{"gene":"HDAC2","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2015,"finding":"Tet2 recruits Hdac2 to the Il6 promoter via the IκBζ transcription factor, mediating histone deacetylation to repress IL-6 transcription during inflammation resolution, independent of DNA methylation or hydroxymethylation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), genetic knockout mouse models, lipopolysaccharide challenge assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, and loss-of-function genetics with specific phenotypic readout in vivo; multiple orthogonal methods in a rigorous study","pmids":["26287468"],"is_preprint":false},{"year":2010,"finding":"HDAC1 and HDAC2 are recruited to DNA double-strand break sites and regulate acetylation of histone H3 Lys56 (H3K56ac), promoting DNA repair by nonhomologous end-joining (NHEJ); depletion of both causes hypersensitivity to DNA-damaging agents and sustained DNA-damage signaling.","method":"siRNA knockdown, immunofluorescence localization to damage sites, H3K56 acetylation assays, cell survival assays with DNA-damaging agents","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization to damage sites with functional consequence, specific histone substrate (H3K56) identified, and multiple orthogonal methods in a single rigorous study","pmids":["20802485"],"is_preprint":false},{"year":2010,"finding":"Hdac2 physically interacts with the transcription factor Gata4 and mediates its deacetylation; this interaction is stabilized by Hopx. Hopx/Hdac2-mediated deacetylation of Gata4 impairs Gata4's ability to transactivate cell cycle genes, thereby restraining cardiac myocyte proliferation during embryonic development.","method":"Co-immunoprecipitation, mouse genetic knockout (Hopx and Hdac2), luciferase reporter assays, cardiac myocyte proliferation quantification","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo genetic loss-of-function, reporter assay, and identification of non-histone substrate (Gata4); multiple orthogonal methods","pmids":["20833366"],"is_preprint":false},{"year":2008,"finding":"HDAC2 physically interacts with CIITA (MHC class II transactivator) in smooth muscle cells and macrophages, deacetylates CIITA, promotes its proteasomal degradation, decreases its recruitment to target promoters, and suppresses its transcriptional activity (MHC II activation and collagen repression). Enzyme-deficient HDAC2 does not promote CIITA degradation.","method":"Co-immunoprecipitation, HDAC inhibitor (TSA) treatment, siRNA knockdown, chromatin immunoprecipitation (ChIP), luciferase reporter assays, quantitative PCR","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, catalytic mutant analysis, and reporter assays identifying non-histone substrate CIITA with multiple orthogonal methods","pmids":["19041327"],"is_preprint":false},{"year":2015,"finding":"USP4 (ubiquitin-specific peptidase 4) directly interacts with and deubiquitinates HDAC2, leading to HDAC2 stabilization. Accumulated HDAC2 in USP4-overexpressing cells compromises p53 acetylation, p53 transcriptional activation, and apoptotic response to DNA damage, and also downregulates TNFα-induced NF-κB activation.","method":"Co-immunoprecipitation, ubiquitination assays, overexpression and knockdown experiments, p53 acetylation assays, apoptosis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct deubiquitination demonstrated, multiple downstream functional readouts, single lab with multiple orthogonal methods","pmids":["26411366"],"is_preprint":false},{"year":2010,"finding":"HDAC2 promotes sumoylation of eIF4E (eukaryotic translation initiation factor 4E) independent of its deacetylase activity, inducing formation of the active eIF4F complex and stimulating cap-dependent mRNA translation of a subset of eIF4E-responsive genes essential for cell proliferation and survival.","method":"In vitro sumoylation assays, co-immunoprecipitation, overexpression studies, translational reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel non-deacetylase enzymatic activity identified; sumoylation-promoting function demonstrated in cell-based assays; single lab","pmids":["20421305"],"is_preprint":false},{"year":2013,"finding":"Protein kinase CK2-catalyzed phosphorylation of HDAC2 (and HDAC1) during mitosis promotes dissociation of HDAC1/HDAC2 heterodimers, leaving each enzyme as