAT activity impairment and target gene regulation, replicated across multiple patient samples","pmids":["21390130"],"is_preprint":false},{"year":2016,"finding":"CREBBP loss-of-function causes focal depletion of enhancer H3K27 acetylation in germinal center B cells. CREBBP-regulated enhancers are counter-regulated by the BCL6/SMRT/HDAC3 repressor complex; loss of CREBBP enables unopposed deacetylation by this complex at enhancers of B-cell signaling and MHC class II genes. HDAC3 loss-of-function rescues these enhancers and suppresses CREBBP-mutant lymphomas.","method":"Conditional mouse knockout, ChIP-seq for H3K27ac, Co-IP demonstrating BCL6/SMRT/HDAC3 complex binding at MHC class II loci, in vitro and in vivo HDAC3 loss-of-function rescue experiments","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, Co-IP, genetic rescue in vitro and in vivo) in a single rigorous study","pmids":["27733359"],"is_preprint":false},{"year":2017,"finding":"CREBBP acts as a haploinsufficient tumor suppressor in germinal center B cells by regulating enhancer/super-enhancer networks controlling B-cell receptor and CD40 receptor signaling, transcriptional control of GC/plasma cell development, and antigen presentation; Crebbp-deficient B cells show enhanced mitogenic response and perturbed plasma cell differentiation.","method":"Conditional GC-specific Crebbp knockout mice, ChIP-seq for enhancer acetylation, B-cell functional assays (mitogenic response, plasma cell differentiation), compound Crebbp-haploinsufficient/BCL2-transgenic mouse lymphoma model","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model with ChIP-seq and multiple defined cellular phenotypes plus in vivo lymphoma model","pmids":["28069569"],"is_preprint":false},{"year":2017,"finding":"CREBBP inactivation in germinal center B cells reduces MHCII surface expression and promotes immune evasion; MHCII deficiency phenocopies the lymphomagenesis-promoting effects of CREBBP loss, and CD4+ T cell depletion facilitates lymphoma engraftment, demonstrating that CREBBP-mediated MHCII expression is required for tumor immune control.","method":"CRISPR-introduced patient mutation in DLBCL cell line, conditional Crebbp/Ep300 mouse knockout, xenograft and serial transplantation models, CD4+ T cell depletion experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic approaches (CRISPR KI + conditional KO) with multiple functional readouts including in vivo immune depletion","pmids":["28831000"],"is_preprint":false},{"year":2017,"finding":"CREBBP inactivation leads to high expression of MYC and altered histone acetylation at intragenic regions enriched for MYC DNA-binding motifs, showing MYC binding; this is associated with Crebbp loss cooperating with Bcl2 overexpression to promote B-cell lymphoma.","method":"Transgenic mouse models with Crebbp deletion, transcriptional and epigenetic profiling (histone acetylation ChIP), Myc binding analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in single lab, showing mechanistic link between CREBBP loss, altered histone acetylation at MYC-bound regions, and MYC upregulation","pmids":["28288979"],"is_preprint":false},{"year":2017,"finding":"Loss of Crebbp in hematopoietic stem and progenitor cells leads to accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response due to failure to acetylate p53; this identifies a premalignant lymphoma stem cell population with decreased H3K27ac that undergoes transcriptional and genetic evolution leading to lymphomagenesis. Loss of Crebbp later in lymphopoiesis attenuates these effects.","method":"Murine Crebbp conditional KO at different hematopoietic stages, p53 acetylation assays, H3K27ac ChIP, functional DNA damage response assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — stage-specific conditional KO with p53 acetylation assay, H3K27ac ChIP, and defined DDR phenotype in a rigorous study","pmids":["28825697"],"is_preprint":false},{"year":2019,"finding":"CREBBP and EP300 modulate common as well as distinct transcriptional programs in germinal center B cells. EP300 but not CREBBP deletion impairs GC B cell fitness in vivo. Combined loss of Crebbp and Ep300 completely abrogates GC formation, demonstrating partial functional compensation through common transcriptional targets and a synthetic lethal interaction retained in CREBBP-mutant DLBCL cells.","method":"Conditional GC-directed mouse deletion models for Crebbp and Ep300 individually and combined; in vivo GC formation assays; pharmacological targeting with selective CREBBP/EP300 inhibitors in DLBCL cells","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual conditional KO mouse models with clear in vivo phenotypes plus pharmacological validation of synthetic lethality","pmids":["31519498"],"is_preprint":false},{"year":2002,"finding":"Crebbp haploinsufficiency in mice causes marked reduction of white adipose tissue (lipodystrophy) but increased insulin sensitivity, increased leptin sensitivity, and increased serum adiponectin, demonstrating that CBP functions as a 'master-switch' between energy storage and expenditure by co-activating transcription factors including SREBPs, C/EBPs, PPARs, and STATs via histone acetylation.","method":"Analysis of Crebbp+/- mice: body composition, glucose tolerance tests, insulin sensitivity, leptin sensitivity, adiponectin measurement; high-fat diet challenge","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous in vivo loss-of-function mouse model with multiple defined metabolic phenotypes","pmids":["11818964"],"is_preprint":false},{"year":2012,"finding":"SRCAP, an SNF2-related chromatin-remodeling factor, serves as a coactivator for CREBBP (CBP). SRCAP mutations causing Floating-Harbor syndrome cluster in a region predicted to abolish AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact, establishing a functional coactivator relationship between SRCAP and CREBBP.","method":"Whole-exome sequencing identifying SRCAP mutations in Floating-Harbor syndrome; protein domain analysis confirming intact CBP-binding domain in mutants","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic identification of SRCAP as CREBBP coactivator with domain analysis; no direct biochemical reconstitution in this paper but consistent with known domain interactions","pmids":["22265015"],"is_preprint":false},{"year":2021,"finding":"CREBBP/EP300 mutation or knockdown inhibits H3K27 acetylation, downregulates FBXW7 expression, activates the NOTCH pathway and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype in DLBCL.","method":"In vitro knockdown and mutation of CREBBP/EP300 in B-lymphoma cells with measurement of H3K27ac, FBXW7, NOTCH pathway activation, CCL2/CSF1 expression; in vivo murine xenograft models with macrophage phenotyping","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with pathway readouts; single lab, mechanistic axis established by knockdown and mutation with multiple downstream endpoints","pmids":["33431788"],"is_preprint":false},{"year":2018,"finding":"Crebbp loss in mouse neuroendocrine cells results in reduced expression of tight junction and cell adhesion genes including Cdh1 (E-cadherin) with reduced histone acetylation at these loci; suppression of Cdh1 promotes transformation in SCLC. HDAC inhibitor Pracinostat restores histone acetylation and CDH1 expression in Crebbp-deficient SCLC.","method":"Autochthonous mouse SCLC model with Crebbp inactivation, gene expression analysis, ChIP for histone acetylation at Cdh1 locus, Cdh1 suppression functional studies, in vivo HDAC inhibitor treatment","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model with ChIP, functional validation of Cdh1 as effector, and in vivo pharmacological rescue","pmids":["30181244"],"is_preprint":false},{"year":2021,"finding":"CREBBP acetyltransferase activity controls H3K27 acetylation at the profibrotic genes ACTA2 and COL1A1 in myofibroblasts; CREBBP/EP300 inhibition with SGC-CBP30 reduces H3K27ac at profibrotic enhancers and identifies collagen VI as a prominent downstream regulator of myofibroblast contractility, ECM production, chemotaxis, and wound healing.","method":"Epigenetic inhibitor screen in Dupuytren's disease fibroblasts; ChIP for H3K27ac; transcriptomic and proteomic profiling after SGC-CBP30 treatment; targeted Col VI knockdown with functional assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — chemical probe with ChIP, transcriptomics, proteomics, and orthogonal genetic knockdown across multiple functional readouts","pmids":["32759223"],"is_preprint":false},{"year":2018,"finding":"CREBBP/EP300 bromodomains are required to sustain the GATA1/MYC regulatory axis in leukemia and lymphoma cell proliferation; bromodomain inhibitor CBP30 displaces CREBBP and EP300 from GATA1 and MYC binding sites at enhancers, reducing H3K27ac levels at these sites and causing G0/G1 cell cycle arrest.","method":"Bromodomain inhibitor treatment of K562 and lymphoma cell lines; ChIP-seq for EP300, GATA1, MYC occupancy; H3K27ac ChIP; cell cycle analysis","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and functional assays in single lab establishing bromodomain-dependent mechanism","pmids":["29884215"],"is_preprint":false},{"year":2020,"finding":"CARM1 inhibition reduces histone acetyltransferase activity of CBP genome-wide and downregulates CBP-target genes in DLBCL, creating a synthetic lethality with CREBBP/EP300 mutations; CREBBP/EP300 mutations are monoallelic and require residual WT expression for cell survival, making mutant cells selectively sensitive to CARM1 inhibition.","method":"In vitro and in vivo CARM1 inhibition studies in DLBCL models; genome-wide HAT activity assessment; CBP-target gene expression analysis; correlation with CREBBP/EP300 mutation load","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo models with mechanistic genome-wide HAT activity data; single lab","pmids":["32576962"],"is_preprint":false},{"year":2022,"finding":"CREBBP directly acetylates RB1CC1/FIP200 at lysine K276 in an intrinsically disordered region; this acetylation reduces ubiquitination of RB1CC1 at K276, thereby inhibiting its ubiquitin-dependent degradation. Both K276 acetylation and the N-terminal IDR are required for canonical autophagy function of RB1CC1 in breast cancer cells.","method":"Mass spectrometry identification of acetylation/ubiquitination sites; acetyltransferase assays; mutational analysis of K276; ubiquitination assays; autophagy functional readouts in breast cancer cells","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic acetylation assay with site-specific mutagenesis, demonstration of cross-talk with ubiquitination, and functional autophagy phenotype; single lab with multiple orthogonal