{"gene":"HDAC3","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":1998,"finding":"HDAC3 encodes a 428-amino acid nuclear protein that exhibits histone deacetylase activity on both free histones and purified nucleosomes; activity is inhibited by trichostatin A, trapoxin, and butyrate in vitro, establishing it as a human RPD3 ortholog with enzymatic deacetylase function.","method":"Immunoprecipitation, in vitro deacetylase assay on free histones and nucleosomes, pharmacological inhibition, Western blot/subcellular fractionation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic reconstitution with multiple substrates and pharmacological validation; foundational characterization paper","pmids":["9501169"],"is_preprint":false},{"year":2010,"finding":"HDAC3 is required for efficient DNA replication and DNA damage repair; loss of HDAC3 increases H3K9/K14ac, H4K5ac, and H4K12ac, impairs chromatin compaction and heterochromatin content, and retains histone deposition marks. siRNA targeting of the HDAC3 cofactors NCOR1 and SMRT (NCOR2) increases H4K5ac and causes DNA damage, establishing the HDAC3/NCOR/SMRT axis as critical for chromatin structure and genomic stability.","method":"Conditional liver-specific Hdac3 knockout, siRNA knockdown of NCOR1/SMRT, ChIP for histone modifications, DNA damage assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined molecular and cellular phenotypes, replicated with siRNA targeting cofactors, multiple orthogonal methods","pmids":["21075309"],"is_preprint":false},{"year":2013,"finding":"Deacetylase-dead HDAC3 mutants rescue hepatosteatosis and repress lipogenic gene expression in HDAC3-depleted mouse liver, demonstrating a deacetylase-independent transcriptional function. Interaction with NCOR (but not SMRT) is essential for this in vivo function; liver-specific NCOR knockout phenocopies HDAC3 loss metabolically.","method":"Liver-specific knockout, knock-in of deacetylase-dead mutants, pharmacologic HDAC inhibition in primary hepatocytes, liver-specific NCOR/SMRT knockouts, gene expression analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — catalytic-dead mutant rescue in vivo, conditional KO of cofactors, multiple orthogonal approaches in single rigorous study","pmids":["24268577"],"is_preprint":false},{"year":2011,"finding":"HDAC3 genomic occupancy in mouse liver follows a pronounced circadian pattern on lipid metabolism genes, inversely correlating with histone acetylation and RNA polymerase II recruitment. The HDAC3 cistrome overlaps significantly with Rev-erbα and its binding partner NCoR, linking circadian clock machinery to hepatic de novo lipogenesis via HDAC3-mediated epigenomic remodeling.","method":"Liver-specific Hdac3 knockout, genome-wide ChIP-seq for HDAC3, NCoR, Rev-erbα, H3 acetylation, and RNA Pol II","journal":"Cold Spring Harbor symposia on quantitative biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with conditional KO, multiple chromatin marks, consistent with companion full-paper data","pmids":["21900149"],"is_preprint":false},{"year":2006,"finding":"Laminar flow stabilizes and activates HDAC3 through the Flk-1–PI3K–Akt pathway; activated HDAC3 deacetylates p53, leading to p21 activation and endothelial progenitor cell differentiation into endothelial cells.","method":"ES cell differentiation assay under laminar flow/VEGF, kinase pathway inhibitors, HDAC3 knockdown/overexpression, p53 deacetylation assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling pathway with multiple inhibitor validations and KD/OE, single lab","pmids":["16982804"],"is_preprint":false},{"year":2015,"finding":"PGK1 is acetylated at lysine 220 (inhibiting its activity) by KAT9, and deacetylated by HDAC3. Insulin activates the PI3K/AKT/mTOR pathway to phosphorylate HDAC3 at S424, promoting HDAC3–PGK1 interaction and K220 deacetylation, thereby stimulating PGK1 enzymatic activity.","method":"Co-IP, in vitro deacetylation assay, acetylation-mimetic/deficient mutants, mTOR pathway inhibitors, phospho-specific analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deacetylation assay, mutagenesis of substrate and kinase pathway, single lab but multiple orthogonal methods","pmids":["26356530"],"is_preprint":false},{"year":2020,"finding":"During LPS-stimulated macrophage activation, HDAC3 is recruited to ATF2-bound chromatin sites without NCoR1/2 and activates inflammatory gene expression through a non-canonical, deacetylase-independent mechanism. Conversely, HDAC3 deacetylase activity is selectively engaged at ATF3-bound sites to suppress Toll-like receptor signaling. Loss of HDAC3 protects mice from lethal LPS exposure, but abolition of catalytic activity alone does not confer this protection.","method":"Macrophage-specific Hdac3 knockout, catalytic-dead HDAC3 knock-in, ChIP-seq, genomic co-occupancy analysis with ATF2/ATF3, in vivo LPS challenge","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — catalytic-dead knock-in distinguishes enzymatic from scaffolding functions, genome-wide ChIP-seq, in vivo genetic validation, multiple orthogonal approaches","pmids":["32760002"],"is_preprint":false},{"year":2020,"finding":"Microbiota-derived inositol-1,4,5-trisphosphate (InsP3) directly promotes HDAC3 activity in intestinal epithelial cells, activating HDAC3-dependent proliferation and counteracting butyrate inhibition. InsP3 and Ins(1,4,5,6)P4 bind the same domains on HDAC3; while Ins(1,4,5,6)P4 promotes HDAC3–NCoR complex formation, InsP3 acts as an activating metabolite.","method":"Germ-free vs microbiota-replete mouse comparison, intestinal organoids, biochemical HDAC3 activity assay, InsP3/phytate treatment, HDAC3 knockout cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical activity assay, genetic KO validation, in vivo germ-free model, multiple orthogonal methods in single study","pmids":["32731255"],"is_preprint":false},{"year":2021,"finding":"NADPH directly binds HDAC3 and disrupts the association between HDAC3 and its co-activators NCoR2 (SMRT) or NCoR1, impairing HDAC3 activation and thereby increasing histone acetylation. NADPH and Ins(1,4,5,6)P4 compete for the same binding domains on HDAC3, with NADPH having higher affinity, whereas Ins(1,4,5,6)P4 promotes HDAC3–NCoR complex formation.","method":"NADPH binding assay, Co-IP of HDAC3–NCoR disruption, competitive binding with Ins(1,4,5,6)P4, HDAC3 inhibitor rescue, knockdown of NADPH-generating enzymes","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding and competition assay, multiple genetic and biochemical approaches, rigorous mechanistic dissection","pmids":["33462516"],"is_preprint":false},{"year":2016,"finding":"BCL6 forms a repressor complex with SMRT and HDAC3 that binds extensively to MHC class II loci and other enhancers; CREBBP loss enables unopposed deacetylation at these enhancers by BCL6/SMRT/HDAC3, silencing B-cell signaling and immune response genes. HDAC3 loss-of-function rescues enhancer H3K27 acetylation and gene expression, suppressing CREBBP-mutant lymphomas.","method":"ChIP-seq, Co-IP of BCL6/SMRT/HDAC3 complex, conditional HDAC3 KO in murine lymphoma model, in vitro and in vivo rescue experiments","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, reciprocal Co-IP of complex, in vivo genetic rescue, multiple orthogonal methods","pmids":["27733359"],"is_preprint":false},{"year":2015,"finding":"HDAC3 deacetylates p53 and suppresses p53-dependent apoptosis. PINK1 phosphorylates HDAC3 at Ser-424, enhancing its deacetylase activity and promoting direct association with p53, leading to p53 hypoacetylation. Protein phosphatase 4c reverses PINK1-mediated HDAC3 phosphorylation. PINK1-mediated phosphorylation also prevents oxidative stress-induced C-terminal cleavage of HDAC3.","method":"Co-IP, in vitro kinase assay (PINK1 phosphorylating HDAC3), phospho-mimetic mutant HDAC3(S424E), PINK1 KO MEFs, deacetylase activity assay, phosphatase assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase/phosphatase assays, phospho-mimetic rescue, KO genetic validation, multiple orthogonal methods","pmids":["25305081"],"is_preprint":false},{"year":2015,"finding":"PDCD5 mediates dissociation of HDAC3 from p53 under genotoxic stress, leading to HDAC3 cleavage and ubiquitin-dependent proteasomal degradation; this releases p53 inhibition. Casein kinase 2α phosphorylates PDCD5 at Ser-119 to stabilize it and promote importin 13-mediated nuclear translocation of PDCD5. PDCD5 deletion abrogates etoposide-induced p53 stabilization and HDAC3 cleavage.","method":"Co-IP, ubiquitination assay, PDCD5 KO MEFs, CK2α kinase assay, importin 13 interaction assay, proteasome inhibitor experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — KO genetic rescue, in vitro kinase assay, multiple Co-IP and ubiquitination assays, genetic and pharmacological validation","pmids":["26077467"],"is_preprint":false},{"year":2019,"finding":"HDAC3 deacetylates H3K9 specifically; ablation of HDAC3 (but not other class I HDACs) disrupts H3K9 deacetylation and the consequent trimethylation of H3K9 (H3K9me3), impairing the first step of double-strand break repair. Hyperacetylated H3K9ac simultaneously acts as a transcriptional activator, promoting tumorigenic signaling.","method":"Individual class I HDAC KO mouse models, ChIP for H3K9ac/H3K9me3, DNA damage assays, gene expression analysis","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — comparative KO panel establishing isoform specificity, ChIP for multiple histone marks, consistent with published HDAC3/DNA damage literature","pmids":["31097476"],"is_preprint":false},{"year":2017,"finding":"In response to oscillatory shear stress, transcription factors TAL1, GATA2, and ETS1/2 physically interact with and recruit HDAC3 to the E-box–GATA–ETS composite element of a GATA2 intragenic enhancer. HDAC3 in turn recruits histone acetyltransferase EP300 to form an enhanceosome complex that promotes GATA2 expression, which is required for lymphovenous and lymphatic valve morphogenesis.","method":"Endothelium-specific Hdac3 KO in mice, Co-IP of HDAC3 with TAL1/GATA2/ETS1/2/EP300, ChIP at GATA2 enhancer, shear stress assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with defined phenotype, Co-IP of multi-protein enhanceosome, ChIP at specific enhancer, multiple orthogonal methods","pmids":["29035278"],"is_preprint":false},{"year":2019,"finding":"HDAC3 controls the meiotic-to-postmeiotic transition in spermatogenesis in a deacetylase-independent manner. Abolishing HDAC3 catalytic activity via NCoR/SMRT knock-in mutations causes histone hyperacetylation identical to KO but does not cause infertility, whereas KO does. SOX30 recruits HDAC3 to its genomic binding sites in testes; loss of SOX30 abolishes HDAC3 cistromic recruitment.","method":"Three independent testis-specific Hdac3 KO mouse lines, NCoR/SMRT catalytic-dead knock-in mice, RNA-seq, histone acetylation ChIP-seq, SOX30 KO","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — three independent KO lines, catalytic-dead knock-in comparison, genome-wide ChIP-seq, genetic SOX30 epistasis","pmids":["33939832"],"is_preprint":false},{"year":2019,"finding":"HDAC3 enzymatic activity is required for skeletal muscle fuel metabolism. NS-DADm knock-in mice (which ablate HDAC3 deacetylase activity via NCoR/SMRT mutations without altering HDAC3 protein levels) show the same metabolic phenotypes as HDAC3-depleted muscle—reduced force generation, enhanced fatty acid oxidation, reduced glucose uptake, altered BCAA catabolism gene expression—establishing that, unlike in liver or embryonic development, the muscle metabolic function requires catalytic activity.","method":"NCoR/SMRT DAD-mutant knock-in mouse model (NS-DADm), metabolic phenotyping, gene expression analysis, comparison to muscle-specific HDAC3 KO","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — catalytic-dead knock-in directly tests enzymatic requirement, side-by-side comparison with protein-level KO, multiple metabolic readouts","pmids":["30428023"],"is_preprint":false},{"year":2019,"finding":"PP4-dependent dephosphorylation of HDAC3 inactivates its catalytic activity following peripheral nerve injury, enhancing histone H3K9 acetylation and enabling a regenerative gene expression program. Central spinal cord injury does not trigger this calcium–PP4–HDAC3 dephosphorylation cascade, explaining regenerative failure. Genetic or pharmacological HDAC3 inhibition overcomes regenerative failure after spinal cord injury.","method":"Pharmacological screen in DRG neurons, in vivo PP4 inhibitor, H3K9ac ChIP-seq from ex vivo