homodimers associated with Sin3, NuRD, and CoREST corepressor complex components. HDAC1/HDAC2 dimerization depends on phosphorylation in interphase, and phosphorylation by CK2 is required for their dissociation during metaphase.","method":"Kinase inhibitor studies, site-directed mutagenesis of phosphorylation sites, co-immunoprecipitation across cell cycle stages, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphorylation site mutagenesis combined with kinase inhibitor experiments and co-IP across cell cycle phases; multiple orthogonal methods in single lab","pmids":["23612983"],"is_preprint":false},{"year":2011,"finding":"In Schwann cells, HDAC2 specifically activates the transcriptional program of myelination in synergy with Sox10. Ablation of Hdac2 in Schwann cells leads to massive Schwann cell loss and virtual absence of peripheral myelin, with greatly reduced Sox10 and Krox20 expression.","method":"Conditional genetic knockout (Schwann cell-specific Hdac1 and Hdac2 deletion), immunofluorescence, gene expression analysis","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional genetic deletion with clear and specific phenotypic readout; distinction from HDAC1 function demonstrated in same study","pmids":["21423190"],"is_preprint":false},{"year":2015,"finding":"HDAC2 forms a physical complex with FOXO3a and selectively enriches at the p21 gene promoter (but not other FOXO3a targets), inhibiting FOXO3a-mediated p21 transcription. Oxidative stress reduces HDAC2–FOXO3a interaction (regulated by phosphorylation at HDAC2 Ser394), leading to increased H4K16 acetylation at the p21 promoter and upregulation of p21 expression in a p53-independent manner.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), site-directed mutagenesis (Ser394), histone acetylation assays, qRT-PCR, neuronal apoptosis assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP with histone mark quantification, and phosphorylation site mutagenesis; multiple orthogonal methods in single lab","pmids":["25609639"],"is_preprint":false},{"year":2015,"finding":"HDAC2 forms a complex with DNMT3A2 in mouse embryonic stem cells; loss of HDAC1 and HDAC2 in oocytes reduces nuclear-associated DNMT3A2 and causes global DNA hypomethylation and failure to establish genomic imprints. Injection of Hdac2 into double-mutant oocytes partially restores DNMT3A2 nuclear localization.","method":"Co-immunoprecipitation (DNMT3A2–HDAC2), oocyte-specific conditional knockout, microinjection rescue experiments, DNA methylation assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, genetic rescue by microinjection, and DNA methylation phenotype in loss-of-function model; multiple orthogonal methods","pmids":["26586441"],"is_preprint":false},{"year":2018,"finding":"HDAC1 and HDAC2 suppress expression of PPP2R3A/PR130 (a regulatory subunit of the serine/threonine phosphatase PP2A). PR130 promotes dephosphorylation of ATM by PP2A. Loss of HDAC1/2 upregulates PR130, leading to dephosphorylation of checkpoint kinases ATM, CHK1, CHK2, and the kinases WEE1/CDK1, impairing S-phase checkpoint and promoting mitotic catastrophe upon replicative stress.","method":"Genetic elimination of HDAC1/HDAC2, PR130 knockout epistasis, phosphorylation assays, PP2A activity assays, cell fate/apoptosis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with PR130 null cells, phosphatase activity assays, and multiple cell fate readouts; mechanistic pathway placement across multiple orthogonal methods","pmids":["29472538"],"is_preprint":false},{"year":2019,"finding":"LncRNA EPB41L4A-AS1 interacts with HDAC2 and NPM1 and sequesters HDAC2 in the nucleolus. Silencing EPB41L4A-AS1 reduces HDAC2–NPM1 interaction, releases HDAC2 from the nucleolus to the nucleoplasm, enhances HDAC2 occupancy on VHL and VDAC1 promoters, and accelerates glycolysis and glutaminolysis.","method":"RNA immunoprecipitation (RIP), RNA pulldown, RNA-FISH/immunofluorescence co-localization, ChIP, siRNA knockdown","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA-protein interaction assays, co-localization, ChIP; lncRNA-mediated HDAC2 re-localization concept supported by multiple methods but single lab","pmids":["30796006"],"is_preprint":false},{"year":2016,"finding":"HDAC2 promotes loss of primary cilia in pancreatic ductal adenocarcinoma cells by controlling Aurora A expression; inhibition