methods","pmids":["36394358"],"is_preprint":false},{"year":2016,"finding":"CREBBP knockdown in ALL cells reduces acetylation of histone H3 at lysine 18 (H3K18ac) and directly acetylates KRAS; CREBBP knockdown enhances signaling through the RAS/RAF/MEK/ERK pathway in Ras pathway-mutated ALL cells, which remain sensitive to MEK inhibitors.","method":"RNA interference knockdown of CREBBP in ALL cell lines and primagraft ALL cells; measurement of H3K18ac; direct KRAS acetylation assay; RAS/RAF/MEK/ERK pathway signaling assessment; MEK inhibitor sensitivity assays","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct acetylation assay for KRAS substrate identification plus downstream pathway readouts; single lab","pmids":["27979926"],"is_preprint":false},{"year":2011,"finding":"The bone marrow microenvironment of Crebbp+/- mice fails to maintain immature stem and progenitor cell pools, instead stimulating myeloid differentiation and myeloproliferation. Haploinsufficiency of Crebbp in the microenvironment decreases matrix metallopeptidase-9 (MMP9) and kit ligand (KITL), increases osteoclastogenesis, and alters expression of endothelial cell adhesion molecules ESAM1 and CDH5.","method":"Analysis of Crebbp+/- mouse BM microenvironment; bone histomorphometry; CFU-F assays; molecular analysis of MMP9, KITL, ESAM1, CDH5 expression in BM microenvironment cells","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined in vivo microenvironmental phenotypes with molecular readouts; single lab","pmids":["21555743"],"is_preprint":false},{"year":2009,"finding":"CREBBP (CBP) physically interacts with the transcription factor PHOX2B using specific domains of each protein; CBP acts as a coactivator to mediate synergistic transcriptional activation with PHOX2B. Disease-associated PHOX2B mutants interact with different CBP domains than wild-type PHOX2B, impairing synergistic activation and exerting dominant-interfering effects.","method":"Co-immunoprecipitation and domain mapping of PHOX2B-CBP interaction; transient cotransfection reporter assays with PHOX2B mutants and CBP","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP domain mapping plus functional reporter assays; single lab with two orthogonal methods","pmids":["19191321"],"is_preprint":false},{"year":2016,"finding":"EP300-ZNF384 and CREBBP-ZNF384 fusion proteins result in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation; ectopic expression alters differentiation of mouse hematopoietic stem and progenitor cells and potentiates oncogenic transformation in vitro.","method":"Whole-transcriptome sequencing identifying ZNF384 fusions; luciferase reporter assays for ZNF384 fusion transcriptional activity; measurement of global histone acetylation in fusion-expressing cells; mouse HSPC differentiation assays; in vitro transformation assays","journal":"Genome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays including HAT activity, HSPC differentiation, and transformation; single lab","pmids":["27903646"],"is_preprint":false},{"year":2023,"finding":"CREBBP directly acetylates KMT2D in germinal center B cells; CREBBP inactivation by FL/DLBCL-associated mutations abrogates KMT2D acetylation, leading to reduced H3K4me1 levels. CREBBP and KMT2D form a biochemical complex on select enhancers/super-enhancers critical for immune signaling in the GC light zone, and dual Crebbp/Kmt2d haploinsufficiency synergistically promotes abnormal GC expansion.","method":"Co-IP demonstrating CREBBP-KMT2D complex on enhancers; direct acetylation assay of KMT2D by CREBBP; ChIP-seq for H3K27ac and H3K4me1; conditional double-KO mouse model; analysis of FL/DLBCL-associated mutations","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct acetyltransferase assay plus Co-IP plus ChIP-seq plus in vivo mouse model with multiple orthogonal methods in one rigorous study","pmids":["36893259"],"is_preprint":false},{"year":2024,"finding":"Combined haploinsufficiency of Crebbp and Kmt2d induces more severe lymphoma phenotype and immune evasion (CD8+ T-cell exhaustion) than either alone; CREBBP and KMT2D show mutually dependent binding and function on chromatin, with combined deficiency preferentially impairing activation of immune synapse-responsive super-enhancers.","method":"Compound Crebbp/Kmt2d haploinsufficient mouse model; ChIP-seq for CREBBP and KMT2D occupancy; immune phenotyping of tumor microenvironment; gene expression analysis of immune synapse genes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model with ChIP-seq demonstrating mutually dependent chromatin binding and defined immune microenvironment phenotypes","pmids":["38570506"],"is_preprint":false},{"year":2021,"finding":"CREBBP HAT inhibition (but not bromodomain inhibition) radiosensitizes CREBBP/EP300-mutant tumors by repressing homologous recombination following DNA damage. Selected CREBBP mutations lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain-of-function targeted by HAT inhibition.","method":"In vivo shRNA screen for radiation response; in vitro and in vivo HAT inhibitor studies in cognate mutant tumors; homologous recombination assays; measurement of CBP and BRCA1 acetylation levels","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo screen plus in vitro/in vivo confirmation with biochemical acetylation measurements; single lab","pmids":["34732714"],"is_preprint":false},{"year":2020,"finding":"CREBBP acetyltransferase activity is required for acetylation of OGG1 DNA glycosylase, DNA polymerase β, and PCNA in base excision repair; mutations in CREBBP that affect protein levels or KAT activity cause reduced OGG1 acetylation and impaired BER initiation in Rubinstein-Taybi syndrome patient-derived lymphoblastoid cell lines, with increased sensitivity to oxidative DNA damage.","method":"BER functional assays in RSTS patient lymphoblastoid cell lines; OGG1, DNA pol β, and PCNA acetylation level measurements; complementation with CBP or p300 expression","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell lines with functional BER assays and acetylation measurements plus complementation rescue; single lab","pmids":["31504229"],"is_preprint":false},{"year":2010,"finding":"CREBBP deletion constructs lacking the CREB, bromo, and HAT domains (CB-HAT) cause hyperproliferation and limited neuronal differentiation, while deletion of the HAT and C-terminal domain (HAT-CT) causes proliferation deficiency and rapid but insufficient neurogenesis; these effects correlate with altered HAT activity, altered binding of CREBBP-transcription factor complexes to promoters of Notch, SHH, Wnt, and retinoid pathway genes, and aberrant transcription of differentiation genes.","method":"CREBBP deletion construct transfection into NT2 neuronal progenitor cells; HAT activity assays; ChIP-PCR; Co-IP; cell cycle profiling; gene expression analysis","journal":"Differentiation; research in biological diversity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct HAT activity assay with domain deletion mutants plus ChIP and Co-IP; single lab with multiple orthogonal methods","pmids":["20207472"],"is_preprint":false},{"year":2021,"finding":"CREBBP CRISPR-dependent screening identifies CREBBP dependency in a DLBCL cell line bearing a truncated EP300 lacking the HAT domain; the synthetic lethal interaction between CREBBP and EP300 was validated across published CRISPR screens and inhibitor assays, confirming that residual WT allele expression is required for survival in cells with EP300 truncation.","method":"Whole-genome CRISPR-Cas9 knockout screen; transcriptome sequencing; validation in published CRISPR screens; HAT inhibitor assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen plus orthogonal inhibitor validation; single lab","pmids":["33911074"],"is_preprint":false},{"year":2016,"finding":"CREBBP mutation in the CH1 domain of CBP in mice (CBPΔCH1/ΔCH1) causes Rubinstein-Taybi syndrome-like phenotype including autism-relevant repetitive behaviors, hyperactivity, social interaction deficits, motor dysfunction, impaired recognition memory, and abnormal synaptic plasticity, establishing that the CH1 (TAZ1) domain is required for normal CBP function in motor control, cognition, and social behavior.","method":"Knock-in mouse model with CH1 domain deletion; behavioral tests (open field, rotarod, novel object recognition, social interaction, marble burying); electrophysiology for synaptic plasticity","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function mouse model with multiple defined behavioral and synaptic phenotypes; single lab","pmids":["26730956"],"is_preprint":false},{"year":2020,"finding":"CREBBP interacts with the NCOA protein through its NCBD domain binding the NCOA CID domain; this high-affinity interaction evolved specifically in vertebrates, as non-vertebrate deuterostome (sea urchin) NCBD:CID interactions show much lower affinity similar to proposed ancestral domains.","method":"Expression and affinity measurement of NCBD and CID domains from multiple species using biophysical binding assays","journal":"Protein science","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct biophysical binding measurements across species; single lab, no mutagenesis or structural validation","pmids":["32329110"],"is_preprint":false},{"year":2022,"finding":"CREBBP acetyltransferase inhibition (CPI-1612) suppresses ER-dependent transcription in ER+ breast cancer by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1, reducing H3K27ac at FOXA1-bound enhancers.","method":"CREBBP/EP300 acetyltransferase inhibitor CPI-1612 treatment; ChIP-seq for H3K27ac and FOXA1 occupancy; in vitro and in vivo breast cancer growth assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with chemical inhibitor plus in vitro and in vivo functional assays; single lab","pmids":["35353838"],"is_preprint":false},{"year":2020,"finding":"ZFP36 directly binds to CREBBP mRNA via its AU-rich element-binding domain, destabilizing CREBBP mRNA; ZFP36 deficiency upregulates CREBBP and enhances I/R-induced lung injury, apoptosis, and fibrosis via the CREBBP/p53/p21/Bax pathway.","method":"RNA immunoprecipitation (RIP) and pulldown assays confirming ZFP36-CREBBP mRNA interaction; in vivo ZFP36-knockdown mouse model; Western blotting and IHC for CREBBP/p53/p21/Bax pathway components","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RIP and pulldown assays demonstrating direct mRNA interaction, plus in vivo knockdown phenotype; single lab","pmids":["34238924"],"is_preprint":false},{"year":2020,"finding":"CREBBP loss in triple-negative breast cancer upregulates and creates dependency on a FOXM1 proliferative program; CREBBP-altered TNBC cells are selectively sensitive to CDK4/6 inhibitors that indirectly