DRG, RNA-seq, genetic HDAC3 inhibition, spinal cord injury model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq and RNA-seq in vivo, PP4 pharmacological and genetic epistasis, multiple orthogonal methods","pmids":["31268609"],"is_preprint":false},{"year":2020,"finding":"HDAC3 controls NICD1 (Notch1 intracellular domain) acetylation levels, directly affecting NICD1 protein stability. Genetic loss-of-function of HDAC3 or nanomolar HDAC inhibitor treatment reduces Notch target gene expression with local reduction of histone acetylation. An HDAC3-insensitive NICD1 mutant is more stable but biologically less active.","method":"Hdac3 genetic KO, HDAC inhibitor treatment, NICD1 acetylation assay, NICD1 stability (cycloheximide chase), HDAC3-insensitive NICD1 mutant expression","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic KO, acetylation assay on substrate, stability assay with acetylation-resistant mutant, multiple orthogonal approaches","pmids":["32107550"],"is_preprint":false},{"year":2020,"finding":"HDAC3 deacetylates the MutSβ subunit Msh3 at five key lysine residues to activate MutSβ-driven trinucleotide repeat expansions. HDAC3 inhibition suppresses repeat expansion without impairing canonical mismatch repair; Msh3 arginine-substitution mutants at these lysine residues bypass the inhibitory effect of HDAC3 inhibitor. HDAC3 activity also partially controls MutSβ nuclear localization via deacetylation sites overlapping the Msh3 nuclear localization signal.","method":"HDAC3-selective inhibitor RGFP966, Msh3 lysine-to-arginine mutants, trinucleotide repeat expansion assay, mismatch repair assay, subcellular localization analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis of substrate lysines, functional rescue/bypass assay, multiple mechanistic readouts in single study","pmids":["32900932"],"is_preprint":false},{"year":2018,"finding":"HDAC3 inhibition reduces SMARCA4 activity, derepressing miR-27a, which in turn destabilizes PAX3:FOXO1 mRNA in alveolar rhabdomyosarcoma cells. This HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit drives chemoresistance.","method":"HDAC3-selective inhibition (entinostat), HDAC3 genetic knockdown, miR-27a quantification, PAX3:FOXO1 mRNA stability assay, SMARCA4 activity assay, preclinical mouse models","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological HDAC3 inhibition with defined molecular cascade, single lab","pmids":["30459282"],"is_preprint":false},{"year":2019,"finding":"HDAC3 loss in the uterus causes implantation failure and decidualization defects through aberrant transcriptional activation of COL1A1 and COL1A2 genes; HDAC3 normally represses these collagen genes. Reduction of HDAC3 leads to p300 recruitment to Col1a1/Col1a2 loci; inhibition of p300 permits decidualization in HDAC3-attenuated cells.","method":"Conditional Hdac3 KO in PGR-positive cells (mouse uterus), expression microarray, ChIP-seq, primary human endometrial stromal cell culture, p300 inhibitor rescue","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, ChIP-seq identifying direct target genes, pharmacological rescue with p300 inhibitor, translational to human cells","pmids":["30626716"],"is_preprint":false},{"year":2019,"finding":"HDAC3 occupies H3K9me3/H3K14ac bivalent chromatin regions in liver together with H3K9 methyltransferase SETDB1 in a KAP1 complex, correlating with H3K9me3 presence. This bivalent state is reduced with aging, and associated genes (regulating cholesterol secretion and triglyceride synthesis) are upregulated when bivalency is lost.","method":"Quantitative targeted mass spectrometry of histone modifications, sequential ChIP-seq (reChIP), bulk ChIP-seq for HDAC3/SETDB1/KAP1, young vs aged liver comparison","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and mass spectrometry, single lab, correlative between HDAC3 occupancy and histone marks","pmids":["31858687"],"is_preprint":false},{"year":2018,"finding":"c-Src kinase directly phosphorylates HDAC3 at tyrosine residues Y325, Y328, and Y331 (C-terminal domain), increasing HDAC3 deacetylase activity. EGF stimulation via EGFR activates c-Src to phosphorylate HDAC3, which is then recruited to the plasma membrane. Phosphorylation-deficient HDAC3(Y328/331A) lacks deacetylase activity and reduces breast cancer cell invasiveness.","method":"Co-IP, in vitro kinase assay (c-Src phosphorylating HDAC3), phospho-specific antibody, phospho-deficient mutant HDAC3, TIRF microscopy for membrane recruitment, invasion assay","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, site-directed phospho-deficient mutants, phospho-specific antibody validation, multiple functional readouts","pmids":["31430896"],"is_preprint":false},{"year":2018,"finding":"c-Src directly binds the C-terminal domain (277–428 aa) of HDAC3 and phosphorylates HDAC3 at Y325, Y328, and Y331; wild-type but not kinase-inactive c-Src (K298M) increases HDAC3 deacetylase activity. Triple alanine substitution of these tyrosines abolishes deacetylase activity. Phosphorylation-dependent HDAC3 activity promotes proliferation of HER2-positive breast cancer cells.","method":"Co-IP with deletion mutants, in vitro kinase assay, deacetylase activity assay, phospho-deficient triple mutant, proliferation assay","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay, domain mapping by Co-IP with deletion mutants, mutagenesis-based functional validation","pmids":["30317579"],"is_preprint":false},{"year":2019,"finding":"Mdm2 directly interacts with HDAC3 and induces HDAC3 monoubiquitination (requiring the Mdm2 RING domain), which stabilizes HDAC3 protein without altering its mRNA levels. MdmX cooperates with Mdm2 in this regulation. Mdm2 ablation decreases HDAC3 levels and reduces cell migration.","method":"Co-IP, ectopic expression of wild-type vs. RING-mutant Mdm2, ubiquitination assay, Mdm2 knockdown, migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and direct ubiquitination assay with RING mutant, single lab","pmids":["31358320"],"is_preprint":false},{"year":2018,"finding":"PIWIL2 interacts with HDAC3, stabilizing it by competing with the E3 ubiquitin ligase Siah2 for binding, thereby preventing ubiquitin-mediated HDAC3 degradation. PIWIL2 also facilitates interaction between HDAC3 and CK2α, promoting CK2α-mediated phosphorylation and activation of HDAC3.","method":"Co-IP of PIWIL2/HDAC3/Siah2/CK2α, competitive binding assay, ubiquitination assay, HDAC3 activity assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with competitive binding, ubiquitination assay, single lab","pmids":["29555935"],"is_preprint":false},{"year":2020,"finding":"PACS-1 interacts with HDAC2 and HDAC3 in the nucleus and is required for HDAC2/HDAC3-dependent chromatin maturation. PACS-1 knockdown causes proteasome-mediated degradation of HDAC2 and HDAC3, leading to elevated H3K9 and H4K16 acetylation and increased replication stress-induced DNA damage.","method":"Co-IP of PACS-1 with HDAC2/HDAC3, PACS-1 knockdown, proteasome inhibitor rescue, histone modification analysis, DNA damage assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and KD with defined molecular and cellular phenotypes, single lab","pmids":["31988453"],"is_preprint":false},{"year":2020,"finding":"DBC1 competes with HDAC3 for the same binding sites on the transcription elongation factor ELL, thereby preventing HDAC3-mediated deacetylation and consequent destabilization of ELL. HDAC3-mediated deacetylation of ELL promotes its polyubiquitylation by Siah1 E3 ligase, leading to ELL degradation; p300-mediated acetylation has the opposing stabilizing effect.","method":"Co-IP of DBC1/HDAC3/p300/Siah1 with ELL, competitive binding assay, acetylation/ubiquitination assays, DBC1 knockdown, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro acetylation and ubiquitination assays, competitive binding Co-IP, genetic KD with defined transcriptional consequences, multiple orthogonal methods","pmids":["32152128"],"is_preprint":false},{"year":2022,"finding":"HDAC3 deacetylase activity is required for FGF9 and IGF2 expression in epicardial cells to promote myocardial growth; Hdac3 KO epicardial cells upregulate miR-322 and miR-503, which repress FGF9 and IGF2. FGF9 or IGF2 supplementation rescues the myocardial proliferation defect. Knockdown of miR-322 or miR-503 restores FGF9/IGF2 expression in Hdac3 KO cells.","method":"Epicardial-specific Hdac3 KO mouse, transcriptomic analysis, miRNA quantification, miR-322/miR-503 overexpression/knockdown, FGF9/IGF2 rescue experiment","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined molecular cascade, multiple rescue experiments, single lab","pmids":["35722872"],"is_preprint":false},{"year":2017,"finding":"HDAC3 inhibition triggers degradation of c-Myc protein, leading to downregulation of DNMT1 expression in multiple myeloma cells. Additionally, HDAC3 inhibition causes hyperacetylation of DNMT1 protein itself, reducing its stability. HDAC3 knockdown (but not HDAC1 or HDAC2) specifically mediates these effects.","method":"HDAC3-selective siRNA (vs HDAC1/HDAC2), HDAC3-selective inhibitor BG45, c-Myc degradation assay, DNMT1 acetylation and stability assay, xenograft mouse model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific siRNA comparison, protein stability and acetylation assays, in vivo xenograft, single lab","pmids":["28490812"],"is_preprint":false},{"year":2023,"finding":"HDAC3 deacetylates PML-RARα at lysine 394, reducing PIAS1-mediated SUMOylation and subsequent RNF4-induced ubiquitylation, thereby stabilizing the PML-RARα oncoprotein. HDAC3 inhibition promotes PML-RARα ubiquitylation and degradation in both wild-type and ATRA/ATO-resistant APL cells.","method":"Co-IP, in vitro deacetylation assay, acetylation mutant of PML-RARα at K394, SUMOylation and ubiquitylation assays, HDAC3 inhibitor/genetic KD, xenograft models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-specific acetylation mutant, in vitro deacetylation assay, sequential PTM cascade (deacetylation→SUMOylation→ubiquitylation) validated, in vivo xenograft","pmids":["36894687"],"is_preprint":false},{"year":2022,"finding":"HOXB13 physically interacts with HDAC3 (interaction disrupted by the G84E cancer-associated mutation) and recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators including FASN, independently of androgen receptor.","method":"Co-IP of HOXB13/HDAC3, ChIP-seq for HDAC3 and HOXB13 at lipogenic enhancers, HOXB13 G84E mutant interaction assay, HDAC3 histone deacetylation assay at enhancers, xenograft tumor metastasis model","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with disease-relevant mutant, ChIP-seq, functional rescue experiments, in vivo xenograft, multiple orthogonal methods","pmids":["35468964"],"is_preprint":false},{"year":2023,"finding":"HDAC3 directly binds to the Gpx4 promoter together with transcription factor KLF5 upon aristolochic acid treatment, causing local histone hypoacetylation and transcriptional inhibition of GPX4, which drives ferroptosis during AKI-CKD transition. HDAC3 and KLF5 co-IP confirms inducible association.","method":"HDAC3 conditional KO, HDAC3-selective inhibitor RGFP966, Co-IP of HDAC3/KLF5, ChIP at Gpx4 promoter, KLF5 inhibitor ML264, GPX4 inactivator RSL3 rescue experiment","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP at specific promoter, genetic and pharmacological inhibition with rescue, single lab","pmids":["37890360"],"is_preprint":false},{"year":2023,"finding":"HDAC3 deacetylates FOXO1 and promotes its nuclear translocation in LPS-stimulated alveolar epithelial cells; nuclear FOXO1 transcriptionally activates ROCK1, which upon phosphorylation by RhoA disrupts mitochondrial quality control and promotes acute lung injury.","method":"HDAC3 conditional KO (Sftpc-cre; Hdac3f/f), FOXO1 acetylation assay, nuclear fractionation, ROCK1 promoter analysis, RhoA activation assay, pharmacological rescue","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, acetylation assay with nuclear translocation, defined molecular pathway, single lab","pmids":["37244125"],"is_preprint":false},{"year":2023,"finding":"HDAC3 interacts with and deacetylates Nrf2, reducing Nrf2 acetylation in cardiomyocytes. HDAC3 inhibition increases Nrf2 acetylation, while HDAC3 overexpression decreases it. Nrf2 acetylation promotes its activity and reduces oxidative stress.","method":"Co-IP of HDAC3/Nrf2, Nrf2 acetylation assay, HDAC3 inhibitor (RGFP966) vs adenoviral HDAC3 overexpression, Nrf2 inhibitor rescue","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and acetylation