or silencing of HDAC2 restores primary cilia formation and decreases Aurora A levels, acting independently of KRAS.","method":"siRNA silencing, pharmacological inhibition, immunofluorescence (cilia formation), Aurora A expression assays, KRAS epistasis experiments","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular target (Aurora A) and cellular phenotype (cilia formation); epistasis with KRAS; single lab","pmids":["28028031"],"is_preprint":false},{"year":2015,"finding":"Lamin A/C forms a protein complex with HDAC2 and histone substrates in skin fibroblasts. This interaction is dynamically reduced at the onset of DNA damage and restored after DNA repair completion, paralleling modulation of p21 (CDKN1A) expression and global histone acetylation. LMNA mutations (progeria) disrupt this interplay, causing impaired lamin A/C–HDAC2 interaction and p21 accumulation during stress recovery.","method":"Co-immunoprecipitation, western blot, oxidative stress induction, comparison between normal and HGPS patient fibroblasts, gene expression analysis","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP of endogenous complex, dynamic modulation shown across conditions, patient cell validation; single lab with multiple orthogonal methods","pmids":["30109767"],"is_preprint":false},{"year":2015,"finding":"USP17 interacts with HDAC2, deubiquitinates it, and stabilizes its protein level. In cigarette smoke extract-exposed airway epithelial cells and macrophages, HDAC2 is excessively ubiquitinated and degraded in the proteasome due to low USP17 expression; USP17 overexpression blocks HDAC2 destruction.","method":"Co-immunoprecipitation, ubiquitination assays, USP17 overexpression, cigarette smoke extract exposure, proteasome inhibition","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — Co-IP and ubiquitination assays in cell-based system; single lab, moderate methods, limited validation","pmids":["26617781"],"is_preprint":false},{"year":2015,"finding":"NEDDylation (NEDD8 conjugation) targets HDAC2 for proteasomal degradation; HDAC2 is a substrate for NEDD8 conjugation potentiated by oxidized LDL. De-NEDDylating enzyme SENP8 and NEDD8 reciprocally regulate HDAC2 levels. HDAC2 reciprocally regulates Arginase2 transcription to modulate endothelial function.","method":"NEDD8 conjugation assays, ectopic expression of NEDD8/SENP8, pharmacological inhibition (MLN4924), Co-IP, mouse aortic ring functional assays","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct substrate modification assay (NEDDylation), reciprocal regulation with de-NEDDylating enzyme, functional vascular assay; single lab","pmids":["25655932"],"is_preprint":false},{"year":2016,"finding":"HDAC2 deacetylates HNF-4α (hepatocyte nuclear factor 4α), disrupting its binding to the miR-101b promoter. Suppression of miR-101b upregulates its target AMPK, causing AD-like tau hyperphosphorylation, aggregation, and dendritic impairments.","method":"Overexpression/knockdown of HDAC2, HNF-4α deacetylation assays, chromatin immunoprecipitation, miRNA mimic/siRNA rescue experiments in AD mouse model","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — non-histone substrate deacetylation (HNF-4α) demonstrated with downstream pathway placement; in vivo rescue; single lab","pmids":["28202389"],"is_preprint":false},{"year":2013,"finding":"MYCN recruits HDAC2 to the miR-183 promoter in neuroblastoma cells; HDAC2 depletion enhances H4 pan-acetylation at the miR-183 promoter and induces miR-183 transcription. MYCN and HDAC2 thus co-repress miR-183, a tumor suppressive microRNA.","method":"Co-immunoprecipitation (MYCN–HDAC2 complexes), chromatin immunoprecipitation (ChIP) at miR-183 promoter, HDAC2 knockdown/overexpression, H4 acetylation assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP of MYCN–HDAC2 complex, ChIP, histone modification assay, and gain/loss-of-function; multiple orthogonal methods in single lab","pmids":["23625969"],"is_preprint":false},{"year":2016,"finding":"HDAC1 and HDAC2 directly bind to the TP53 gene locus together with MYC; inhibition of HDAC1/HDAC2 with HDAC inhibitors reduces MYC recruitment to the TP53 gene and decreases mutant p53 mRNA and protein expression in pancreatic cancer cells.","method":"Chromatin immunoprecipitation (ChIP) of HDAC1, HDAC2, and MYC at TP53 locus, HDAC inhibitor treatment, genetic