target FOXM1-driven proliferation.","method":"3D spheroid functional genomics screen of 200 frequently mutated breast cancer genes; CREBBP KO/knockdown with FOXM1 pathway analysis; CDK4/6 inhibitor sensitivity in cell line xenografts and patient-derived models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased functional screen plus mechanistic follow-up with patient-derived models; single lab","pmids":["33509944"],"is_preprint":false},{"year":2024,"finding":"EP300 and CREBBP are core epigenetic regulators in MLL-rearranged AML; EP300/CREBBP inhibitor A-485 selectively depresses MLL-r cell proliferation by downregulating the CDK4/RB/E2F axis and blocking MLL-r-BET complex binding to H3K27ac at critical gene loci, distinct from global histone acetylation effects.","method":"ATAC-seq; RNA-seq; CUT&TAG for H3K27ac; EP300/CREBBP knockout and A-485 inhibitor treatment in MLL-r vs. MLL-WT AML cells","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genomics approaches (ATAC-seq, RNA-seq, CUT&TAG) with genetic and pharmacological perturbation; single lab","pmids":["38693103"],"is_preprint":false},{"year":2018,"finding":"CREBBP/EP300 bromodomain inhibition in ER-negative AR-expressing breast cancer (MDA-MB-453) downregulates AR-dependent gene expression and reduces H3K27ac levels at AR-binding sites; super-enhancer-associated gene expression is selectively downregulated by CREBBP/EP300 bromodomain inhibitors.","method":"Genetic (siRNA) and chemical (CREBBP/EP300 bromodomain inhibitor) approaches; transcriptome analysis; H3K27ac ChIP at AR-binding sites; AR occupancy analysis","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and chemical approaches with ChIP and transcriptomic analysis; single lab","pmids":["30606771"],"is_preprint":false},{"year":2021,"finding":"CREBBP interacts with E2F3a transcription factor (Co-IP, co-localization by immunofluorescence) and regulates E2F3a protein levels; CREBBP binds to the promoter of CASP8AP2 (a downstream E2F3a target) by ChIP assay. CREBBP downregulation inhibits leukemia cell proliferation, arrests cells in G0/G1 phase, decreases E2F3a and CASP8AP2 expression, and increases daunorubicin resistance.","method":"RNA interference knockdown and overexpression of CREBBP; Co-IP demonstrating CREBBP-E2F3a interaction; immunofluorescence co-localization; ChIP assay for CREBBP at CASP8AP2 promoter; cell cycle analysis; IC50 measurements","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus ChIP plus functional cellular phenotypes; single lab with multiple orthogonal methods","pmids":["32945392"],"is_preprint":false},{"year":2018,"finding":"CREBBP-mutated follicular lymphoma cells fail to upregulate PRDM1 in response to IL21 due to abnormal enrichment of BCL6 repressor protein at the PRDM1 gene; pan-HDAC inhibitor vorinostat restores PRDM1 response to IL21 by lowering BCL6 bound to PRDM1 promoter.","method":"ChIP-qPCR for BCL6 at PRDM1 locus in CREBBP-mutated vs. wild-type FL cells; IL21 stimulation assays; vorinostat treatment; flow cytometry; transcriptome analysis in patient samples","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR mechanistic data plus functional rescue by HDAC inhibition; single lab","pmids":["30348636"],"is_preprint":false},{"year":1997,"finding":"The human CREBBP gene was cloned, physically mapped to chromosome 16p13.3 within a 100-kb region where all tested Rubinstein-Taybi syndrome and t(8;16)-associated AML breakpoints disrupt a single gene; the full cDNA was sequenced and CREBBP was characterized as an integrator in the assembly of multiprotein regulatory complexes necessary for transcription in multiple signaling pathways.","method":"Cosmid contig construction; FISH mapping; Southern blot; full cDNA sequencing","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical mapping and cDNA characterization establishing genomic position and full sequence; single study","pmids":["9177780"],"is_preprint":false}],"current_model":"CREBBP (CBP/KAT3A) is a lysine acetyltransferase (HAT domain) and transcriptional coactivator that acetylates histones (H3K18ac, H3K27ac) and non-histone substrates including p53, KRAS, KMT2D, RB1CC1/FIP200, OGG1, DNA pol β, and PCNA; it forms biochemical complexes with BCL6/SMRT/HDAC3 at enhancers (where it opposes HDAC3-mediated deacetylation), physically interacts with KMT2D at super-enhancers to co-activate immune-synapse and B-cell-signaling gene programs, co-activates transcription factors including PHOX2B and GATA1/MYC through its CH1 and bromodomains, regulates DNA base excision repair through substrate acetylation, and functions as a haploinsufficient tumor suppressor in germinal center B cells, neuroendocrine cells, and other tissues by maintaining enhancer H3K27 acetylation and MHC class II expression to prevent immune evasion."},"narrative":{"mechanistic_narrative":"CREBBP encodes a lysine acetyltransferase and transcriptional coactivator that integrates multiprotein regulatory complexes to deposit enhancer histone acetylation and acetylate non-histone substrates across diverse signaling pathways [PMID:9177780, PMID:27733359]. Through its HAT domain, CREBBP maintains H3K27 acetylation at enhancers and super-enhancers that drive B-cell receptor and CD40 signaling, germinal-center/plasma-cell development, and MHC class II antigen presentation; loss of function permits unopposed deacetylation by the BCL6/SMRT/HDAC3 repressor complex, and HDAC3 inhibition restores these enhancers and suppresses CREBBP-mutant lymphoma [PMID:27733359, PMID:28069569]. CREBBP physically partners with KMT2D on select enhancers and directly acetylates KMT2D to sustain H3K4me1, with combined Crebbp/Kmt2d haploinsufficiency synergistically driving abnormal germinal-center expansion and immune evasion through CD8+ T-cell exhaustion [PMID:36893259, PMID:38570506]. As a haploinsufficient tumor suppressor, CREBBP loss reduces MHCII surface expression to enable immune escape, derepresses MYC, and partially overlaps with EP300, with which it has a synthetic-lethal relationship in mutant DLBCL [PMID:28831000, PMID:28288979, PMID:31519498]. Its acetyltransferase activity extends beyond chromatin to direct substrates—p53 in the DNA-damage response, KRAS in RAS/MAPK signaling, RB1CC1/FIP200 in autophagy, and OGG1/DNA pol β/PCNA in base excision repair—linking CREBBP to genome maintenance, growth signaling, and cellular homeostasis [PMID:28825697, PMID:27979926, PMID:36394358, PMID:31504229]. Beyond cancer, CREBBP coactivates lineage transcription factors (SREBPs, C/EBPs, PPARs, STATs, PHOX2B, GATA1) governing energy metabolism, neuronal differentiation, and neuroendocrine programs [PMID:11818964, PMID:19191321, PMID:20207472]. Germline CREBBP dysfunction underlies Rubinstein-Taybi syndrome, with CH1-domain and HAT-impairing mutations producing neurobehavioral deficits and impaired base excision repair [PMID:26730956, PMID:31504229].","teleology":[{"year":1997,"claim":"Establishing CREBBP's genomic identity and disease relevance answered where the gene lay and why it mattered, defining it as a transcriptional integrator disrupted in Rubinstein-Taybi syndrome and t(8;16) AML.","evidence":"Cosmid contig construction, FISH mapping, and full cDNA sequencing of the chromosome 16p13.3 locus","pmids":["9177780"],"confidence":"Medium","gaps":["Did not define catalytic mechanism or specific substrates","No enhancer-level functional data"]},{"year":2002,"claim":"Crebbp haploinsufficiency phenotyping showed CBP coordinates whole-body energy balance, establishing it as a coactivator of metabolic transcription factors rather than solely a chromatin enzyme.","evidence":"Metabolic phenotyping of Crebbp+/- mice (body composition, glucose/insulin/leptin sensitivity, high-fat challenge)","pmids":["11818964"],"confidence":"High","gaps":["Direct acetylation of named metabolic TFs not biochemically demonstrated here","Tissue-autonomous mechanism not dissected"]},{"year":2009,"claim":"Domain-mapped interaction with PHOX2B answered how CBP achieves transcription-factor-specific coactivation and how disease mutants subvert it.","evidence":"Co-IP domain mapping and cotransfection reporter assays with PHOX2B mutants","pmids":["19191321"],"confidence":"Medium","gaps":["Single-system reporter context","No genome-wide PHOX2B target validation"]},{"year":2010,"claim":"Deletion-construct analysis in neuronal progenitors linked specific CBP domains to proliferation-versus-differentiation control through HAT activity and TF-complex promoter binding.","evidence":"CREBBP deletion-construct transfection in NT2 cells with HAT assays, ChIP-PCR, Co-IP, and cell-cycle profiling","pmids":["20207472"],"confidence":"Medium","gaps":["Overexpressed deletion constructs may not reflect endogenous regulation","Pathway gene effects not validated in vivo"]},{"year":2011,"claim":"Sequencing relapsed ALL pinpointed HAT-domain mutations as recurrent and functionally impairing, establishing loss of acetyltransferase activity as a driver of altered target-gene regulation including glucocorticoid response.","evidence":"Resequencing of matched diagnosis/relapse ALL with HAT-activity and target-gene functional assays","pmids":["21390130"],"confidence":"High","gaps":["Did not resolve enhancer-level consequences","Non-histone substrate contributions unaddressed"]},{"year":2011,"claim":"Microenvironmental analysis showed CBP haploinsufficiency acts non-cell-autonomously in bone marrow, altering niche factors that govern stem/progenitor maintenance versus myeloproliferation.","evidence":"Crebbp+/- BM microenvironment analysis with histomorphometry, CFU-F assays, and MMP9/KITL/ESAM1/CDH5 expression","pmids":["21555743"],"confidence":"Medium","gaps":["Direct transcriptional targets in niche cells not mapped","Single-lab phenotype"]},{"year":2012,"claim":"Identifying SRCAP as a CBP coactivator extended the partner network and linked it to Floating-Harbor syndrome via an intact CBP-binding domain.","evidence":"Whole-exome sequencing and protein domain analysis in Floating-Harbor syndrome","pmids":["22265015"],"confidence":"Medium","gaps":["No direct biochemical reconstitution of the SRCAP-CBP complex","Functional cooperativity inferred from domain integrity"]},{"year":2016,"claim":"Defining the BCL6/SMRT/HDAC3 counter-regulatory axis answered the mechanism of enhancer dysfunction in CREBBP-mutant B cells and revealed HDAC3 inhibition as a corrective strategy.","evidence":"Conditional KO, H3K27ac ChIP-seq, Co-IP, and in vitro/in vivo HDAC3 loss-of-function rescue","pmids":["27733359"],"confidence":"High","gaps":["Direct CREBBP enhancer recruitment mechanism not fully resolved","Generality beyond GC B cells untested here"]},{"year":2016,"claim":"Demonstrating