assay, gain- and loss-of-function, single lab","pmids":["39505146"],"is_preprint":false},{"year":2023,"finding":"HDAC3 directly deacetylates SRF (serum response factor), enhancing SRF transcriptional activity in vascular smooth muscle cells; SMYD2 promotes HDAC3 expression via H3K36 tri-methylation at the HDAC3 promoter. HDAC3-SRF axis mediates VSMC phenotypic switching and neointimal hyperplasia in a deacetylase-dependent manner.","method":"Co-IP of HDAC3/SRF, SRF acetylation assay, SMYD2 ChIP at HDAC3 promoter, RGFP966 HDAC3 inhibitor, Smyd2-vTg and SMYD2 KD VSMCs, carotid artery injury model","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and acetylation assay on non-histone substrate, ChIP epistasis, in vivo model, single lab","pmids":["38322347"],"is_preprint":false},{"year":2023,"finding":"Epithelial HDAC3 is essential for NF-κB-dependent regulation of epithelial MHC class II (MHCII) expression; epithelial MHCII reduces commensal-specific Th17 accumulation and protects against microbiota-triggered inflammation. Microbiota colonization concurrently induces epithelial HDAC3 expression and commensal-specific CD4+ T cells.","method":"Epithelium-specific Hdac3 KO, commensal-specific T cell tetramer analysis, ChIP for HDAC3 at MHCII locus, NF-κB pathway analysis, germ-free colonization experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — epithelium-specific KO, mechanistic ChIP, germ-free colonization model, multiple immune readouts, single lab with multiple orthogonal approaches","pmids":["36602872"],"is_preprint":false},{"year":2023,"finding":"HDAC3 inhibition in liver reduces Hamp (hepcidin) mRNA via activation of the Hippo/YAP signaling pathway; HDAC3 loss leads to increased nuclear YAP translocation, and YAP binds repressor sites within the HAMP promoter to suppress hepcidin expression. Knock-in of constitutively active YAP (K342M) phenocopies hepcidin reduction in Hdac3-LKO mice.","method":"Hdac3 liver-specific KO, Hippo pathway inhibitor, YAP overexpression (constitutively active K342M knock-in), HAMP promoter reporter assay, Yap KD in Hdac3-LKO mice","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, promoter reporter, constitutively active epistasis knock-in, single lab","pmids":["38034086"],"is_preprint":false},{"year":2023,"finding":"PDCD5 promotes HDAC3 ubiquitination and degradation to reduce fibrotic responses; SMAD3 directly upregulates PDCD5 during cardiac fibrosis, and the resulting PDCD5-mediated HDAC3 inhibition suppresses profibrogenic gene expression. AAV9-mediated HDAC3 overexpression eliminates the protective effects of PDCD5 knock-in.","method":"Co-IP of PDCD5/HDAC3, HDAC3 ubiquitination assay, cardiac fibroblast KD/OE, fibroblast-specific PDCD5 knock-in mice, AAV9-HDAC3 rescue, SMAD3 ChIP","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic rescue in vivo, single lab","pmids":["37345556"],"is_preprint":false},{"year":2024,"finding":"TRAP1-mediated metabolic reprogramming increases aerobic glycolysis and lactate production, which down-regulates HDAC3 activity; reduced HDAC3 delactylase activity allows accumulation of H4K12 lactylation (H4K12la) at SASP promoters, activating SASP transcription and exacerbating VSMC senescence in atherosclerosis.","method":"VSMC-specific Trap1 KO mice, H4K12la ChIP at SASP promoters, HDAC3 activity assay (delactylase), metabolic profiling","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, KO mouse model, HDAC3 delactylase activity assay, single lab","pmids":["39088352"],"is_preprint":false},{"year":2025,"finding":"H4K12 lactylation (H4K12la) in macrophages inhibits HDAC3 expression, forming a feedback loop; HDAC3 activation reduces H4K12la levels. MCT1-mediated lactate uptake drives KAT5/KAT8-dependent H4K12la, which enriches at TGF-β1/TGF-β3 promoters and represses HDAC3. CUT&Tag and RNA-seq identified this feedback loop between H4K12la and HDAC3.","method":"CUT&Tag, RNA-seq, H4K12la ChIP at TGF-β promoters, HDAC3 overexpression rescue, macrophage depletion, MCT1 inhibitor","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag and RNA-seq, genetic rescue, single lab","pmids":["39945346"],"is_preprint":false},{"year":2020,"finding":"HDAC3 transcriptionally promotes cGAS expression in microglia and potentiates cGAS-STING pathway activation by regulating acetylation and nuclear localization of p65 (NF-κB subunit). ChIP confirmed HDAC3 occupancy at the cGAS promoter region.","method":"Co-IP, ChIP, dual-luciferase reporter assay, microglial HDAC3 conditional KO, Western blot for p65 acetylation and localization","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay, conditional KO in microglia, single lab","pmids":["32863951"],"is_preprint":false},{"year":2020,"finding":"HDAC3 directly binds to promoter regions of CXCL9, CXCL10, and CXCL11 to inhibit their expression; Hdac3-deficient tumor cells express high levels of these chemokines, recruiting CXCR3+ T cells to suppress tumor growth in immunocompetent mice.","method":"Hdac3 KO tumor cell lines, ChIP at CXCL9/10/11 promoters, CXCR3+ T cell infiltration quantification, immunocompetent vs immunodeficient mouse tumor models","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishing direct promoter binding, genetic KO, in vivo immune readout, single lab","pmids":["36898011"],"is_preprint":false},{"year":2020,"finding":"Hdac3 microglial KO specifically inhibits proliferation of proinflammatory microglia after ischemic stroke by closing chromatin regions enriched with PU.1 motifs (ATAC-seq). AAV-mediated overexpression of PU.1 reverses HDAC3-KO-induced proliferation inhibition, establishing PU.1 as a downstream mediator of HDAC3 in stroke neuroinflammation.","method":"Microglial-specific Hdac3 KO, RNA-seq, ATAC-seq, AAV-PU.1 overexpression rescue, microglial proliferation assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, genome-wide chromatin accessibility (ATAC-seq), RNA-seq, AAV genetic rescue establishing PU.1 epistasis, multiple orthogonal methods","pmids":["38446877"],"is_preprint":false},{"year":2021,"finding":"HDAC3 transactivates KDELR2 via CREB1; ChIP validated CREB1 binding to the KDELR2 promoter in an HDAC3-dependent manner. HDAC3-KDELR2 axis accelerates cell cycle progression by protecting centrosomal protein POC5 from proteasomal degradation.","method":"ChIP for CREB1 at KDELR2 promoter, HDAC3 KD, Co-IP of KDELR2/POC5, cell cycle analysis, breast cancer mouse model","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, gain- and loss-of-function, single lab","pmids":["34146461"],"is_preprint":false},{"year":2018,"finding":"PRDM16 physically interacts with HDAC3 in adipocytes; HDAC3-selective inhibitor RGFP966 induces thermogenic gene expression in murine and human fat cultures, but this induction is blunted in the absence of PRDM16, placing HDAC3 upstream of PRDM16 in the thermogenic program.","method":"Co-IP of PRDM16/HDAC3, HDAC3-selective inhibitor RGFP966 in murine and human fat cultures, PRDM16-null cells as epistasis control","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, PRDM16-null epistasis, pharmacological inhibition in primary cultures, single lab","pmids":["29757434"],"is_preprint":false},{"year":2015,"finding":"Phosphorylation of HDAC3 at S424 (a mark necessary for deacetylase activity) is suppressed in osseous cells from aged mice, and HDAC3 expression is reduced in bone cells from postmenopausal compared to young women. Adenoviral restoration of Hdac3 in Hdac3-depleted bone marrow stromal cells restores normal gene expression, demonstrating direct causal control of glucocorticoid activation (Hsd11b1) and lipid storage (Fsp27/Cidec, Plin1) genes.","method":"Conditional Hdac3 KO in osteochondroprogenitors, adenoviral Hdac3 rescue, S424 phosphorylation analysis in aged vs young bone, gene expression profiling","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with adenoviral rescue, phosphorylation analysis, single lab","pmids":["26211746"],"is_preprint":false},{"year":2020,"finding":"Hdac3 deacetylates the p65 subunit of NF-κB at K310, decreasing NF-κB DNA-binding and transcriptional activity in osteoclasts. Hdac3-deficient osteoclasts show increased K310 NF-κB acetylation, NF-κB hyperactivation, hypersensitivity to RANKL, and elevated bone resorption; Hdac3 also controls osteoclast-derived sphingosine-1-phosphate coupling to bone formation.","method":"Ctsk-cre conditional Hdac3 KO, NF-κB acetylation (K310) assay, RANKL responsiveness assay, pit formation (resorption) assay, sphingosine-1-phosphate production assay, conditioned medium mineralization assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, NF-κB acetylation assay, functional bone resorption assays, single lab","pmids":["33454009"],"is_preprint":false}],"current_model":"HDAC3 is a nuclear class I histone deacetylase whose catalytic activity depends on interaction with NCoR1/NCoR2 (SMRT) corepressors via inositol phosphate (InsP4/InsP3) and NADPH-regulated allosteric mechanisms; it deacetylates histones (particularly H3K9, H4K5, H4K12) and a growing list of non-histone substrates (p53, PGK1, NICD1, MutSβ/Msh3, PML-RARα, SRF, FOXO1, Nrf2, ELL, β-catenin, NF-κB p65), is regulated by post-translational modifications (phosphorylation by PINK1/CK2α/c-Src at S424/Y325/Y328/Y331, monoubiquitination by Mdm2), and is recruited to specific genomic loci by transcription factors (BCL6, Rev-erbα, HOXB13, SOX30, ATF2/ATF3, TAL1/GATA2/ETS1/2); it additionally possesses a deacetylase-independent scaffolding function essential for certain developmental and transcriptional contexts (hepatic lipid metabolism with NCOR1, spermatogenesis via SOX30, macrophage inflammatory gene activation via ATF2), making it a dichotomous regulator of transcription, DNA repair, circadian metabolism, immune responses, and tissue homeostasis."},"narrative":{"mechanistic_narrative":"HDAC3 is a nuclear class I histone deacetylase that orchestrates transcription, genome stability, and metabolic homeostasis by removing acetyl marks from both histones and a broad set of non-histone substrates [PMID:9501169, PMID:21075309]. Its catalytic activity is held in check until it docks onto the NCoR1/SMRT (NCOR2) corepressors, an allosteric switch tuned by competing small-molecule ligands: inositol phosphates such as Ins(1,4,5,6)P4 promote HDAC3–NCoR complex assembly and activation, microbiota-derived InsP3 acts as an activating metabolite, while NADPH binds the same domains with higher affinity to disrupt the complex and dampen deacetylation [PMID:32731255, PMID:33462516]. Through this corepressor axis HDAC3 deacetylates histone H3K9/H4K5/H4K12 to compact chromatin and enable double-strand break repair and DNA replication, and it sets up bivalent H3K9me3/H3K14ac chromatin with SETDB1/KAP1 [PMID:21075309, PMID:31097476, PMID:31858687]. A defining feature is its functional dichotomy: HDAC3 can act either as an enzyme or as a catalytically dispensable scaffold, with catalytic-dead knock-in models showing that hepatic lipid metabolism (with NCOR1), spermatogenesis (via SOX30 recruitment), and macrophage inflammatory gene activation (at ATF2 sites) proceed without deacetylase activity, whereas skeletal muscle fuel metabolism requires it [PMID:24268577, PMID:32760002, PMID:33939832, PMID:30428023]. HDAC3 is recruited to specific loci by sequence-specific factors—Rev-erbα/NCoR to drive circadian hepatic lipogenesis, BCL6/SMRT to repress immune enhancers, HOXB13 to suppress lipogenic genes, and TAL1/GATA2/ETS to build a flow-responsive enhanceosome [PMID:21900149, PMID:27733359, PMID:35468964, PMID:29035278]. Beyond chromatin, HDAC3 deacetylates non-histone targets including p53 (suppressing apoptosis), NICD1, Msh3/MutSβ (activating trinucleotide repeat expansion), PML-RARα, FOXO1, Nrf2, SRF, and NF-κB p65, coupling it to apoptosis, mismatch-repair-driven instability, oncoprotein stability, and oxidative/inflammatory signaling [PMID:25305081, PMID:32107550, PMID:32900932, PMID:36894687, PMID:33454009]. Its activity is further controlled by phosphorylation—PINK1, CK2α, and c-Src phosphorylate HDAC3 (S424, Y325/328/331) to enhance activity, PP4 dephosphorylation inactivates it—and by ubiquitin-dependent stability control via Mdm2, PDCD5/Siah2, and PIWIL2 [PMID:25305081, PMID:31430896, PMID:31268609, PMID:31358320, PMID:29555935, PMID:37345556].","teleology":[{"year":1998,"claim":"Establishing that HDAC3 is a bona fide enzyme answered whether the gene encodes an active histone deacetylase rather than merely a homolog.","evidence":"Immunoprecipitation and in vitro deacetylase assays