elimination of HDAC1/HDAC2, qRT-PCR, western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter occupancy of HDAC2, genetic KO combined with pharmacological inhibition; single lab, multiple methods","pmids":["27721407"],"is_preprint":false},{"year":2023,"finding":"HDAC2 controls chromatin accessibility at HDAC2–NuRD complex-bound genomic sites; targeted degradation of HDAC2 in HDAC1-deficient neuroblastoma cells prompts degradation of several NuRD complex subunits (MTA1, MTA2, MBD3, RBBP4/7) and impairs control of enhancer-associated transcription. HDAC1 and HDAC2 are synthetically lethal in cells with hemizygous deletion of the other paralog.","method":"dTAG-mediated targeted protein degradation, CRISPR genetic disruption, chromatin accessibility (ATAC-seq), proteomics, in vitro and in vivo tumor growth assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — dTAG degradation with chromatin accessibility profiling, proteomic NuRD complex analysis, in vivo validation, and genetic epistasis; multiple orthogonal methods","pmids":["37488358"],"is_preprint":false},{"year":2020,"finding":"PACS-1 accumulates in the nucleus during cell cycle progression and interacts with HDAC2 (and HDAC3) to regulate chromatin dynamics by maintaining histone acetylation status. PACS-1 knockdown causes proteasome-mediated degradation of HDAC2 and HDAC3, elevated H3K9ac and H4K16ac, and increased replication stress-induced DNA damage.","method":"Co-immunoprecipitation, siRNA knockdown, histone acetylation assays, γH2AX assays, cell cycle fractionation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP of endogenous complex, loss-of-function with histone modification readout; single lab with multiple orthogonal methods","pmids":["31988453"],"is_preprint":false},{"year":2022,"finding":"HDAC2 constitutively enriches at the Cacna2d1 (α2δ-1) gene promoter in dorsal root ganglion (DRG) neurons to repress its transcription. Nerve injury reduces HDAC2 enrichment at this promoter, causing histone hyperacetylation, α2δ-1 upregulation, and increased NMDA receptor synaptic trafficking/activity in the spinal cord, promoting chronic pain. Conditional knockout or knockdown of Hdac2 in DRG neurons phenocopies nerve injury and is reversed by gabapentin or α2δ-1 knockout.","method":"Conditional knockout (DRG-specific Hdac2 deletion), ChIP (HDAC2 at Cacna2d1 promoter), siRNA knockdown, electrophysiology, behavioral pain assays, epistasis with Cacna2d1 knockout mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic KO, ChIP, epistasis with Cacna2d1 KO, electrophysiology, and behavioral rescue in vivo; multiple orthogonal methods with mechanistic clarity","pmids":["36257688"],"is_preprint":false},{"year":2019,"finding":"HDAC2, but not HDAC1, co-localizes with Kv1.2 in NF200-positive large neurons of the DRG; HDAC2 siRNA (not HDAC1 siRNA) treatment relieves mechanical/thermal hypersensitivity and upregulates Kv1.2 expression in a CCI neuropathic pain model, establishing HDAC2 as a selective regulator of Kv1.2 gene expression in primary sensory neurons.","method":"siRNA knockdown (HDAC1 vs HDAC2), immunofluorescence co-localization, intrathecal injection, western blot, qRT-PCR, behavioral pain assays","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA-based loss-of-function with specific phenotypic readout; HDAC1 vs HDAC2 specificity demonstrated; single lab","pmids":["31022463"],"is_preprint":false},{"year":2016,"finding":"During RANKL-induced osteoclastogenesis, HDAC2 activates Akt; Akt directly phosphorylates and inactivates FoxO1 (a negative regulator of osteoclastogenesis that reduces reactive oxygen species). HDAC2 deletion decreases Akt activation and increases FoxO1 activity, suppressing osteoclastogenesis.","method":"Lentiviral overexpression/deletion in bone marrow macrophages, western blot (Akt phosphorylation, FoxO1 activity), osteoclast differentiation assays, bone resorption assays","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic loss- and gain-of-function with Akt/FoxO1 pathway intermediary measurements; single lab with pathway placement","pmids":["26962001"],"is_preprint":false},{"year":2019,"finding":"HDAC2 promotes FOXA3 deacetylation by interacting with FOXA3, stabilized by lncRNA DACT3-AS1. Deacetylated FOXA3 is downregulated, relieving its transcriptional repression of PKM2, thereby