direct KRAS acetylation and H3K18ac loss connected CREBBP to RAS/MAPK signaling and MEK-inhibitor sensitivity in ALL.","evidence":"RNAi knockdown in ALL lines and primagrafts with direct KRAS acetylation assay and pathway/MEK-inhibitor readouts","pmids":["27979926"],"confidence":"Medium","gaps":["KRAS acetylation site and stoichiometry not defined","Single-lab finding"]},{"year":2016,"claim":"CH1-domain knock-in mice established that this domain is required for CBP's role in cognition, social behavior, and synaptic plasticity, modeling Rubinstein-Taybi neurobehavior.","evidence":"CH1-deletion knock-in mouse with behavioral battery and synaptic electrophysiology","pmids":["26730956"],"confidence":"Medium","gaps":["Molecular targets underlying behavior not identified","Single mutant allele"]},{"year":2016,"claim":"ZNF384 fusion analysis showed that fusion of CREBBP/EP300 produces dominant-negative loss of HAT activity, linking global acetylation loss to aberrant hematopoietic differentiation and transformation.","evidence":"Transcriptome sequencing, luciferase reporters, global acetylation measurement, and HSPC differentiation/transformation assays","pmids":["27903646"],"confidence":"Medium","gaps":["Specific deregulated loci not pinpointed","In vitro transformation only"]},{"year":2017,"claim":"Multiple complementary studies established CREBBP as a haploinsufficient tumor suppressor in germinal-center B cells, governing enhancer networks for BCR/CD40 signaling, MHCII-dependent immune surveillance, MYC repression, and p53-dependent DNA-damage response.","evidence":"GC-specific conditional KO mice, ChIP-seq, B-cell functional assays, CRISPR knock-in, xenograft/transplant with CD4+ depletion, p53 acetylation assays, and BCL2-cooperation lymphoma models","pmids":["28069569","28831000","28288979","28825697"],"confidence":"High","gaps":["Relative contribution of each program to malignant transformation unresolved","Stage-dependence of premalignant clone selection only partly mapped"]},{"year":2018,"claim":"Bromodomain-dependent and substrate-specific studies broadened the mechanistic picture: bromodomains sustain GATA1/MYC and AR enhancer programs, while neuroendocrine CREBBP loss silences Cdh1 to drive SCLC, and FL cells fail to upregulate PRDM1 via aberrant BCL6 retention.","evidence":"Bromodomain inhibitor CBP30, ChIP-seq, autochthonous SCLC mouse with Cdh1 ChIP and HDAC-inhibitor rescue, and BCL6 ChIP-qPCR with vorinostat rescue","pmids":["29884215","30181244","30606771","30348636"],"confidence":"Medium","gaps":["Distinct bromodomain versus HAT contributions context-dependent and not unified","Several mechanisms from single labs"]},{"year":2019,"claim":"Dual Crebbp/Ep300 deletion modeling resolved their overlap-and-divergence, revealing partial compensation through common targets and a synthetic-lethal dependency exploitable in CREBBP-mutant DLBCL.","evidence":"Individual and combined GC-directed conditional deletions with in vivo GC assays and selective CREBBP/EP300 inhibitors","pmids":["31519498"],"confidence":"High","gaps":["Molecular basis of distinct versus shared targets not fully defined","Therapeutic window in patients untested"]},{"year":2020,"claim":"A cluster of substrate and dependency studies extended CREBBP into base excision repair (OGG1/pol β/PCNA), autophagy precursors, NCOA-binding evolution, and lineage-dependent vulnerabilities in TNBC (FOXM1), CARM1 synthetic lethality, and breast-cancer FOXA1 enhancers.","evidence":"RSTS lymphoblast BER assays with complementation, cross-species NCBD:CID biophysics, functional genomics screens, CARM1 inhibition, and CPI-1612 with FOXA1/H3K27ac ChIP-seq","pmids":["31504229","32329110","33509944","32576962","35353838"],"confidence":"Medium","gaps":["Several substrate roles from single labs without reciprocal validation","Acetylation sites not always mapped"]},{"year":2021,"claim":"Refinements detailed how CREBBP HAT activity controls homologous recombination/radiosensitivity (with a hyperacetylation gain-of-function on BRCA1), macrophage polarization via FBXW7/NOTCH, profibrotic enhancers (ACTA2/COL1A1, collagen VI), E2F3a-CASP8AP2 leukemic proliferation, and a CRISPR-validated CREBBP dependency under EP300 truncation.","evidence":"In vivo shRNA radiation screen and HAT inhibitors, CREBBP/EP300 knockdown with NOTCH/CCL2/CSF1 readouts, SGC-CBP30 with ChIP/proteomics, Co-IP/ChIP for E2F3a, and whole-genome CRISPR screens","pmids":["34732714","33431788","32759223","32945392","33911074"],"confidence":"Medium","gaps":["Gain-of-function hyperacetylation mechanism needs broader confirmation","Many axes are single-lab"]},{"year":2022,"claim":"Direct acetylation of RB1CC1/FIP200 at K276 established acetylation-ubiquitination crosstalk stabilizing an autophagy regulator, extending CREBBP's non-histone substrate scope.","evidence":"Mass spectrometry, acetyltransferase assays, K276 mutagenesis, ubiquitination assays, and autophagy readouts in breast cancer cells","pmids":["36394358"],"confidence":"High","gaps":["Physiological contexts beyond breast cancer untested","Single-lab finding"]},{"year":2023,"claim":"Identifying direct KMT2D acetylation by CREBBP and their enhancer co-complex unified two GC tumor suppressors mechanistically, linking acetylation to H3K4me1 maintenance and synergistic lymphomagenesis.","evidence":"Co-IP, direct acetylation assay, H3K27ac/H3K4me1 ChIP-seq, and conditional double-KO mouse model","pmids":["36893259"],"confidence":"High","gaps":["KMT2D acetylation site(s) and effect on its catalytic activity not fully resolved","Generality beyond GC B cells untested"]},{"year":2024,"claim":"Compound haploinsufficiency studies showed CREBBP and KMT2D bind chromatin mutually dependently, jointly enabling immune-synapse super-enhancers, with combined loss driving severe immune evasion via CD8+ T-cell exhaustion.","evidence":"Compound Crebbp/Kmt2d haploinsufficient mouse with CREBBP/KMT2D ChIP-seq, immune phenotyping, and immune-synapse gene expression; plus A-485 in MLL-r AML with multi-omics","pmids":["38570506","38693103"],"confidence":"High","gaps":["Mechanism of mutually dependent recruitment not structurally resolved","Clinical translatability of dual-targeting unestablished"]},{"year":null,"claim":"How CREBBP selects between its many histone and non-histone substrates and is targeted to specific enhancers in each cell type remains unresolved, as does whether gain-of-function hyperacetylation states are a generalizable feature of mutant alleles.","evidence":"Not addressed by the available corpus","pmids":[],"confidence":"Low","gaps":["No unifying model of enhancer/substrate selection","Structural basis of CREBBP-KMT2D mutual recruitment unknown","Gain-of-function versus loss-of-function balance across mutation classes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[14,15,19,22,5]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,11,14,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,17,23,34]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,2,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[34,17]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,19,32]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,2,19]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,17,34]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,2,19,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,20]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5,22,21]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,29,30,32]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,25,22]}],"complexes":["CREBBP/KMT2D enhancer complex","BCL6/SMRT/HDAC3 repressor complex (counter-regulatory)"],"partners":["KMT2D","EP300","BCL6","HDAC3","PHOX2B","SRCAP","E2F3A","NCOA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92793","full_name":"CREB-binding protein","aliases":["Histone lysine acetyltransferase CREBBP","Protein lactyltransferas CREBBP","Protein-lysine acetyltransferase CREBBP"],"length_aa":2442,"mass_kda":265.4,"function":"Acetylates histones, giving a specific tag for transcriptional activation (PubMed:21131905, PubMed:24616510). Mediates acetylation of histone H3 at 'Lys-18' and 'Lys-27' (H3K18ac and H3K27ac, respectively) (PubMed:21131905). Also acetylates non-histone proteins, like DDX21, FBL, IRF2, MAFG, NCOA3, POLR1E/PAF53 and FOXO1 (PubMed:10490106, PubMed:11154691, PubMed:12738767, PubMed:12929931, PubMed:24207024, PubMed:28790157, PubMed:30540930, PubMed:35675826, PubMed:9707565). Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers (PubMed:14645221). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates POLR1E/PAF53, leading to decreased association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). Acetylates DDX21, thereby inhibiting DDX21 helicase activity (PubMed:28790157). Acetylates FBL, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me) (PubMed:30540930). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as lactoyl-CoA, and is able to mediate protein lactylation (PubMed:38128537). Catalyzes lactylation of MRE11 in response to DNA damage, thereby promoting DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:38128537). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q92793/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CREBBP","classification":"Not Classified","n_dependent_lines":146,"n_total_lines":1208,"dependency_fraction":0.12086092715231789},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSNK2B","stoichiometry":0.2},{"gene":"CTBP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CREBBP","total_profiled":1310},"omim":[{"mim_id":"621294","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 3; ZBTB3","url":"https://www.omim.org/entry/621294"},{"mim_id":"618333","title":"MENKE-HENNEKAM SYNDROME 2; MKHK2","url":"https://www.omim.org/entry/618333"},{"mim_id":"618332","title":"MENKE-HENNEKAM SYNDROME 1; MKHK1","url":"https://www.omim.org/entry/618332"},{"mim_id":"616936","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 9; CHD9","url":"https://www.omim.org/entry/616936"},{"mim_id":"616571","title":"C-TYPE LECTIN DOMAIN FAMILY 18, MEMBER A; CLEC18A","url":"https://www.omim.org/entry/616571"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nuclear bodies","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CREBBP"},"hgnc":{"alias_symbol":["RTS","CBP","KAT3A"],"prev_symbol":["RSTS"]},"alphafold":{"accession":"Q92793","domains":[{"cath_id":"1.20.1020.10","chopping":"353-370_383-436","consensus_level":"medium","plddt":85.1136,"start":353,"end":436},{"cath_id":"1.10.246.20","chopping":"595-674","consensus_level":"medium","plddt":79.5078,"start":595,"end":674},{"cath_id":"1.20.920.10","chopping":"1088-1197","consensus_level":"medium","plddt":94.5312,"start":1088,"end":1197},{"cath_id":"-","chopping":"1326-1565_1612-1698","consensus_level":"high","plddt":92.3702,"start":1326,"end":1698},{"cath_id":"3.30.60.90","chopping":"1702-1746","consensus_level":"medium","plddt":71.3804,"start":1702,"end":1746},{"cath_id":"1.20.1020.10","chopping":"1747-1752_1764-1871","consensus_level":"high","plddt":72.8068,"start":1747,"end":1871}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92793","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92793-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92793-F1-predicted_aligned_error_v6.png","plddt_mean":52.