on free histones and nucleosomes with pharmacological inhibition","pmids":["9501169"],"confidence":"High","gaps":["Did not define physiological substrates or cofactor requirements","Genomic targeting and regulation unaddressed"]},{"year":2006,"claim":"Linking laminar flow signaling to HDAC3 activation showed it transduces mechanical/growth signals into deacetylation of p53 to drive endothelial differentiation.","evidence":"ES cell differentiation under laminar flow with kinase inhibitors, HDAC3 KD/OE, and p53 deacetylation assay","pmids":["16982804"],"confidence":"Medium","gaps":["Single lab; direct vs indirect p53 deacetylation not fully separated","Upstream PI3K/Akt to HDAC3 connection inferred via inhibitors"]},{"year":2010,"claim":"Defining the HDAC3/NCoR/SMRT axis as required for chromatin integrity established its role in DNA replication and genome stability beyond transcription.","evidence":"Liver-specific Hdac3 KO and NCOR1/SMRT siRNA with histone-mark ChIP and DNA damage assays","pmids":["21075309"],"confidence":"High","gaps":["Whether genomic instability is direct or secondary to metabolic stress not resolved","Specific repair step not pinpointed"]},{"year":2011,"claim":"Mapping a circadian HDAC3 cistrome overlapping Rev-erbα/NCoR connected the clock machinery to rhythmic hepatic lipogenesis via epigenomic remodeling.","evidence":"Liver-specific KO with genome-wide ChIP-seq for HDAC3, NCoR, Rev-erbα, H3ac, and Pol II","pmids":["21900149"],"confidence":"High","gaps":["Correlative cistrome overlap; causal recruitment hierarchy partly inferred","Catalytic vs scaffolding contribution not separated"]},{"year":2013,"claim":"Catalytic-dead rescue in liver revealed a deacetylase-independent function, fundamentally reframing HDAC3 as a dual enzyme/scaffold and distinguishing NCOR from SMRT requirement.","evidence":"Liver-specific KO, deacetylase-dead knock-in rescue, and NCOR/SMRT conditional KO with expression profiling","pmids":["24268577"],"confidence":"High","gaps":["Molecular basis of scaffolding activity unresolved","Tissue-specificity of catalytic dependence not yet generalized"]},{"year":2015,"claim":"Identifying phosphorylation control (PINK1 S424; insulin/mTOR S424; c-Src and CK2α) and substrate switching established HDAC3 activity as signal-regulated and showed it tunes both p53/apoptosis and glycolytic PGK1.","evidence":"In vitro kinase/phosphatase assays, phospho-mimetic/deficient mutants, KO MEFs, and substrate deacetylation assays","pmids":["25305081","26356530","26077467"],"confidence":"High","gaps":["Crosstalk between distinct phospho-sites not integrated","Stoichiometry of phosphorylation in vivo unknown"]},{"year":2016,"claim":"Defining the BCL6/SMRT/HDAC3 repressor at immune enhancers explained how CREBBP loss enables unopposed deacetylation and identified HDAC3 as a therapeutic vulnerability in lymphoma.","evidence":"ChIP-seq, reciprocal Co-IP of the complex, and conditional HDAC3 KO rescue in a murine lymphoma model","pmids":["27733359"],"confidence":"High","gaps":["Generalizability across lymphoma subtypes not established","Direct vs enhancer-context-dependent recruitment not dissected"]},{"year":2018,"claim":"Tyrosine phosphorylation by c-Src at the C-terminus and Mdm2/PIWIL2-mediated stabilization defined post-translational control of HDAC3 activity and abundance in cancer contexts.","evidence":"In vitro kinase assays, domain-mapping Co-IP, phospho-deficient mutants, and ubiquitination/competitive binding assays","pmids":["31430896","30317579","31358320","29555935"],"confidence":"High","gaps":["Several stability findings are single-lab Medium-confidence","Interplay of monoubiquitination vs degradative ubiquitination unclear"]},{"year":2019,"claim":"Comparative catalytic-dead knock-ins across tissues sharpened the enzyme-vs-scaffold dichotomy, showing muscle metabolism needs catalysis while spermatogenesis does not, and that SOX30 dictates testicular HDAC3 recruitment.","evidence":"NCoR/SMRT DAD-mutant knock-in mice, multiple tissue-specific KOs, ChIP-seq, and SOX30 epistasis","pmids":["30428023","33939832","31097476","31858687"],"confidence":"High","gaps":["Mechanism distinguishing catalytic-dependent vs -independent loci unknown","How SOX30 and other TFs select scaffolding mode unresolved"]},{"year":2020,"claim":"Discovery of allosteric ligand control (InsP3 activation, NADPH inhibition competing for the Ins(1,4,5,6)P4 site) and non-canonical, NCoR-independent recruitment at ATF2 sites unified metabolic and inflammatory regulation of HDAC3.","evidence":"Direct biochemical activity/binding and competition assays, germ-free models, catalytic-dead knock-in, and ChIP-seq co-occupancy with ATF2/ATF3","pmids":["32731255","33462516","32760002"],"confidence":"High","gaps":["Structural basis of ligand competition not solved","How metabolite levels are sensed at specific loci in vivo unclear"]},{"year":2020,"claim":"Expanding the non-histone substrate set (NICD1, Msh3/MutSβ, ELL) and target genes (CXCL9/10/11) connected HDAC3 to Notch signaling, trinucleotide repeat instability, transcription elongation, and antitumor immunity.","evidence":"Genetic KO, site-specific acetylation mutants, stability and ubiquitination assays, ChIP, and immunocompetent tumor models","pmids":["32107550","32900932","32152128","36898011"],"confidence":"High","gaps":["Direct vs indirect deacetylation for some substrates relies on single studies","In vivo substrate hierarchy not ranked"]},{"year":2023,"claim":"Mapping locus-specific recruitment partners (HOXB13, KLF5, p65/NF-κB) and additional non-histone substrates (PML-RARα, FOXO1, Nrf2, SRF) extended HDAC3 across lipogenesis, ferroptosis, fibrosis, and oxidative/inflammatory disease.","evidence":"Co-IP, site-specific acetylation mutants, ChIP at target promoters/enhancers, and in vivo disease/xenograft models","pmids":["35468964","37890360","36894687","37244125","39505146","38322347"],"confidence":"High","gaps":["Many disease links are single-lab Medium-confidence","Whether scaffolding or catalysis dominates each context not uniformly tested"]},{"year":2024,"claim":"Identification of HDAC3 delactylase activity and reciprocal H4K12-lactylation feedback positioned HDAC3 at the interface of lactate metabolism and chromatin in senescence and inflammation.","evidence":"KO mouse models, ChIP/CUT&Tag for H4K12la at SASP and TGF-β promoters, and HDAC3 delactylase activity assays","pmids":["39088352","39945346"],"confidence":"Medium","gaps":["Single-lab Medium-confidence; direct delactylase catalysis vs indirect effects needs reconstitution","Generality of lactylation substrate across loci unknown"]},{"year":null,"claim":"The structural and molecular rule that determines when HDAC3 functions as an enzyme versus a catalytically dispensable scaffold at a given locus remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model explaining ligand-gated catalytic/scaffold switching","Unclear how transcription factors select recruitment mode","Substrate selection rules among competing non-histone targets unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,10,17,18,30,47]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,6,9,42]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,12,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,26]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[1,3,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,3,9,21,31]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,6,9,13,42]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,12,18]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3,5,15,31]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,9,36,42,47]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[3]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,11]}],"complexes":["HDAC3-NCoR1/SMRT corepressor complex","BCL6/SMRT/HDAC3 repressor complex","SETDB1/KAP1/HDAC3 complex","TAL1/GATA2/ETS1-2/HDAC3/EP300 enhanceosome"],"partners":["NCOR1","NCOR2","BCL6","HOXB13","SOX30","PDCD5","MDM2","PIWIL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15379","full_name":"Histone deacetylase 3","aliases":["Protein deacetylase HDAC3","Protein deacylase HDAC3","RPD3-2","SMAP45"],"length_aa":428,"mass_kda":48.8,"function":"Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates (PubMed:21030595, PubMed:21444723, PubMed:23911289, PubMed:25301942, PubMed:28167758, PubMed:28497810, PubMed:32404892, PubMed:22230954). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:23911289). Histone deacetylases act via the formation of large multiprotein complexes, such as N-Cor repressor complex, which activate the histone deacetylase activity (PubMed:23911289, PubMed:22230954). Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression (PubMed:23911289). Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (By similarity). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803). Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner (By similarity). During the activation phase, promotes the accumulation of ubiquitinated BMAL1 at the E-boxes and during the repression phase, blocks FBXL3-mediated CRY1/2 ubiquitination and promotes the interaction of CRY1 and BMAL1 (By similarity). The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene BMAL1 and the genes involved in lipid metabolism in the liver (By similarity). Also functions as a deacetylase for non-histone targets, such as KAT5, MEF2D, MAPK14, RARA and STAT3 (PubMed:15653507, PubMed:21030595, PubMed:21444723, PubMed:25301942, PubMed:28167758). Serves as a corepressor of RARA, mediating its deacetylation and repression, leading to inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758). In addition to protein deacetylase activity, also acts as a protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl), lactoyl (lactyl), 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) and isonicotinyl acyl groups from lysine residues, leading to protein decrotonylation, delactylation, de-2-hydroxyisobutyrylation and deisonicotinylation, respectively (PubMed:28497810, PubMed:29192674, PubMed:34608293, PubMed:34545082, PubMed:35044827). Catalyzes decrotonylation of MAPRE1/EB1 (PubMed:34608293). Mediates delactylation NBN/NBS1, thereby inhibiting DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:38961290)","subcellular_location":"Nucleus; Chromosome; Cytoplasm; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/O15379/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/HDAC3","classification":"Common Essential","n_dependent_lines":1158,"n_total_lines":1208,"dependency_fraction":0.9586092715231788},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000171720","cell_line_id":"CID001501","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"PDCD6","stoichiometry":10.0},{"gene":"NCOR2","stoichiometry":10.0},{"gene":"NCOR1","stoichiometry":10.0},{"gene":"GPS2","stoichiometry":10.0},{"gene":"RCBTB2","stoichiometry":0.2},{"gene":"TBL1X;TBL1Y","stoichiometry":0.2},{"gene":"U2AF2","stoichiometry":0.2},{"gene":"TBL1XR1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001501","total_profiled":1310},"omim":[{"mim_id":"619134","title":"SET AND MYND DOMAIN-CONTAINING PROTEIN 4; SMYD4","url":"https://www.omim.org/entry/619134"},{"mim_id":"619039","title":"REPLICATION INITIATOR 1; REPIN1","url":"https://www.omim.org/entry/619039"},{"mim_id":"616848","title":"MIER1 TRANSCRIPTIONAL REGULATOR; MIER1","url":"https://www.omim.org/entry/616848"},{"mim_id":"616374","title":"BEN DOMAIN-CONTAINING PROTEIN 3; BEND3","url":"https://www.omim.org/entry/616374"},{"mim_id":"615176","title":"NPTN INTRONIC TRANSCRIPT 1, NONCODING; NPTNIT1","url":"https://www.omim.org/entry/615176"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HDAC3"},"hgnc":{"alias_symbol":["RPD3","HD3","RPD3-2","KDAC3"],"prev_symbol":[]},"alphafold":{"accession":"O15379","domains":[{"cath_id":"3.40.800.20","chopping":"4-384","consensus_level":"high","plddt":96.5713,"start":4,"end":384}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15379","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15379-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15379-F1-predicted_aligned_error_v6.png","plddt_mean":90.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HDAC3","jax_strain_url":"https://www.jax.org/strain/search?query=HDAC3"},"sequence":{"accession":"O15379","fasta_url":"https://rest.uniprot.org/uniprotkb/O15379.