upregulating PKM2 to promote HCC metastasis.","method":"Co-immunoprecipitation, ChIP, RIP, western blot, overexpression/knockdown, in vivo metastasis assays","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and ChIP support the HDAC2–FOXA3 interaction; single lab with multiple methods","pmids":["35764883"],"is_preprint":false},{"year":2019,"finding":"UBIQUITIN-SPECIFIC PROTEASE 5 (USP5) interacts with and deubiquitinates HDAC2, protecting it from ubiquitin-mediated proteasomal degradation. USP5 knockdown reduces HDAC2 levels and increases p27 (cell cycle inhibitor) expression, suppressing ovarian cancer cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, xenograft tumor models, western blot","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay establishing deubiquitination; functional rescue experiments; single lab","pmids":["31727867"],"is_preprint":false},{"year":2024,"finding":"HDAC2 mediates delactylation of METTL3 (m6A methyltransferase), facilitating METTL3 interaction with WTAP and increasing m6A modification of DNA damage repair transcripts, thereby promoting cisplatin resistance in triple-negative breast cancer.","method":"Co-immunoprecipitation, m6A sequencing, HDAC2 inhibitor (Tucidinostat) treatment, western blot, in vitro and in vivo cisplatin resistance assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, m6A modification assays, pharmacological and genetic manipulation; novel non-histone substrate (METTL3 delactylation); single lab","pmids":["39950833"],"is_preprint":false},{"year":2024,"finding":"HDAC2 suppresses chromatin accessibility at the NLRP3 promoter by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of a BRD4–phospho-p65 complex to enhance NLRP3 transcription, enabling NLRP3/GSDMD-mediated pyroptosis in colorectal cancer cells.","method":"ATAC-seq, RNA-seq, ChIP-qPCR (H3K27ac, BRD4, p65), CRISPR knockout, western blot, xenograft models","journal":"Clinical and translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ATAC-seq and ChIP-qPCR directly linking HDAC2 to chromatin state and transcription factor recruitment at a specific locus; genetic KO with in vivo validation; multiple orthogonal methods","pmids":["38804602"],"is_preprint":false},{"year":2024,"finding":"HDAC2 acts as an eraser of H3K9 lactylation (H3K9la); hyperlactylation of H3K9 inhibits HDAC2 expression, creating a feedback loop that drives VEGF-induced angiogenesis. HDAC2 overexpression decreases H3K9 lactylation and suppresses angiogenesis in endothelial cells.","method":"CUT&Tag (H3K9la chromatin mapping), pharmacological glycolysis inhibition, HDAC2 overexpression, in vivo angiogenesis assays","journal":"Genome biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&Tag chromatin mapping with functional validation; identifies novel substrate (H3K9la); single lab with multiple methods","pmids":["38918851"],"is_preprint":false},{"year":2023,"finding":"HDAC2 regulates the M2-like tumor-associated macrophage phenotype via histone H3 acetylation and through the transcription factor SP1. Myeloid-specific deletion of Hdac2 or pharmacological class I HDAC inhibition shifts macrophages from M2-like to M1-like, alters T-cell infiltration, and reduces tumor growth and angiogenesis in murine lung cancer models.","method":"Conditional myeloid Hdac2 knockout (four murine cancer models), pharmacological inhibition, histone acetylation assays, SP1 ChIP/co-IP, coculture systems, tumor growth assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic KO in four independent models, ChIP/co-IP for HDAC2-SP1 interaction, multiple in vivo and in vitro readouts; replicated across models","pmids":["37205635"],"is_preprint":false},{"year":2017,"finding":"TRPV1-mediated glucocorticoid receptor (GR) signaling induces HDAC2 expression in the hippocampus. In Trpv1-deficient mice, GR-mediated HDAC2 expression and activity are reduced, altering HDAC2-regulated cell-cycle- and neuroplasticity-related gene expression. Hippocampal HDAC2 knockdown phenocopies TRPV1 deficiency, and HDAC2 overexpression blocks the stress-resilient behavioral effects of TRPV1 deficiency.","method":"Trpv1 knockout mice, hippocampal siRNA knockdown, HDAC2 overexpression (viral), chronic unpredictable stress behavioral assays, western blot","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic and viral manipulation with