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CREBBP","jax_strain_url":"https://www.jax.org/strain/search?query=CREBBP"},"sequence":{"accession":"Q92793","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92793.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92793/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92793"}},"corpus_meta":[{"pmid":"21390130","id":"PMC_21390130","title":"CREBBP 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CREBBP-regulated enhancers are counter-regulated by the BCL6/SMRT/HDAC3 repressor complex; loss of CREBBP enables unopposed deacetylation by this complex at enhancers of B-cell signaling and MHC class II genes. HDAC3 loss-of-function rescues these enhancers and suppresses CREBBP-mutant lymphomas.\",\n      \"method\": \"Conditional mouse knockout, ChIP-seq for H3K27ac, Co-IP demonstrating BCL6/SMRT/HDAC3 complex binding at MHC class II loci, in vitro and in vivo HDAC3 loss-of-function rescue experiments\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, Co-IP, genetic rescue in vitro and in vivo) in a single rigorous study\",\n      \"pmids\": [\"27733359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREBBP acts as a haploinsufficient tumor suppressor in germinal center B cells by regulating enhancer/super-enhancer networks controlling B-cell receptor and CD40 receptor signaling, transcriptional control of GC/plasma cell development, and antigen presentation; Crebbp-deficient B cells show enhanced mitogenic response and perturbed plasma cell differentiation.\",\n      \"method\": \"Conditional GC-specific Crebbp knockout mice, ChIP-seq for enhancer acetylation, B-cell functional assays (mitogenic response, plasma cell differentiation), compound Crebbp-haploinsufficient/BCL2-transgenic mouse lymphoma model\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model with ChIP-seq and multiple defined cellular phenotypes plus in vivo lymphoma model\",\n      \"pmids\": [\"28069569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREBBP inactivation in germinal center B cells reduces MHCII surface expression and promotes immune evasion; MHCII deficiency phenocopies the lymphomagenesis-promoting effects of CREBBP loss, and CD4+ T cell depletion facilitates lymphoma engraftment, demonstrating that CREBBP-mediated MHCII expression is required for tumor immune control.\",\n      \"method\": \"CRISPR-introduced patient mutation in DLBCL cell line, conditional Crebbp/Ep300 mouse knockout, xenograft and serial transplantation models, CD4+ T cell depletion experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic approaches (CRISPR KI + conditional KO) with multiple functional readouts including in vivo immune depletion\",\n      \"pmids\": [\"28831000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CREBBP inactivation leads to high expression of MYC and altered histone acetylation at intragenic regions enriched for MYC DNA-binding motifs, showing MYC binding; this is associated with Crebbp loss cooperating with Bcl2 overexpression to promote B-cell lymphoma.\",\n      \"method\": \"Transgenic mouse models with Crebbp deletion, transcriptional and epigenetic profiling (histone acetylation ChIP), Myc binding analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in single lab, showing mechanistic link between CREBBP loss, altered histone acetylation at MYC-bound regions, and MYC upregulation\",\n      \"pmids\": [\"28288979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of Crebbp in hematopoietic stem and progenitor cells leads to accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response due to failure to acetylate p53; this identifies a premalignant lymphoma stem cell population with decreased H3K27ac that undergoes transcriptional and genetic evolution leading to lymphomagenesis. Loss of Crebbp later in lymphopoiesis attenuates these effects.\",\n      \"method\": \"Murine Crebbp conditional KO at different hematopoietic stages, p53 acetylation assays, H3K27ac ChIP, functional DNA damage response assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — stage-specific conditional KO with p53 acetylation assay, H3K27ac ChIP, and defined DDR phenotype in a rigorous study\",\n      \"pmids\": [\"28825697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CREBBP and EP300 modulate common as well as distinct transcriptional programs in germinal center B cells. EP300 but not CREBBP deletion impairs GC B cell fitness in vivo. Combined loss of Crebbp and Ep300 completely abrogates GC formation, demonstrating partial functional compensation through common transcriptional targets and a synthetic lethal interaction retained in CREBBP-mutant DLBCL cells.\",\n      \"method\": \"Conditional GC-directed mouse deletion models for Crebbp and Ep300 individually and combined; in vivo GC formation assays; pharmacological targeting with selective CREBBP/EP300 inhibitors in DLBCL cells\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual conditional KO mouse models with clear in vivo phenotypes plus pharmacological validation of synthetic lethality\",\n      \"pmids\": [\"31519498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crebbp haploinsufficiency in mice causes marked reduction of white adipose tissue (lipodystrophy) but increased insulin sensitivity, increased leptin sensitivity, and increased serum adiponectin, demonstrating that CBP functions as a 'master-switch' between energy storage and expenditure by co-activating transcription factors including SREBPs, C/EBPs, PPARs, and STATs via histone acetylation.\",\n      \"method\": \"Analysis of Crebbp+/- mice: body composition, glucose tolerance tests, insulin sensitivity, leptin sensitivity, adiponectin measurement; high-fat diet challenge\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous in vivo loss-of-function mouse model with multiple defined metabolic phenotypes\",\n      \"pmids\": [\"11818964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SRCAP, an SNF2-related chromatin-remodeling factor, serves as a coactivator for CREBBP (CBP). SRCAP mutations causing Floating-Harbor syndrome cluster in a region predicted to abolish AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact, establishing a functional coactivator relationship between SRCAP and CREBBP.\",\n      \"method\": \"Whole-exome sequencing identifying SRCAP mutations in Floating-Harbor syndrome; protein domain analysis confirming intact CBP-binding domain in mutants\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic identification of SRCAP as CREBBP coactivator with domain analysis; no direct biochemical reconstitution in this paper but consistent with known domain interactions\",\n      \"pmids\": [\"22265015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREBBP/EP300 mutation or knockdown inhibits H3K27 acetylation, downregulates FBXW7 expression, activates the NOTCH pathway and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype in DLBCL.\",\n      \"method\": \"In vitro knockdown and mutation of CREBBP/EP300 in B-lymphoma cells with measurement of H3K27ac, FBXW7, NOTCH pathway activation, CCL2/CSF1 expression; in vivo murine xenograft models with macrophage phenotyping\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with pathway readouts; single lab, mechanistic axis established by knockdown and mutation with multiple downstream endpoints\",\n      \"pmids\": [\"33431788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crebbp loss in mouse neuroendocrine cells results in reduced expression of tight junction and cell adhesion genes including Cdh1 (E-cadherin) with reduced histone acetylation at these loci; suppression of Cdh1 promotes transformation in SCLC. HDAC inhibitor Pracinostat restores histone acetylation and CDH1 expression in Crebbp-deficient SCLC.\",\n      \"method\": \"Autochthonous mouse SCLC model with Crebbp inactivation, gene expression analysis, ChIP for histone acetylation at Cdh1 locus, Cdh1 suppression functional studies, in vivo HDAC inhibitor treatment\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model with ChIP, functional validation of Cdh1 as effector, and in vivo pharmacological rescue\",\n      \"pmids\": [\"30181244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREBBP acetyltransferase activity controls H3K27 acetylation at the profibrotic genes ACTA2 and COL1A1 in myofibroblasts; CREBBP/EP300 inhibition with SGC-CBP30 reduces H3K27ac at profibrotic enhancers and identifies collagen VI as a prominent downstream regulator of myofibroblast contractility, ECM production, chemotaxis, and wound healing.\",\n      \"method\": \"Epigenetic inhibitor screen in Dupuytren's disease fibroblasts; ChIP for H3K27ac; transcriptomic and proteomic profiling after SGC-CBP30 treatment; targeted Col VI knockdown with functional assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chemical probe with ChIP, transcriptomics, proteomics, and orthogonal genetic knockdown across multiple functional readouts\",\n      \"pmids\": [\"32759223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CREBBP/EP300 bromodomains are required to sustain the GATA1/MYC regulatory axis in leukemia and lymphoma cell proliferation; bromodomain inhibitor CBP30 displaces CREBBP and EP300 from GATA1 and MYC binding sites at enhancers, reducing H3K27ac levels at these sites and causing G0/G1 cell cycle arrest.\",\n      \"method\": \"Bromodomain inhibitor treatment of K562 and lymphoma cell lines; ChIP-seq for EP300, GATA1, MYC occupancy; H3K27ac ChIP; cell cycle analysis\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and functional assays in single lab establishing bromodomain-dependent mechanism\",\n      \"pmids\": [\"29884215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CARM1 inhibition reduces histone acetyltransferase activity of CBP genome-wide and downregulates CBP-target genes in DLBCL, creating a synthetic lethality with CREBBP/EP300 mutations; CREBBP/EP300 mutations are monoallelic and require residual WT expression for cell survival, making mutant cells selectively sensitive to CARM1 inhibition.