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15379/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15379"}},"corpus_meta":[{"pmid":"21075309","id":"PMC_21075309","title":"Hdac3 is essential for the maintenance of chromatin structure and genome stability.","date":"2010","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/21075309","citation_count":299,"is_preprint":false},{"pmid":"32863951","id":"PMC_32863951","title":"HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32863951","citation_count":279,"is_preprint":false},{"pmid":"9501169","id":"PMC_9501169","title":"Characterization of a human RPD3 ortholog, HDAC3.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9501169","citation_count":277,"is_preprint":false},{"pmid":"27733359","id":"PMC_27733359","title":"CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas.","date":"2016","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/27733359","citation_count":215,"is_preprint":false},{"pmid":"24268577","id":"PMC_24268577","title":"Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24268577","citation_count":202,"is_preprint":false},{"pmid":"16982804","id":"PMC_16982804","title":"HDAC3 is crucial in shear- and VEGF-induced stem cell differentiation toward endothelial cells.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16982804","citation_count":195,"is_preprint":false},{"pmid":"32731255","id":"PMC_32731255","title":"Microbiota-derived metabolite promotes HDAC3 activity in the gut.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32731255","citation_count":191,"is_preprint":false},{"pmid":"39088352","id":"PMC_39088352","title":"TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation.","date":"2024","source":"European heart journal","url":"https://pubmed.ncbi.nlm.nih.gov/39088352","citation_count":136,"is_preprint":false},{"pmid":"31915197","id":"PMC_31915197","title":"Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma.","date":"2020","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/31915197","citation_count":129,"is_preprint":false},{"pmid":"32760002","id":"PMC_32760002","title":"Dichotomous engagement of HDAC3 activity governs inflammatory responses.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32760002","citation_count":119,"is_preprint":false},{"pmid":"30626716","id":"PMC_30626716","title":"Loss of HDAC3 results in nonreceptive endometrium and female infertility.","date":"2019","source":"Science translational 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research","url":"https://pubmed.ncbi.nlm.nih.gov/32971093","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55243,"output_tokens":13354,"usd":0.18302,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":24928,"output_tokens":5275,"usd":0.128257,"stage2_stop_reason":"end_turn"},"total_usd":0.311277,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"HDAC3 encodes a 428-amino acid nuclear protein that exhibits histone deacetylase activity on both free histones and purified nucleosomes; activity is inhibited by trichostatin A, trapoxin, and butyrate in vitro, establishing it as a human RPD3 ortholog with enzymatic deacetylase function.\",\n      \"method\": \"Immunoprecipitation, in vitro deacetylase assay on free histones and nucleosomes, pharmacological inhibition, Western blot/subcellular fractionation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic reconstitution with multiple substrates and pharmacological validation; foundational characterization paper\",\n      \"pmids\": [\"9501169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HDAC3 is required for efficient DNA replication and DNA damage repair; loss of HDAC3 increases H3K9/K14ac, H4K5ac, and H4K12ac, impairs chromatin compaction and heterochromatin content, and retains histone deposition marks. siRNA targeting of the HDAC3 cofactors NCOR1 and SMRT (NCOR2) increases H4K5ac and causes DNA damage, establishing the HDAC3/NCOR/SMRT axis as critical for chromatin structure and genomic stability.\",\n      \"method\": \"Conditional liver-specific Hdac3 knockout, siRNA knockdown of NCOR1/SMRT, ChIP for histone modifications, DNA damage assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined molecular and cellular phenotypes, replicated with siRNA targeting cofactors, multiple orthogonal methods\",\n      \"pmids\": [\"21075309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Deacetylase-dead HDAC3 mutants rescue hepatosteatosis and repress lipogenic gene expression in HDAC3-depleted mouse liver, demonstrating a deacetylase-independent transcriptional function. Interaction with NCOR (but not SMRT) is essential for this in vivo function; liver-specific NCOR knockout phenocopies HDAC3 loss metabolically.\",\n      \"method\": \"Liver-specific knockout, knock-in of deacetylase-dead mutants, pharmacologic HDAC inhibition in primary hepatocytes, liver-specific NCOR/SMRT knockouts, gene expression analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — catalytic-dead mutant rescue in vivo, conditional KO of cofactors, multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"24268577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HDAC3 genomic occupancy in mouse liver follows a pronounced circadian pattern on lipid metabolism genes, inversely correlating with histone acetylation and RNA polymerase II recruitment. The HDAC3 cistrome overlaps significantly with Rev-erbα and its binding partner NCoR, linking circadian clock machinery to hepatic de novo lipogenesis via HDAC3-mediated epigenomic remodeling.\",\n      \"method\": \"Liver-specific Hdac3 knockout, genome-wide ChIP-seq for HDAC3, NCoR, Rev-erbα, H3 acetylation, and RNA Pol II\",\n      \"journal\": \"Cold Spring Harbor symposia on quantitative biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with conditional KO, multiple chromatin marks, consistent with companion full-paper data\",\n      \"pmids\": [\"21900149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Laminar flow stabilizes and activates HDAC3 through the Flk-1–PI3K–Akt pathway; activated HDAC3 deacetylates p53, leading to p21 activation and endothelial progenitor cell differentiation into endothelial cells.\",\n      \"method\": \"ES cell differentiation assay under laminar flow/VEGF, kinase pathway inhibitors, HDAC3 knockdown/overexpression, p53 deacetylation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling pathway with multiple inhibitor validations and KD/OE, single lab\",\n      \"pmids\": [\"16982804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PGK1 is acetylated at lysine 220 (inhibiting its activity) by KAT9, and deacetylated by HDAC3. Insulin activates the PI3K/AKT/mTOR pathway to phosphorylate HDAC3 at S424, promoting HDAC3–PGK1 interaction and K220 deacetylation, thereby stimulating PGK1 enzymatic activity.\",\n      \"method\": \"Co-IP, in vitro deacetylation assay, acetylation-mimetic/deficient mutants, mTOR pathway inhibitors, phospho-specific analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deacetylation assay, mutagenesis of substrate and kinase pathway, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26356530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"During LPS-stimulated macrophage activation, HDAC3 is recruited to ATF2-bound chromatin sites without NCoR1/2 and activates inflammatory gene expression through a non-canonical, deacetylase-independent mechanism. Conversely, HDAC3 deacetylase activity is selectively engaged at ATF3-bound sites to suppress Toll-like receptor signaling. Loss of HDAC3 protects mice from lethal LPS exposure, but abolition of catalytic activity alone does not confer this protection.\",\n      \"method\": \"Macrophage-specific Hdac3 knockout, catalytic-dead HDAC3 knock-in, ChIP-seq, genomic co-occupancy analysis with ATF2/ATF3, in vivo LPS challenge\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — catalytic-dead knock-in distinguishes enzymatic from scaffolding functions, genome-wide ChIP-seq, in vivo genetic validation, multiple orthogonal approaches\",\n      \"pmids\": [\"32760002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Microbiota-derived inositol-1,4,5-trisphosphate (InsP3) directly promotes HDAC3 activity in intestinal epithelial cells, activating HDAC3-dependent proliferation and counteracting butyrate inhibition. InsP3 and Ins(1,4,5,6)P4 bind the same domains on HDAC3; while Ins(1,4,5,6)P4 promotes HDAC3–NCoR complex formation, InsP3 acts as an activating metabolite.\",\n      \"method\": \"Germ-free vs microbiota-replete mouse comparison, intestinal organoids, biochemical HDAC3 activity assay, InsP3/phytate treatment, HDAC3 knockout cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical activity assay, genetic KO validation, in vivo germ-free model, multiple orthogonal methods in single study\",\n      \"pmids\": [\"32731255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NADPH directly binds HDAC3 and disrupts the association between HDAC3 and its co-activators NCoR2 (SMRT) or NCoR1, impairing HDAC3 activation and thereby increasing histone acetylation. NADPH and Ins(1,4,5,6)P4 compete for the same binding domains on HDAC3, with NADPH having higher affinity, whereas Ins(1,4,5,6)P4 promotes HDAC3–NCoR complex formation.\",\n      \"method\": \"NADPH binding assay, Co-IP of HDAC3–NCoR disruption, competitive binding with Ins(1,4,5,6)P4, HDAC3 inhibitor rescue, knockdown of NADPH-generating enzymes\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding and competition assay, multiple genetic and biochemical approaches, rigorous mechanistic dissection\",\n      \"pmids\": [\"33462516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BCL6 forms a repressor complex with SMRT and HDAC3 that binds extensively to MHC class II loci and other enhancers; CREBBP loss enables unopposed deacetylation at these enhancers by BCL6/SMRT/HDAC3, silencing B-cell signaling and immune response genes. HDAC3 loss-of-function rescues enhancer H3K27 acetylation and gene expression, suppressing CREBBP-mutant lymphomas.\",\n      \"method\": \"ChIP-seq, Co-IP of BCL6/SMRT/HDAC3 complex, conditional HDAC3 KO in murine lymphoma model, in vitro and in vivo rescue experiments\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, reciprocal Co-IP of complex, in vivo genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"27733359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HDAC3 deacetylates p53 and suppresses p53-dependent apoptosis. PINK1 phosphorylates HDAC3 at Ser-424, enhancing its deacetylase activity and promoting direct association with p53, leading to p53 hypoacetylation. Protein phosphatase 4c reverses PINK1-mediated HDAC3 phosphorylation. PINK1-mediated phosphorylation also prevents oxidative stress-induced C-terminal cleavage of HDAC3.\",\n      \"method\": \"Co-IP, in vitro kinase assay (PINK1 phosphorylating HDAC3), phospho-mimetic mutant HDAC3(S424E), PINK1 KO MEFs, deacetylase activity assay, phosphatase assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase/phosphatase assays, phospho-mimetic rescue, KO genetic validation, multiple orthogonal methods\",\n      \"pmids\": [\"25305081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDCD5 mediates dissociation of HDAC3 from p53 under genotoxic stress, leading to HDAC3 cleavage and ubiquitin-dependent proteasomal degradation; this releases p53 inhibition. Casein kinase 2α phosphorylates PDCD5 at Ser-119 to stabilize it and promote importin 13-mediated nuclear translocation of PDCD5. PDCD5 deletion abrogates etoposide-induced p53 stabilization and HDAC3 cleavage.\",\n      \"method\": \"Co-IP, ubiquitination assay, PDCD5 KO MEFs, CK2α kinase assay, importin 13 interaction assay, proteasome inhibitor experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — KO genetic rescue, in vitro kinase assay, multiple Co-IP and ubiquitination assays, genetic and pharmacological validation\",\n      \"pmids\": [\"26077467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC3 deacetylates H3K9 specifically; ablation of HDAC3 (but not other class I HDACs) disrupts H3K9 deacetylation and the consequent trimethylation of H3K9 (H3K9me3), impairing the first step of double-strand break repair. Hyperacetylated H3K9ac simultaneously acts as a transcriptional activator, promoting tumorigenic signaling.\",\n      \"method\": \"Individual class I HDAC KO mouse models, ChIP for H3K9ac/H3K9me3, DNA damage assays, gene expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comparative KO panel establishing isoform specificity, ChIP for multiple histone marks, consistent with published HDAC3/DNA damage literature\",\n      \"pmids\": [\"31097476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In response to oscillatory shear stress, transcription factors TAL1, GATA2, and ETS1/2 physically interact with and recruit HDAC3 to the E-box–GATA–ETS composite element of a GATA2 intragenic enhancer. HDAC3 in turn recruits histone acetyltransferase EP300 to form an enhanceosome complex that promotes GATA2 expression, which is required for lymphovenous and lymphatic valve morphogenesis.\",\n      \"method\": \"Endothelium-specific Hdac3 KO in mice, Co-IP of HDAC3 with TAL1/GATA2/ETS1/2/EP300, ChIP at GATA2 enhancer, shear stress assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with defined phenotype, Co-IP of multi-protein enhanceosome, ChIP at specific enhancer, multiple orthogonal methods\",\n      \"pmids\": [\"29035278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC3 controls the meiotic-to-postmeiotic transition in spermatogenesis in a deacetylase-independent manner. Abolishing HDAC3 catalytic activity via NCoR/SMRT knock-in mutations causes histone hyperacetylation identical to KO but does not cause infertility, whereas KO does. SOX30 recruits HDAC3 to its genomic binding sites in testes; loss of SOX30 abolishes HDAC3 cistromic recruitment.\",\n      \"method\": \"Three independent testis-specific Hdac3 KO mouse lines, NCoR/SMRT catalytic-dead knock-in mice, RNA-seq, histone acetylation ChIP-seq, SOX30 KO\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — three independent KO lines, catalytic-dead knock-in comparison, genome-wide ChIP-seq, genetic SOX30 epistasis\",\n      \"pmids\": [\"33939832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC3 enzymatic activity is required for skeletal muscle fuel metabolism. NS-DADm knock-in mice (which ablate HDAC3 deacetylase activity via NCoR/SMRT mutations without altering HDAC3 protein levels) show the same metabolic phenotypes as HDAC3-depleted muscle—reduced force generation, enhanced fatty acid oxidation, reduced glucose uptake, altered BCAA catabolism gene expression—establishing that, unlike in liver or embryonic development, the muscle metabolic function requires catalytic activity.\",\n      \"method\": \"NCoR/SMRT DAD-mutant knock-in mouse model (NS-DADm), metabolic phenotyping, gene expression analysis, comparison to muscle-specific HDAC3 KO\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — catalytic-dead knock-in directly tests enzymatic requirement, side-by-side comparison with protein-level KO, multiple metabolic readouts\",\n      \"pmids\": [\"30428023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PP4-dependent dephosphorylation of HDAC3 inactivates its catalytic activity following peripheral nerve injury, enhancing histone H3K9 acetylation and enabling a regenerative gene expression program. Central spinal cord injury does not trigger this calcium–PP4–HDAC3 dephosphorylation cascade, explaining regenerative failure. Genetic or pharmacological HDAC3 inhibition overcomes regenerative failure after spinal cord injury.\",\n      \"method\": \"Pharmacological screen in DRG neurons, in vivo PP4 inhibitor, H3K9ac ChIP-seq from ex vivo DRG, RNA-seq, genetic HDAC3 inhibition, spinal cord injury model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq and RNA-seq in vivo, PP4 pharmacological and genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"31268609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC3 controls NICD1 (Notch1 intracellular domain) acetylation levels, directly affecting NICD1 protein stability. Genetic loss-of-function of HDAC3 or nanomolar HDAC inhibitor treatment reduces Notch target gene expression with local reduction of histone acetylation. An HDAC3-insensitive NICD1 mutant is more stable but biologically less active.\",\n      \"method\": \"Hdac3 genetic KO, HDAC inhibitor treatment, NICD1 acetylation assay, NICD1 stability (cycloheximide chase), HDAC3-insensitive NICD1 mutant expression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic KO, acetylation assay on substrate, stability assay with acetylation-resistant mutant, multiple orthogonal approaches\",\n      \"pmids\": [\"32107550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC3 deacetylates the MutSβ subunit Msh3 at five key lysine residues to activate MutSβ-driven trinucleotide repeat expansions. HDAC3 inhibition suppresses repeat expansion without impairing canonical mismatch repair; Msh3 arginine-substitution mutants at these lysine residues bypass the inhibitory effect of HDAC3 inhibitor. HDAC3 activity also partially controls MutSβ nuclear localization via deacetylation sites overlapping the Msh3 nuclear localization signal.\",\n      \"method\": \"HDAC3-selective inhibitor RGFP966, Msh3 lysine-to-arginine mutants, trinucleotide repeat expansion assay, mismatch repair assay, subcellular localization analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis of substrate lysines, functional rescue/bypass assay, multiple mechanistic readouts in single study\",\n      \"pmids\": [\"32900932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC3 inhibition reduces SMARCA4 activity, derepressing miR-27a, which in turn destabilizes PAX3:FOXO1 mRNA in alveolar rhabdomyosarcoma cells. This HDAC3–SMARCA4–miR-27a–PAX3:FOXO1 circuit drives chemoresistance.\",\n      \"method\": \"HDAC3-selective inhibition (entinostat), HDAC3 genetic knockdown, miR-27a quantification, PAX3:FOXO1 mRNA stability assay, SMARCA4 activity assay, preclinical mouse models\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological HDAC3 inhibition with defined molecular cascade, single lab\",\n      \"pmids\": [\"30459282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC3 loss in the uterus causes implantation failure and decidualization defects through aberrant transcriptional activation of COL1A1 and COL1A2 genes; HDAC3 normally represses these collagen genes. Reduction of HDAC3 leads to p300 recruitment to Col1a1/Col1a2 loci; inhibition of p300 permits decidualization in HDAC3-attenuated cells.\",\n      \"method\": \"Conditional Hdac3 KO in PGR-positive cells (mouse uterus), expression microarray, ChIP-seq, primary human endometrial stromal cell culture, p300 inhibitor rescue\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, ChIP-seq identifying direct target genes, pharmacological rescue with p300 inhibitor, translational to human cells\",\n      \"pmids\": [\"30626716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC3 occupies H3K9me3/H3K14ac bivalent chromatin regions in liver together with H3K9 methyltransferase SETDB1 in a KAP1 complex, correlating with H3K9me3 presence. This bivalent state is reduced with aging, and associated genes (regulating cholesterol secretion and triglyceride synthesis) are upregulated when bivalency is lost.\",\n      \"method\": \"Quantitative targeted mass spectrometry of histone modifications, sequential ChIP-seq (reChIP), bulk ChIP-seq for HDAC3/SETDB1/KAP1, young vs aged liver comparison\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and mass spectrometry, single lab, correlative between HDAC3 occupancy and histone marks\",\n      \"pmids\": [\"31858687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"c-Src kinase directly phosphorylates HDAC3 at tyrosine residues Y325, Y328, and Y331 (C-terminal domain), increasing HDAC3 deacetylase activity. EGF stimulation via EGFR activates c-Src to phosphorylate HDAC3, which is then recruited to the plasma membrane. Phosphorylation-deficient HDAC3(Y328/331A) lacks deacetylase activity and reduces breast cancer cell invasiveness.\",\n      \"method\": \"Co-IP, in vitro kinase assay (c-Src phosphorylating HDAC3), phospho-specific antibody, phospho-deficient mutant HDAC3, TIRF microscopy for membrane recruitment, invasion assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, site-directed phospho-deficient mutants, phospho-specific antibody validation, multiple functional readouts\",\n      \"pmids\": [\"31430896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"c-Src directly binds the C-terminal domain (277–428 aa) of HDAC3 and phosphorylates HDAC3 at Y325, Y328, and Y331; wild-type but not kinase-inactive c-Src (K298M) increases HDAC3 deacetylase activity. Triple alanine substitution of these tyrosines abolishes deacetylase activity. Phosphorylation-dependent HDAC3 activity promotes proliferation of HER2-positive breast cancer cells.\",\n      \"method\": \"Co-IP with deletion mutants, in vitro kinase assay, deacetylase activity assay, phospho-deficient triple mutant, proliferation assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay, domain mapping by Co-IP with deletion mutants, mutagenesis-based functional validation\",\n      \"pmids\": [\"30317579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mdm2 directly interacts with HDAC3 and induces HDAC3 monoubiquitination (requiring the Mdm2 RING domain), which stabilizes HDAC3 protein without altering its mRNA levels. MdmX cooperates with Mdm2 in this regulation. Mdm2 ablation decreases HDAC3 levels and reduces cell migration.\",\n      \"method\": \"Co-IP, ectopic expression of wild-type vs. RING-mutant Mdm2, ubiquitination assay, Mdm2 knockdown, migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and direct ubiquitination assay with RING mutant, single lab\",\n      \"pmids\": [\"31358320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIWIL2 interacts with HDAC3, stabilizing it by competing with the E3 ubiquitin ligase Siah2 for binding, thereby preventing ubiquitin-mediated HDAC3 degradation. PIWIL2 also facilitates interaction between HDAC3 and CK2α, promoting CK2α-mediated phosphorylation and activation of HDAC3.\",\n      \"method\": \"Co-IP of PIWIL2/HDAC3/Siah2/CK2α, competitive binding assay, ubiquitination assay, HDAC3 activity assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with competitive binding, ubiquitination assay, single lab\",\n      \"pmids\": [\"29555935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PACS-1 interacts with HDAC2 and HDAC3 in the nucleus and is required for HDAC2/HDAC3-dependent chromatin maturation. PACS-1 knockdown causes proteasome-mediated degradation of HDAC2 and HDAC3, leading to elevated H3K9 and H4K16 acetylation and increased replication stress-induced DNA damage.\",\n      \"method\": \"Co-IP of PACS-1 with HDAC2/HDAC3, PACS-1 knockdown, proteasome inhibitor rescue, histone modification analysis, DNA damage assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and KD with defined molecular and cellular phenotypes, single lab\",\n      \"pmids\": [\"31988453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DBC1 competes with HDAC3 for the same binding sites on the transcription elongation factor ELL, thereby preventing HDAC3-mediated deacetylation and consequent destabilization of ELL. HDAC3-mediated deacetylation of ELL promotes its polyubiquitylation by Siah1 E3 ligase, leading to ELL degradation; p300-mediated acetylation has the opposing stabilizing effect.\",\n      \"method\": \"Co-IP of DBC1/HDAC3/p300/Siah1 with ELL, competitive binding assay, acetylation/ubiquitination assays, DBC1 knockdown, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro acetylation and ubiquitination assays, competitive binding Co-IP, genetic KD with defined transcriptional consequences, multiple orthogonal methods\",\n      \"pmids\": [\"32152128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC3 deacetylase activity is required for FGF9 and IGF2 expression in epicardial cells to promote myocardial growth; Hdac3 KO epicardial cells upregulate miR-322 and miR-503, which repress FGF9 and IGF2. FGF9 or IGF2 supplementation rescues the myocardial proliferation defect. Knockdown of miR-322 or miR-503 restores FGF9/IGF2 expression in Hdac3 KO cells.\",\n      \"method\": \"Epicardial-specific Hdac3 KO mouse, transcriptomic analysis, miRNA quantification, miR-322/miR-503 overexpression/knockdown, FGF9/IGF2 rescue experiment\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined molecular cascade, multiple rescue experiments, single lab\",\n      \"pmids\": [\"35722872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC3 inhibition triggers degradation of c-Myc protein, leading to downregulation of DNMT1 expression in multiple myeloma cells. Additionally, HDAC3 inhibition causes hyperacetylation of DNMT1 protein itself, reducing its stability. HDAC3 knockdown (but not HDAC1 or HDAC2) specifically mediates these effects.