\",\n      \"method\": \"In vitro and in vivo CARM1 inhibition studies in DLBCL models; genome-wide HAT activity assessment; CBP-target gene expression analysis; correlation with CREBBP/EP300 mutation load\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo models with mechanistic genome-wide HAT activity data; single lab\",\n      \"pmids\": [\"32576962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CREBBP directly acetylates RB1CC1/FIP200 at lysine K276 in an intrinsically disordered region; this acetylation reduces ubiquitination of RB1CC1 at K276, thereby inhibiting its ubiquitin-dependent degradation. Both K276 acetylation and the N-terminal IDR are required for canonical autophagy function of RB1CC1 in breast cancer cells.\",\n      \"method\": \"Mass spectrometry identification of acetylation/ubiquitination sites; acetyltransferase assays; mutational analysis of K276; ubiquitination assays; autophagy functional readouts in breast cancer cells\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic acetylation assay with site-specific mutagenesis, demonstration of cross-talk with ubiquitination, and functional autophagy phenotype; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36394358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CREBBP knockdown in ALL cells reduces acetylation of histone H3 at lysine 18 (H3K18ac) and directly acetylates KRAS; CREBBP knockdown enhances signaling through the RAS/RAF/MEK/ERK pathway in Ras pathway-mutated ALL cells, which remain sensitive to MEK inhibitors.\",\n      \"method\": \"RNA interference knockdown of CREBBP in ALL cell lines and primagraft ALL cells; measurement of H3K18ac; direct KRAS acetylation assay; RAS/RAF/MEK/ERK pathway signaling assessment; MEK inhibitor sensitivity assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct acetylation assay for KRAS substrate identification plus downstream pathway readouts; single lab\",\n      \"pmids\": [\"27979926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The bone marrow microenvironment of Crebbp+/- mice fails to maintain immature stem and progenitor cell pools, instead stimulating myeloid differentiation and myeloproliferation. Haploinsufficiency of Crebbp in the microenvironment decreases matrix metallopeptidase-9 (MMP9) and kit ligand (KITL), increases osteoclastogenesis, and alters expression of endothelial cell adhesion molecules ESAM1 and CDH5.\",\n      \"method\": \"Analysis of Crebbp+/- mouse BM microenvironment; bone histomorphometry; CFU-F assays; molecular analysis of MMP9, KITL, ESAM1, CDH5 expression in BM microenvironment cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined in vivo microenvironmental phenotypes with molecular readouts; single lab\",\n      \"pmids\": [\"21555743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CREBBP (CBP) physically interacts with the transcription factor PHOX2B using specific domains of each protein; CBP acts as a coactivator to mediate synergistic transcriptional activation with PHOX2B. Disease-associated PHOX2B mutants interact with different CBP domains than wild-type PHOX2B, impairing synergistic activation and exerting dominant-interfering effects.\",\n      \"method\": \"Co-immunoprecipitation and domain mapping of PHOX2B-CBP interaction; transient cotransfection reporter assays with PHOX2B mutants and CBP\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP domain mapping plus functional reporter assays; single lab with two orthogonal methods\",\n      \"pmids\": [\"19191321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EP300-ZNF384 and CREBBP-ZNF384 fusion proteins result in loss of histone lysine acetyltransferase activity in a dominant-negative fashion, with concomitant global reduction of histone acetylation; ectopic expression alters differentiation of mouse hematopoietic stem and progenitor cells and potentiates oncogenic transformation in vitro.\",\n      \"method\": \"Whole-transcriptome sequencing identifying ZNF384 fusions; luciferase reporter assays for ZNF384 fusion transcriptional activity; measurement of global histone acetylation in fusion-expressing cells; mouse HSPC differentiation assays; in vitro transformation assays\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays including HAT activity, HSPC differentiation, and transformation; single lab\",\n      \"pmids\": [\"27903646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREBBP directly acetylates KMT2D in germinal center B cells; CREBBP inactivation by FL/DLBCL-associated mutations abrogates KMT2D acetylation, leading to reduced H3K4me1 levels. CREBBP and KMT2D form a biochemical complex on select enhancers/super-enhancers critical for immune signaling in the GC light zone, and dual Crebbp/Kmt2d haploinsufficiency synergistically promotes abnormal GC expansion.\",\n      \"method\": \"Co-IP demonstrating CREBBP-KMT2D complex on enhancers; direct acetylation assay of KMT2D by CREBBP; ChIP-seq for H3K27ac and H3K4me1; conditional double-KO mouse model; analysis of FL/DLBCL-associated mutations\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct acetyltransferase assay plus Co-IP plus ChIP-seq plus in vivo mouse model with multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"36893259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Combined haploinsufficiency of Crebbp and Kmt2d induces more severe lymphoma phenotype and immune evasion (CD8+ T-cell exhaustion) than either alone; CREBBP and KMT2D show mutually dependent binding and function on chromatin, with combined deficiency preferentially impairing activation of immune synapse-responsive super-enhancers.\",\n      \"method\": \"Compound Crebbp/Kmt2d haploinsufficient mouse model; ChIP-seq for CREBBP and KMT2D occupancy; immune phenotyping of tumor microenvironment; gene expression analysis of immune synapse genes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model with ChIP-seq demonstrating mutually dependent chromatin binding and defined immune microenvironment phenotypes\",\n      \"pmids\": [\"38570506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREBBP HAT inhibition (but not bromodomain inhibition) radiosensitizes CREBBP/EP300-mutant tumors by repressing homologous recombination following DNA damage. Selected CREBBP mutations lead to a hyperacetylated state that increases CBP and BRCA1 acetylation, representing a gain-of-function targeted by HAT inhibition.\",\n      \"method\": \"In vivo shRNA screen for radiation response; in vitro and in vivo HAT inhibitor studies in cognate mutant tumors; homologous recombination assays; measurement of CBP and BRCA1 acetylation levels\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo screen plus in vitro/in vivo confirmation with biochemical acetylation measurements; single lab\",\n      \"pmids\": [\"34732714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CREBBP acetyltransferase activity is required for acetylation of OGG1 DNA glycosylase, DNA polymerase β, and PCNA in base excision repair; mutations in CREBBP that affect protein levels or KAT activity cause reduced OGG1 acetylation and impaired BER initiation in Rubinstein-Taybi syndrome patient-derived lymphoblastoid cell lines, with increased sensitivity to oxidative DNA damage.\",\n      \"method\": \"BER functional assays in RSTS patient lymphoblastoid cell lines; OGG1, DNA pol β, and PCNA acetylation level measurements; complementation with CBP or p300 expression\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell lines with functional BER assays and acetylation measurements plus complementation rescue; single lab\",\n      \"pmids\": [\"31504229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CREBBP deletion constructs lacking the CREB, bromo, and HAT domains (CB-HAT) cause hyperproliferation and limited neuronal differentiation, while deletion of the HAT and C-terminal domain (HAT-CT) causes proliferation deficiency and rapid but insufficient neurogenesis; these effects correlate with altered HAT activity, altered binding of CREBBP-transcription factor complexes to promoters of Notch, SHH, Wnt, and retinoid pathway genes, and aberrant transcription of differentiation genes.\",\n      \"method\": \"CREBBP deletion construct transfection into NT2 neuronal progenitor cells; HAT activity assays; ChIP-PCR; Co-IP; cell cycle profiling; gene expression analysis\",\n      \"journal\": \"Differentiation; research in biological diversity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct HAT activity assay with domain deletion mutants plus ChIP and Co-IP; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20207472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREBBP CRISPR-dependent screening identifies CREBBP dependency in a DLBCL cell line bearing a truncated EP300 lacking the HAT domain; the synthetic lethal interaction between CREBBP and EP300 was validated across published CRISPR screens and inhibitor assays, confirming that residual WT allele expression is required for survival in cells with EP300 truncation.\",\n      \"method\": \"Whole-genome CRISPR-Cas9 knockout screen; transcriptome sequencing; validation in published CRISPR screens; HAT inhibitor assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen plus orthogonal inhibitor validation; single lab\",\n      \"pmids\": [\"33911074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CREBBP mutation in the CH1 domain of CBP in mice (CBPΔCH1/ΔCH1) causes Rubinstein-Taybi syndrome-like phenotype including autism-relevant repetitive behaviors, hyperactivity, social interaction deficits, motor dysfunction, impaired recognition memory, and abnormal synaptic plasticity, establishing that the CH1 (TAZ1) domain is required for normal CBP function in motor control, cognition, and social behavior.\",\n      \"method\": \"Knock-in mouse model with CH1 domain deletion; behavioral tests (open field, rotarod, novel object recognition, social interaction, marble burying); electrophysiology for synaptic plasticity\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function mouse model with multiple defined behavioral and synaptic phenotypes; single lab\",\n      \"pmids\": [\"26730956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CREBBP interacts with the NCOA protein through its NCBD domain binding the NCOA CID domain; this high-affinity interaction evolved specifically in vertebrates, as non-vertebrate deuterostome (sea urchin) NCBD:CID interactions show much lower affinity similar to proposed ancestral domains.