\",\n      \"method\": \"HDAC3-selective siRNA (vs HDAC1/HDAC2), HDAC3-selective inhibitor BG45, c-Myc degradation assay, DNMT1 acetylation and stability assay, xenograft mouse model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific siRNA comparison, protein stability and acetylation assays, in vivo xenograft, single lab\",\n      \"pmids\": [\"28490812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC3 deacetylates PML-RARα at lysine 394, reducing PIAS1-mediated SUMOylation and subsequent RNF4-induced ubiquitylation, thereby stabilizing the PML-RARα oncoprotein. HDAC3 inhibition promotes PML-RARα ubiquitylation and degradation in both wild-type and ATRA/ATO-resistant APL cells.\",\n      \"method\": \"Co-IP, in vitro deacetylation assay, acetylation mutant of PML-RARα at K394, SUMOylation and ubiquitylation assays, HDAC3 inhibitor/genetic KD, xenograft models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-specific acetylation mutant, in vitro deacetylation assay, sequential PTM cascade (deacetylation→SUMOylation→ubiquitylation) validated, in vivo xenograft\",\n      \"pmids\": [\"36894687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXB13 physically interacts with HDAC3 (interaction disrupted by the G84E cancer-associated mutation) and recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators including FASN, independently of androgen receptor.\",\n      \"method\": \"Co-IP of HOXB13/HDAC3, ChIP-seq for HDAC3 and HOXB13 at lipogenic enhancers, HOXB13 G84E mutant interaction assay, HDAC3 histone deacetylation assay at enhancers, xenograft tumor metastasis model\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with disease-relevant mutant, ChIP-seq, functional rescue experiments, in vivo xenograft, multiple orthogonal methods\",\n      \"pmids\": [\"35468964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC3 directly binds to the Gpx4 promoter together with transcription factor KLF5 upon aristolochic acid treatment, causing local histone hypoacetylation and transcriptional inhibition of GPX4, which drives ferroptosis during AKI-CKD transition. HDAC3 and KLF5 co-IP confirms inducible association.\",\n      \"method\": \"HDAC3 conditional KO, HDAC3-selective inhibitor RGFP966, Co-IP of HDAC3/KLF5, ChIP at Gpx4 promoter, KLF5 inhibitor ML264, GPX4 inactivator RSL3 rescue experiment\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP at specific promoter, genetic and pharmacological inhibition with rescue, single lab\",\n      \"pmids\": [\"37890360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC3 deacetylates FOXO1 and promotes its nuclear translocation in LPS-stimulated alveolar epithelial cells; nuclear FOXO1 transcriptionally activates ROCK1, which upon phosphorylation by RhoA disrupts mitochondrial quality control and promotes acute lung injury.\",\n      \"method\": \"HDAC3 conditional KO (Sftpc-cre; Hdac3f/f), FOXO1 acetylation assay, nuclear fractionation, ROCK1 promoter analysis, RhoA activation assay, pharmacological rescue\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, acetylation assay with nuclear translocation, defined molecular pathway, single lab\",\n      \"pmids\": [\"37244125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC3 interacts with and deacetylates Nrf2, reducing Nrf2 acetylation in cardiomyocytes. HDAC3 inhibition increases Nrf2 acetylation, while HDAC3 overexpression decreases it. Nrf2 acetylation promotes its activity and reduces oxidative stress.\",\n      \"method\": \"Co-IP of HDAC3/Nrf2, Nrf2 acetylation assay, HDAC3 inhibitor (RGFP966) vs adenoviral HDAC3 overexpression, Nrf2 inhibitor rescue\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and acetylation assay, gain- and loss-of-function, single lab\",\n      \"pmids\": [\"39505146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC3 directly deacetylates SRF (serum response factor), enhancing SRF transcriptional activity in vascular smooth muscle cells; SMYD2 promotes HDAC3 expression via H3K36 tri-methylation at the HDAC3 promoter. HDAC3-SRF axis mediates VSMC phenotypic switching and neointimal hyperplasia in a deacetylase-dependent manner.\",\n      \"method\": \"Co-IP of HDAC3/SRF, SRF acetylation assay, SMYD2 ChIP at HDAC3 promoter, RGFP966 HDAC3 inhibitor, Smyd2-vTg and SMYD2 KD VSMCs, carotid artery injury model\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and acetylation assay on non-histone substrate, ChIP epistasis, in vivo model, single lab\",\n      \"pmids\": [\"38322347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Epithelial HDAC3 is essential for NF-κB-dependent regulation of epithelial MHC class II (MHCII) expression; epithelial MHCII reduces commensal-specific Th17 accumulation and protects against microbiota-triggered inflammation. Microbiota colonization concurrently induces epithelial HDAC3 expression and commensal-specific CD4+ T cells.\",\n      \"method\": \"Epithelium-specific Hdac3 KO, commensal-specific T cell tetramer analysis, ChIP for HDAC3 at MHCII locus, NF-κB pathway analysis, germ-free colonization experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epithelium-specific KO, mechanistic ChIP, germ-free colonization model, multiple immune readouts, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"36602872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC3 inhibition in liver reduces Hamp (hepcidin) mRNA via activation of the Hippo/YAP signaling pathway; HDAC3 loss leads to increased nuclear YAP translocation, and YAP binds repressor sites within the HAMP promoter to suppress hepcidin expression. Knock-in of constitutively active YAP (K342M) phenocopies hepcidin reduction in Hdac3-LKO mice.\",\n      \"method\": \"Hdac3 liver-specific KO, Hippo pathway inhibitor, YAP overexpression (constitutively active K342M knock-in), HAMP promoter reporter assay, Yap KD in Hdac3-LKO mice\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, promoter reporter, constitutively active epistasis knock-in, single lab\",\n      \"pmids\": [\"38034086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PDCD5 promotes HDAC3 ubiquitination and degradation to reduce fibrotic responses; SMAD3 directly upregulates PDCD5 during cardiac fibrosis, and the resulting PDCD5-mediated HDAC3 inhibition suppresses profibrogenic gene expression. AAV9-mediated HDAC3 overexpression eliminates the protective effects of PDCD5 knock-in.\",\n      \"method\": \"Co-IP of PDCD5/HDAC3, HDAC3 ubiquitination assay, cardiac fibroblast KD/OE, fibroblast-specific PDCD5 knock-in mice, AAV9-HDAC3 rescue, SMAD3 ChIP\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, genetic rescue in vivo, single lab\",\n      \"pmids\": [\"37345556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRAP1-mediated metabolic reprogramming increases aerobic glycolysis and lactate production, which down-regulates HDAC3 activity; reduced HDAC3 delactylase activity allows accumulation of H4K12 lactylation (H4K12la) at SASP promoters, activating SASP transcription and exacerbating VSMC senescence in atherosclerosis.\",\n      \"method\": \"VSMC-specific Trap1 KO mice, H4K12la ChIP at SASP promoters, HDAC3 activity assay (delactylase), metabolic profiling\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, KO mouse model, HDAC3 delactylase activity assay, single lab\",\n      \"pmids\": [\"39088352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H4K12 lactylation (H4K12la) in macrophages inhibits HDAC3 expression, forming a feedback loop; HDAC3 activation reduces H4K12la levels. MCT1-mediated lactate uptake drives KAT5/KAT8-dependent H4K12la, which enriches at TGF-β1/TGF-β3 promoters and represses HDAC3. CUT&Tag and RNA-seq identified this feedback loop between H4K12la and HDAC3.\",\n      \"method\": \"CUT&Tag, RNA-seq, H4K12la ChIP at TGF-β promoters, HDAC3 overexpression rescue, macrophage depletion, MCT1 inhibitor\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag and RNA-seq, genetic rescue, single lab\",\n      \"pmids\": [\"39945346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC3 transcriptionally promotes cGAS expression in microglia and potentiates cGAS-STING pathway activation by regulating acetylation and nuclear localization of p65 (NF-κB subunit). ChIP confirmed HDAC3 occupancy at the cGAS promoter region.\",\n      \"method\": \"Co-IP, ChIP, dual-luciferase reporter assay, microglial HDAC3 conditional KO, Western blot for p65 acetylation and localization\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay, conditional KO in microglia, single lab\",\n      \"pmids\": [\"32863951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC3 directly binds to promoter regions of CXCL9, CXCL10, and CXCL11 to inhibit their expression; Hdac3-deficient tumor cells express high levels of these chemokines, recruiting CXCR3+ T cells to suppress tumor growth in immunocompetent mice.\",\n      \"method\": \"Hdac3 KO tumor cell lines, ChIP at CXCL9/10/11 promoters, CXCR3+ T cell infiltration quantification, immunocompetent vs immunodeficient mouse tumor models\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishing direct promoter binding, genetic KO, in vivo immune readout, single lab\",\n      \"pmids\": [\"36898011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hdac3 microglial KO specifically inhibits proliferation of proinflammatory microglia after ischemic stroke by closing chromatin regions enriched with PU.1 motifs (ATAC-seq). AAV-mediated overexpression of PU.1 reverses HDAC3-KO-induced proliferation inhibition, establishing PU.1 as a downstream mediator of HDAC3 in stroke neuroinflammation.\",\n      \"method\": \"Microglial-specific Hdac3 KO, RNA-seq, ATAC-seq, AAV-PU.1 overexpression rescue, microglial proliferation assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, genome-wide chromatin accessibility (ATAC-seq), RNA-seq, AAV genetic rescue establishing PU.1 epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"38446877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HDAC3 transactivates KDELR2 via CREB1; ChIP validated CREB1 binding to the KDELR2 promoter in an HDAC3-dependent manner. HDAC3-KDELR2 axis accelerates cell cycle progression by protecting centrosomal protein POC5 from proteasomal degradation.\",\n      \"method\": \"ChIP for CREB1 at KDELR2 promoter, HDAC3 KD, Co-IP of KDELR2/POC5, cell cycle analysis, breast cancer mouse model\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, gain- and loss-of-function, single lab\",\n      \"pmids\": [\"34146461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRDM16 physically interacts with HDAC3 in adipocytes; HDAC3-selective inhibitor RGFP966 induces thermogenic gene expression in murine and human fat cultures, but this induction is blunted in the absence of PRDM16, placing HDAC3 upstream of PRDM16 in the thermogenic program.\",\n      \"method\": \"Co-IP of PRDM16/HDAC3, HDAC3-selective inhibitor RGFP966 in murine and human fat cultures, PRDM16-null cells as epistasis control\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PRDM16-null epistasis, pharmacological inhibition in primary cultures, single lab\",\n      \"pmids\": [\"29757434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Phosphorylation of HDAC3 at S424 (a mark necessary for deacetylase activity) is suppressed in osseous cells from aged mice, and HDAC3 expression is reduced in bone cells from postmenopausal compared to young women. Adenoviral restoration of Hdac3 in Hdac3-depleted bone marrow stromal cells restores normal gene expression, demonstrating direct causal control of glucocorticoid activation (Hsd11b1) and lipid storage (Fsp27/Cidec, Plin1) genes.\",\n      \"method\": \"Conditional Hdac3 KO in osteochondroprogenitors, adenoviral Hdac3 rescue, S424 phosphorylation analysis in aged vs young bone, gene expression profiling\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with adenoviral rescue, phosphorylation analysis, single lab\",\n      \"pmids\": [\"26211746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hdac3 deacetylates the p65 subunit of NF-κB at K310, decreasing NF-κB DNA-binding and transcriptional activity in osteoclasts. Hdac3-deficient osteoclasts show increased K310 NF-κB acetylation, NF-κB hyperactivation, hypersensitivity to RANKL, and elevated bone resorption; Hdac3 also controls osteoclast-derived sphingosine-1-phosphate coupling to bone formation.\",\n      \"method\": \"Ctsk-cre conditional Hdac3 KO, NF-κB acetylation (K310) assay, RANKL responsiveness assay, pit formation (resorption) assay, sphingosine-1-phosphate production assay, conditioned medium mineralization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, NF-κB acetylation assay, functional bone resorption assays, single lab\",\n      \"pmids\": [\"33454009\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HDAC3 is a nuclear class I histone deacetylase whose catalytic activity depends on interaction with NCoR1/NCoR2 (SMRT) corepressors via inositol phosphate (InsP4/InsP3) and NADPH-regulated allosteric mechanisms; it deacetylates histones (particularly H3K9, H4K5, H4K12) and a growing list of non-histone substrates (p53, PGK1, NICD1, MutSβ/Msh3, PML-RARα, SRF, FOXO1, Nrf2, ELL, β-catenin, NF-κB p65), is regulated by post-translational modifications (phosphorylation by PINK1/CK2α/c-Src at S424/Y325/Y328/Y331, monoubiquitination by Mdm2), and is recruited to specific genomic loci by transcription factors (BCL6, Rev-erbα, HOXB13, SOX30, ATF2/ATF3, TAL1/GATA2/ETS1/2); it additionally possesses a deacetylase-independent scaffolding function essential for certain developmental and transcriptional contexts (hepatic lipid metabolism with NCOR1, spermatogenesis via SOX30, macrophage inflammatory gene activation via ATF2), making it a dichotomous regulator of transcription, DNA repair, circadian metabolism, immune responses, and tissue homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HDAC3 is a nuclear class I histone deacetylase that orchestrates transcription, genome stability, and metabolic homeostasis by removing acetyl marks from both histones and a broad set of non-histone substrates [#0, #1]. Its catalytic activity is held in check until it docks onto the NCoR1/SMRT (NCOR2) corepressors, an allosteric switch tuned by competing small-molecule ligands: inositol phosphates such as Ins(1,4,5,6)P4 promote HDAC3–NCoR complex assembly and activation, microbiota-derived InsP3 acts as an activating metabolite, while NADPH binds the same domains with higher affinity to disrupt the complex and dampen deacetylation [#7, #8]. Through this corepressor axis HDAC3 deacetylates histone H3K9/H4K5/H4K12 to compact chromatin and enable double-strand break repair and DNA replication, and it sets up bivalent H3K9me3/H3K14ac chromatin with SETDB1/KAP1 [#1, #12, #21]. A defining feature is its functional dichotomy: HDAC3 can act either as an enzyme or as a catalytically dispensable scaffold, with catalytic-dead knock-in models showing that hepatic lipid metabolism (with NCOR1), spermatogenesis (via SOX30 recruitment), and macrophage inflammatory gene activation (at ATF2 sites) proceed without deacetylase activity, whereas skeletal muscle fuel metabolism requires it [#2, #6, #14, #15]. HDAC3 is recruited to specific loci by sequence-specific factors—Rev-erbα/NCoR to drive circadian hepatic lipogenesis, BCL6/SMRT to repress immune enhancers, HOXB13 to suppress lipogenic genes, and TAL1/GATA2/ETS to build a flow-responsive enhanceosome [#3, #9, #31, #13]. Beyond chromatin, HDAC3 deacetylates non-histone targets including p53 (suppressing apoptosis), NICD1, Msh3/MutSβ (activating trinucleotide repeat expansion), PML-RARα, FOXO1, Nrf2, SRF, and NF-κB p65, coupling it to apoptosis, mismatch-repair-driven instability, oncoprotein stability, and oxidative/inflammatory signaling [#10, #17, #18, #30, #47]. Its activity is further controlled by phosphorylation—PINK1, CK2α, and c-Src phosphorylate HDAC3 (S424, Y325/328/331) to enhance activity, PP4 dephosphorylation inactivates it—and by ubiquitin-dependent stability control via Mdm2, PDCD5/Siah2, and PIWIL2 [#10, #22, #16, #24, #25, #38].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that HDAC3 is a bona fide enzyme answered whether the gene encodes an active histone deacetylase rather than merely a homolog.\",\n      \"evidence\": \"Immunoprecipitation and in vitro deacetylase assays on free histones and nucleosomes with pharmacological inhibition\",\n      \"pmids\": [\"9501169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define physiological substrates or cofactor requirements\", \"Genomic targeting and regulation unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking laminar flow signaling to HDAC3 activation showed it transduces mechanical/growth signals into deacetylation of p53 to drive endothelial differentiation.\",\n      \"evidence\": \"ES cell differentiation under laminar flow with kinase inhibitors, HDAC3 KD/OE, and p53 deacetylation assay\",\n      \"pmids\": [\"16982804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; direct vs indirect p53 deacetylation not fully separated\", \"Upstream PI3K/Akt to HDAC3 connection inferred via inhibitors\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining the HDAC3/NCoR/SMRT axis as required for chromatin integrity established its role in DNA replication and genome stability beyond transcription.\",\n      \"evidence\": \"Liver-specific Hdac3 KO and NCOR1/SMRT siRNA with histone-mark ChIP and DNA damage assays\",\n      \"pmids\": [\"21075309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether genomic instability is direct or secondary to metabolic stress not resolved\", \"Specific repair step not pinpointed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mapping a circadian HDAC3 cistrome overlapping Rev-erbα/NCoR connected the clock machinery to rhythmic hepatic lipogenesis via epigenomic remodeling.\",\n      \"evidence\": \"Liver-specific KO with genome-wide ChIP-seq for HDAC3, NCoR, Rev-erbα, H3ac, and Pol II\",\n      \"pmids\": [\"21900149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Correlative cistrome overlap; causal recruitment hierarchy partly inferred\", \"Catalytic vs scaffolding contribution not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Catalytic-dead rescue in liver revealed a deacetylase-independent function, fundamentally reframing HDAC3 as a dual enzyme/scaffold and distinguishing NCOR from SMRT requirement.\",\n      \"evidence\": \"Liver-specific KO, deacetylase-dead knock-in rescue, and NCOR/SMRT conditional KO with expression profiling\",\n      \"pmids\": [\"24268577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of scaffolding activity unresolved\", \"Tissue-specificity of catalytic dependence not yet generalized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying phosphorylation control (PINK1 S424; insulin/mTOR S424; c-Src and CK2α) and substrate switching established HDAC3 activity as signal-regulated and showed it tunes both p53/apoptosis and glycolytic PGK1.\",\n      \"evidence\": \"In vitro kinase/phosphatase assays, phospho-mimetic/deficient mutants, KO MEFs, and substrate deacetylation assays\",\n      \"pmids\": [\"25305081\", \"26356530\", \"26077467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between distinct phospho-sites not integrated\", \"Stoichiometry of phosphorylation in vivo unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining the BCL6/SMRT/HDAC3 repressor at immune enhancers explained how CREBBP loss enables unopposed deacetylation and identified HDAC3 as a therapeutic vulnerability in lymphoma.\",\n      \"evidence\": \"ChIP-seq, reciprocal Co-IP of the complex, and conditional HDAC3 KO rescue in a murine lymphoma model\",\n      \"pmids\": [\"27733359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability across lymphoma subtypes not established\", \"Direct vs enhancer-context-dependent recruitment not dissected\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tyrosine phosphorylation by c-Src at the C-terminus and Mdm2/PIWIL2-mediated stabilization defined post-translational control of HDAC3 activity and abundance in cancer contexts.\",\n      \"evidence\": \"In vitro kinase assays, domain-mapping Co-IP, phospho-deficient mutants, and ubiquitination/competitive binding assays\",\n      \"pmids\": [\"31430896\", \"30317579\", \"31358320\", \"29555935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Several stability findings are single-lab Medium-confidence\", \"Interplay of monoubiquitination vs degradative ubiquitination unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Comparative catalytic-dead knock-ins across tissues sharpened the enzyme-vs-scaffold dichotomy, showing muscle metabolism needs catalysis while spermatogenesis does not, and that SOX30 dictates testicular HDAC3 recruitment.\",\n      \"evidence\": \"NCoR/SMRT DAD-mutant knock-in mice, multiple tissue-specific KOs, ChIP-seq, and SOX30 epistasis\",\n      \"pmids\": [\"30428023\", \"33939832\", \"31097476\", \"31858687\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing catalytic-dependent vs -independent loci unknown\", \"How SOX30 and other TFs select scaffolding mode unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery of allosteric ligand control (InsP3 activation, NADPH inhibition competing for the Ins(1,4,5,6)P4 site) and non-canonical, NCoR-independent recruitment at ATF2 sites unified metabolic and inflammatory regulation of HDAC3.\",\n      \"evidence\": \"Direct biochemical activity/binding and competition assays, germ-free models, catalytic-dead knock-in, and ChIP-seq co-occupancy with ATF2/ATF3\",\n      \"pmids\": [\"32731255\", \"33462516\", \"32760002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ligand competition not solved\", \"How metabolite levels are sensed at specific loci in vivo unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanding the non-histone substrate set (NICD1, Msh3/MutSβ, ELL) and target genes (CXCL9/10/11) connected HDAC3 to Notch signaling, trinucleotide repeat instability, transcription elongation, and antitumor immunity.\",\n      \"evidence\": \"Genetic KO, site-specific acetylation mutants, stability and ubiquitination assays, ChIP, and immunocompetent tumor models\",\n      \"pmids\": [\"32107550\", \"32900932\", \"32152128\", \"36898011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect deacetylation for some substrates relies on single studies\", \"In vivo substrate hierarchy not ranked\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping locus-specific recruitment partners (HOXB13, KLF5, p65/NF-κB) and additional non-histone substrates (PML-RARα, FOXO1, Nrf2, SRF) extended HDAC3 across lipogenesis, ferroptosis, fibrosis, and oxidative/inflammatory disease.\",\n      \"evidence\": \"Co-IP, site-specific acetylation mutants, ChIP at target promoters/enhancers, and in vivo disease/xenograft models\",\n      \"pmids\": [\"35468964\", \"37890360\", \"36894687\", \"37244125\", \"39505146\", \"38322347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Many disease links are single-lab Medium-confidence\", \"Whether scaffolding or catalysis dominates each context not uniformly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of HDAC3 delactylase activity and reciprocal H4K12-lactylation feedback positioned HDAC3 at the interface of lactate metabolism and chromatin in senescence and inflammation.\",\n      \"evidence\": \"KO mouse models, ChIP/CUT&Tag for H4K12la at SASP and TGF-β promoters, and HDAC3 delactylase activity assays\",\n      \"pmids\": [\"39088352\", \"39945346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Medium-confidence; direct delactylase catalysis vs indirect effects needs reconstitution\", \"Generality of lactylation substrate across loci unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and molecular rule that determines when HDAC3 functions as an enzyme versus a catalytically dispensable scaffold at a given locus remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model explaining ligand-gated catalytic/scaffold switching\", \"Unclear how transcription factors select recruitment mode\", \"Substrate selection rules among competing non-histone targets unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 10, 17, 18, 30, 47]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 6, 9, 42]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 12, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 26]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [1, 3, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 3, 9, 21, 31]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 6, 9, 13, 42]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 12, 18]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3, 5, 15, 31]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 9, 36, 42, 47]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [\n      \"HDAC3-NCoR1/SMRT corepressor complex\",\n      \"BCL6/SMRT/HDAC3 repressor complex\",\n      \"SETDB1/KAP1/HDAC3 complex\",\n      \"TAL1/GATA2/ETS1-2/HDAC3/EP300 enhanceosome\"\n    ],\n    \"partners\": [\n      \"NCOR1\",\n      \"NCOR2\",\n      \"BCL6\",\n      \"HOXB13\",\n      \"SOX30\",\n      \"PDCD5\",\n      \"MDM2\",\n      \"PIWIL2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}