\",\n      \"method\": \"Expression and affinity measurement of NCBD and CID domains from multiple species using biophysical binding assays\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct biophysical binding measurements across species; single lab, no mutagenesis or structural validation\",\n      \"pmids\": [\"32329110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CREBBP acetyltransferase inhibition (CPI-1612) suppresses ER-dependent transcription in ER+ breast cancer by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1, reducing H3K27ac at FOXA1-bound enhancers.\",\n      \"method\": \"CREBBP/EP300 acetyltransferase inhibitor CPI-1612 treatment; ChIP-seq for H3K27ac and FOXA1 occupancy; in vitro and in vivo breast cancer growth assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with chemical inhibitor plus in vitro and in vivo functional assays; single lab\",\n      \"pmids\": [\"35353838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ZFP36 directly binds to CREBBP mRNA via its AU-rich element-binding domain, destabilizing CREBBP mRNA; ZFP36 deficiency upregulates CREBBP and enhances I/R-induced lung injury, apoptosis, and fibrosis via the CREBBP/p53/p21/Bax pathway.\",\n      \"method\": \"RNA immunoprecipitation (RIP) and pulldown assays confirming ZFP36-CREBBP mRNA interaction; in vivo ZFP36-knockdown mouse model; Western blotting and IHC for CREBBP/p53/p21/Bax pathway components\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RIP and pulldown assays demonstrating direct mRNA interaction, plus in vivo knockdown phenotype; single lab\",\n      \"pmids\": [\"34238924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CREBBP loss in triple-negative breast cancer upregulates and creates dependency on a FOXM1 proliferative program; CREBBP-altered TNBC cells are selectively sensitive to CDK4/6 inhibitors that indirectly target FOXM1-driven proliferation.\",\n      \"method\": \"3D spheroid functional genomics screen of 200 frequently mutated breast cancer genes; CREBBP KO/knockdown with FOXM1 pathway analysis; CDK4/6 inhibitor sensitivity in cell line xenografts and patient-derived models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased functional screen plus mechanistic follow-up with patient-derived models; single lab\",\n      \"pmids\": [\"33509944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EP300 and CREBBP are core epigenetic regulators in MLL-rearranged AML; EP300/CREBBP inhibitor A-485 selectively depresses MLL-r cell proliferation by downregulating the CDK4/RB/E2F axis and blocking MLL-r-BET complex binding to H3K27ac at critical gene loci, distinct from global histone acetylation effects.\",\n      \"method\": \"ATAC-seq; RNA-seq; CUT&TAG for H3K27ac; EP300/CREBBP knockout and A-485 inhibitor treatment in MLL-r vs. MLL-WT AML cells\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genomics approaches (ATAC-seq, RNA-seq, CUT&TAG) with genetic and pharmacological perturbation; single lab\",\n      \"pmids\": [\"38693103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CREBBP/EP300 bromodomain inhibition in ER-negative AR-expressing breast cancer (MDA-MB-453) downregulates AR-dependent gene expression and reduces H3K27ac levels at AR-binding sites; super-enhancer-associated gene expression is selectively downregulated by CREBBP/EP300 bromodomain inhibitors.\",\n      \"method\": \"Genetic (siRNA) and chemical (CREBBP/EP300 bromodomain inhibitor) approaches; transcriptome analysis; H3K27ac ChIP at AR-binding sites; AR occupancy analysis\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and chemical approaches with ChIP and transcriptomic analysis; single lab\",\n      \"pmids\": [\"30606771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CREBBP interacts with E2F3a transcription factor (Co-IP, co-localization by immunofluorescence) and regulates E2F3a protein levels; CREBBP binds to the promoter of CASP8AP2 (a downstream E2F3a target) by ChIP assay. CREBBP downregulation inhibits leukemia cell proliferation, arrests cells in G0/G1 phase, decreases E2F3a and CASP8AP2 expression, and increases daunorubicin resistance.\",\n      \"method\": \"RNA interference knockdown and overexpression of CREBBP; Co-IP demonstrating CREBBP-E2F3a interaction; immunofluorescence co-localization; ChIP assay for CREBBP at CASP8AP2 promoter; cell cycle analysis; IC50 measurements\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus ChIP plus functional cellular phenotypes; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32945392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CREBBP-mutated follicular lymphoma cells fail to upregulate PRDM1 in response to IL21 due to abnormal enrichment of BCL6 repressor protein at the PRDM1 gene; pan-HDAC inhibitor vorinostat restores PRDM1 response to IL21 by lowering BCL6 bound to PRDM1 promoter.\",\n      \"method\": \"ChIP-qPCR for BCL6 at PRDM1 locus in CREBBP-mutated vs. wild-type FL cells; IL21 stimulation assays; vorinostat treatment; flow cytometry; transcriptome analysis in patient samples\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR mechanistic data plus functional rescue by HDAC inhibition; single lab\",\n      \"pmids\": [\"30348636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The human CREBBP gene was cloned, physically mapped to chromosome 16p13.3 within a 100-kb region where all tested Rubinstein-Taybi syndrome and t(8;16)-associated AML breakpoints disrupt a single gene; the full cDNA was sequenced and CREBBP was characterized as an integrator in the assembly of multiprotein regulatory complexes necessary for transcription in multiple signaling pathways.\",\n      \"method\": \"Cosmid contig construction; FISH mapping; Southern blot; full cDNA sequencing\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical mapping and cDNA characterization establishing genomic position and full sequence; single study\",\n      \"pmids\": [\"9177780\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CREBBP (CBP/KAT3A) is a lysine acetyltransferase (HAT domain) and transcriptional coactivator that acetylates histones (H3K18ac, H3K27ac) and non-histone substrates including p53, KRAS, KMT2D, RB1CC1/FIP200, OGG1, DNA pol β, and PCNA; it forms biochemical complexes with BCL6/SMRT/HDAC3 at enhancers (where it opposes HDAC3-mediated deacetylation), physically interacts with KMT2D at super-enhancers to co-activate immune-synapse and B-cell-signaling gene programs, co-activates transcription factors including PHOX2B and GATA1/MYC through its CH1 and bromodomains, regulates DNA base excision repair through substrate acetylation, and functions as a haploinsufficient tumor suppressor in germinal center B cells, neuroendocrine cells, and other tissues by maintaining enhancer H3K27 acetylation and MHC class II expression to prevent immune evasion.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CREBBP encodes a lysine acetyltransferase and transcriptional coactivator that integrates multiprotein regulatory complexes to deposit enhancer histone acetylation and acetylate non-histone substrates across diverse signaling pathways [#34, #1]. Through its HAT domain, CREBBP maintains H3K27 acetylation at enhancers and super-enhancers that drive B-cell receptor and CD40 signaling, germinal-center/plasma-cell development, and MHC class II antigen presentation; loss of function permits unopposed deacetylation by the BCL6/SMRT/HDAC3 repressor complex, and HDAC3 inhibition restores these enhancers and suppresses CREBBP-mutant lymphoma [#1, #2]. CREBBP physically partners with KMT2D on select enhancers and directly acetylates KMT2D to sustain H3K4me1, with combined Crebbp/Kmt2d haploinsufficiency synergistically driving abnormal germinal-center expansion and immune evasion through CD8+ T-cell exhaustion [#19, #20]. As a haploinsufficient tumor suppressor, CREBBP loss reduces MHCII surface expression to enable immune escape, derepresses MYC, and partially overlaps with EP300, with which it has a synthetic-lethal relationship in mutant DLBCL [#3, #4, #6]. Its acetyltransferase activity extends beyond chromatin to direct substrates—p53 in the DNA-damage response, KRAS in RAS/MAPK signaling, RB1CC1/FIP200 in autophagy, and OGG1/DNA pol β/PCNA in base excision repair—linking CREBBP to genome maintenance, growth signaling, and cellular homeostasis [#5, #15, #14, #22]. Beyond cancer, CREBBP coactivates lineage transcription factors (SREBPs, C/EBPs, PPARs, STATs, PHOX2B, GATA1) governing energy metabolism, neuronal differentiation, and neuroendocrine programs [#7, #17, #23]. Germline CREBBP dysfunction underlies Rubinstein-Taybi syndrome, with CH1-domain and HAT-impairing mutations producing neurobehavioral deficits and impaired base excision repair [#25, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing CREBBP's genomic identity and disease relevance answered where the gene lay and why it mattered, defining it as a transcriptional integrator disrupted in Rubinstein-Taybi syndrome and t(8;16) AML.\",\n      \"evidence\": \"Cosmid contig construction, FISH mapping, and full cDNA sequencing of the chromosome 16p13.3 locus\",\n      \"pmids\": [\"9177780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define catalytic mechanism or specific substrates\", \"No enhancer-level functional data\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Crebbp haploinsufficiency phenotyping showed CBP coordinates whole-body energy balance, establishing it as a coactivator of metabolic transcription factors rather than solely a chromatin enzyme.\",\n      \"evidence\": \"Metabolic phenotyping of Crebbp+/- mice (body composition, glucose/insulin/leptin sensitivity, high-fat challenge)\",\n      \"pmids\": [\"11818964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct acetylation of named metabolic TFs not biochemically demonstrated here\", \"Tissue-autonomous mechanism not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Domain-mapped interaction with PHOX2B answered how CBP achieves transcription-factor-specific coactivation and how disease mutants subvert it.\",\n      \"evidence\": \"Co-IP domain mapping and cotransfection reporter assays with PHOX2B mutants\",\n      \"pmids\": [\"19191321\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-system reporter context\", \"No genome-wide PHOX2B target validation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Deletion-construct analysis in neuronal progenitors linked specific CBP domains to proliferation-versus-differentiation control through HAT activity and TF-complex promoter binding.\",\n      \"evidence\": \"CREBBP deletion-construct transfection in NT2 cells with HAT assays, ChIP-PCR, Co-IP, and cell-cycle profiling\",\n      \"pmids\": [\"20207472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpressed deletion constructs may not reflect endogenous regulation\", \"Pathway gene effects not validated in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Sequencing relapsed ALL pinpointed HAT-domain mutations as recurrent and functionally impairing, establishing loss of acetyltransferase activity as a driver of altered target-gene regulation including glucocorticoid response.\",\n      \"evidence\": \"Resequencing of matched diagnosis/relapse ALL with HAT-activity and target-gene functional assays\",\n      \"pmids\": [\"21390130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve enhancer-level consequences\", \"Non-histone substrate contributions unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Microenvironmental analysis showed CBP haploinsufficiency acts non-cell-autonomously in bone marrow, altering niche factors that govern stem/progenitor maintenance versus myeloproliferation.\",\n      \"evidence\": \"Crebbp+/- BM microenvironment analysis with histomorphometry, CFU-F assays, and MMP9/KITL/ESAM1/CDH5 expression\",\n      \"pmids\": [\"21555743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in niche cells not mapped\", \"Single-lab phenotype\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying SRCAP as a CBP coactivator extended the partner network and linked it to Floating-Harbor syndrome via an intact CBP-binding domain.\",\n      \"evidence\": \"Whole-exome sequencing and protein domain analysis in Floating-Harbor syndrome\",\n      \"pmids\": [\"22265015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical reconstitution of the SRCAP-CBP complex\", \"Functional cooperativity inferred from domain integrity\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining the BCL6/SMRT/HDAC3 counter-regulatory axis answered the mechanism of enhancer dysfunction in CREBBP-mutant B cells and revealed HDAC3 inhibition as a corrective strategy.\",\n      \"evidence\": \"Conditional KO, H3K27ac ChIP-seq, Co-IP, and in vitro/in vivo HDAC3 loss-of-function rescue\",\n      \"pmids\": [\"27733359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct CREBBP enhancer recruitment mechanism not fully resolved\", \"Generality beyond GC B cells untested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating direct KRAS acetylation and H3K18ac loss connected CREBBP to RAS/MAPK signaling and MEK-inhibitor sensitivity in ALL.\",\n      \"evidence\": \"RNAi knockdown in ALL lines and primagrafts with direct KRAS acetylation assay and pathway/MEK-inhibitor readouts\",\n      \"pmids\": [\"27979926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KRAS acetylation site and stoichiometry not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CH1-domain knock-in mice established that this domain is required for CBP's role in cognition, social behavior, and synaptic plasticity, modeling Rubinstein-Taybi neurobehavior.\",\n      \"evidence\": \"CH1-deletion knock-in mouse with behavioral battery and synaptic electrophysiology\",\n      \"pmids\": [\"26730956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular targets underlying behavior not identified\", \"Single mutant allele\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"ZNF384 fusion analysis showed that fusion of CREBBP/EP300 produces dominant-negative loss of HAT activity, linking global acetylation loss to aberrant hematopoietic differentiation and transformation.\",\n      \"evidence\": \"Transcriptome sequencing, luciferase reporters, global acetylation measurement, and HSPC differentiation/transformation assays\",\n      \"pmids\": [\"27903646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific deregulated loci not pinpointed\", \"In vitro transformation only\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple complementary studies established CREBBP as a haploinsufficient tumor suppressor in germinal-center B cells, governing enhancer networks for BCR/CD40 signaling, MHCII-dependent immune surveillance, MYC repression, and p53-dependent DNA-damage response.\",\n      \"evidence\": \"GC-specific conditional KO mice, ChIP-seq, B-cell functional assays, CRISPR knock-in, xenograft/transplant with CD4+ depletion, p53 acetylation assays, and BCL2-cooperation lymphoma models\",\n      \"pmids\": [\"28069569\", \"28831000\", \"28288979\", \"28825697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each program to malignant transformation unresolved\", \"Stage-dependence of premalignant clone selection only partly mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Bromodomain-dependent and substrate-specific studies broadened the mechanistic picture: bromodomains sustain GATA1/MYC and AR enhancer programs, while neuroendocrine CREBBP loss silences Cdh1 to drive SCLC, and FL cells fail to upregulate PRDM1 via aberrant BCL6 retention.\",\n      \"evidence\": \"Bromodomain inhibitor CBP30, ChIP-seq, autochthonous SCLC mouse with Cdh1 ChIP and HDAC-inhibitor rescue, and BCL6 ChIP-qPCR with vorinostat rescue\",\n      \"pmids\": [\"29884215\", \"30181244\", \"30606771\", \"30348636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinct bromodomain versus HAT contributions context-dependent and not unified\", \"Several mechanisms from single labs\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dual Crebbp/Ep300 deletion modeling resolved their overlap-and-divergence, revealing partial compensation through common targets and a synthetic-lethal dependency exploitable in CREBBP-mutant DLBCL.\",\n      \"evidence\": \"Individual and combined GC-directed conditional deletions with in vivo GC assays and selective CREBBP/EP300 inhibitors\",\n      \"pmids\": [\"31519498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of distinct versus shared targets not fully defined\", \"Therapeutic window in patients untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A cluster of substrate and dependency studies extended CREBBP into base excision repair (OGG1/pol β/PCNA), autophagy precursors, NCOA-binding evolution, and lineage-dependent vulnerabilities in TNBC (FOXM1), CARM1 synthetic lethality, and breast-cancer FOXA1 enhancers.\",\n      \"evidence\": \"RSTS lymphoblast BER assays with complementation, cross-species NCBD:CID biophysics, functional genomics screens, CARM1 inhibition, and CPI-1612 with FOXA1/H3K27ac ChIP-seq\",\n      \"pmids\": [\"31504229\", \"32329110\", \"33509944\", \"32576962\", \"35353838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several substrate roles from single labs without reciprocal validation\", \"Acetylation sites not always mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refinements detailed how CREBBP HAT activity controls homologous recombination/radiosensitivity (with a hyperacetylation gain-of-function on BRCA1), macrophage polarization via FBXW7/NOTCH, profibrotic enhancers (ACTA2/COL1A1, collagen VI), E2F3a-CASP8AP2 leukemic proliferation, and a CRISPR-validated CREBBP dependency under EP300 truncation.\",\n      \"evidence\": \"In vivo shRNA radiation screen and HAT inhibitors, CREBBP/EP300 knockdown with NOTCH/CCL2/CSF1 readouts, SGC-CBP30 with ChIP/proteomics, Co-IP/ChIP for E2F3a, and whole-genome CRISPR screens\",\n      \"pmids\": [\"34732714\", \"33431788\", \"32759223\", \"32945392\", \"33911074\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gain-of-function hyperacetylation mechanism needs broader confirmation\", \"Many axes are single-lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Direct acetylation of RB1CC1/FIP200 at K276 established acetylation-ubiquitination crosstalk stabilizing an autophagy regulator, extending CREBBP's non-histone substrate scope.\",\n      \"evidence\": \"Mass spectrometry, acetyltransferase assays, K276 mutagenesis, ubiquitination assays, and autophagy readouts in breast cancer cells\",\n      \"pmids\": [\"36394358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts beyond breast cancer untested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying direct KMT2D acetylation by CREBBP and their enhancer co-complex unified two GC tumor suppressors mechanistically, linking acetylation to H3K4me1 maintenance and synergistic lymphomagenesis.\",\n      \"evidence\": \"Co-IP, direct acetylation assay, H3K27ac/H3K4me1 ChIP-seq, and conditional double-KO mouse model\",\n      \"pmids\": [\"36893259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"KMT2D acetylation site(s) and effect on its catalytic activity not fully resolved\", \"Generality beyond GC B cells untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Compound haploinsufficiency studies showed CREBBP and KMT2D bind chromatin mutually dependently, jointly enabling immune-synapse super-enhancers, with combined loss driving severe immune evasion via CD8+ T-cell exhaustion.\",\n      \"evidence\": \"Compound Crebbp/Kmt2d haploinsufficient mouse with CREBBP/KMT2D ChIP-seq, immune phenotyping, and immune-synapse gene expression; plus A-485 in MLL-r AML with multi-omics\",\n      \"pmids\": [\"38570506\", \"38693103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mutually dependent recruitment not structurally resolved\", \"Clinical translatability of dual-targeting unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CREBBP selects between its many histone and non-histone substrates and is targeted to specific enhancers in each cell type remains unresolved, as does whether gain-of-function hyperacetylation states are a generalizable feature of mutant alleles.\",\n      \"evidence\": \"Not addressed by the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model of enhancer/substrate selection\", \"Structural basis of CREBBP-KMT2D mutual recruitment unknown\", \"Gain-of-function versus loss-of-function balance across mutation classes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [14, 15, 19, 22, 5]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 11, 14, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 17, 23, 34]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [34, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 19, 32]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 2, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 17, 34]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 2, 19, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 20]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5, 22, 21]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 29, 30, 32]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 25, 22]}\n    ],\n    \"complexes\": [\n      \"CREBBP/KMT2D enhancer complex\",\n      \"BCL6/SMRT/HDAC3 repressor complex (counter-regulatory)\"\n    ],\n    \"partners\": [\n      \"KMT2D\",\n      \"EP300\",\n      \"BCL6\",\n      \"HDAC3\",\n      \"PHOX2B\",\n      \"SRCAP\",\n      \"E2F3a\",\n      \"NCOA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}