behavioral readout and epistasis demonstration; single lab","pmids":["28402861"],"is_preprint":false},{"year":2009,"finding":"HDAC2 selectively deacetylates histones at chromatin, and its siRNA depletion (but not HDAC1 or HDAC6 depletion) leads to reduced expression of heterochromatin maintenance proteins, chromatin decondensation, and sensitization of breast cancer cells to topoisomerase inhibitor-induced apoptosis. HDAC2 expression correlates with HDAC inhibitor-induced histone acetylation in surrogate tissue.","method":"siRNA knockdown (HDAC1, HDAC2, HDAC6), morphological chromatin analysis, heterochromatin protein assays, apoptosis assays with topoisomerase inhibitors","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — isoform-specific siRNA knockdown demonstrating specific role of HDAC2 vs paralogs; single lab; functional phenotype with molecular readout","pmids":["19372552"],"is_preprint":false},{"year":2024,"finding":"HDAC2 enhances ACSL4 acetylation indirectly by inhibiting transcription of the deacetylase SIRT3. Separately, HAT1 directly promotes ACSL4 acetylation at lysine 383. ACSL4 acetylation inhibits FBXO10-mediated K48-linked ubiquitination, stabilizing ACSL4 and promoting ferroptosis-sensitive properties in nasopharyngeal carcinoma.","method":"Co-IP, acetylation assays (ACSL4-K383), ubiquitination assays, HDAC2 overexpression/knockdown, SIRT3 expression assays, in vitro and in vivo radiosensitivity assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — indirect mechanism (HDAC2 inhibits SIRT3 transcription to increase ACSL4 acetylation); co-IP and acetylation assays; single lab","pmids":["40050614"],"is_preprint":false},{"year":2023,"finding":"HDAC2 forms a co-repressor complex with SMAD3 and SKI (TGF-β pathway proteins) in brain tumor stem cells (BTSCs), maintaining chromatin accessibility required for BTSC self-renewal and growth. Disruption of the HDAC2–SMAD3–SKI axis via pharmacological inhibition or genetic loss-of-function reduces tumorigenic potential in vitro and in orthotopic xenograft models.","method":"Pharmacological HDAC inhibition, genetic loss and gain of function, chromatin accessibility assays, co-immunoprecipitation, BTSC self-renewal assays, orthotopic xenograft models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of endogenous complex, chromatin accessibility, in vivo xenograft validation; single lab with multiple orthogonal methods","pmids":["37598220"],"is_preprint":false},{"year":2011,"finding":"HDAC2 maintains HIF-1α protein stability in oral squamous cell carcinoma cells via direct physical interaction; HDAC2 overexpression prevents VHL-mediated ubiquitination of HIF-1α, while HDAC2 knockdown reduces HIF-1α levels and impairs cell invasion/migration. Co-immunoprecipitation confirmed direct interaction of HIF-1α with VHL as modulated by HDAC2.","method":"Co-immunoprecipitation (HDAC2–HIF-1α, HIF-1α–VHL), protein synthesis/degradation inhibitor studies, shRNA knockdown, overexpression, in vivo tumor models","journal":"Journal of oral pathology & medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP supports HDAC2–HIF-1α interaction; mechanism of VHL interaction modulation inferred; single lab","pmids":["21332579"],"is_preprint":false},{"year":2024,"finding":"HDAC2 directly binds to the LAPTM4B promoter at four distinct sites to activate its transcription, promoting autophagy in hepatocellular carcinoma. HDAC2 binding at LAPTM4B was confirmed by ChIP, establishing LAPTM4B as a direct HDAC2 transcriptional target.","method":"ChIP (HDAC2 at LAPTM4B promoter), promoter binding site mapping, knockdown/overexpression, autophagy assays, in vivo xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with multiple binding site mapping and functional validation; single lab with in vivo validation","pmids":["39147759"],"is_preprint":false},{"year":2021,"finding":"MIER3 interacts with HDAC1, HDAC2, and Snail to form a co-repressor complex that binds the E-cadherin promoter and mediates its deacetylation, promoting epithelial-mesenchymal transition in breast cancer cells.","method":"Co-immunoprecipitation (MIER3–HDAC1/HDAC2–Snail), chromatin immunoprecipitation (ChIP at E-cadherin promoter), western blot, in vitro migration/invasion assays","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP of multi-protein complex and ChIP at target promoter; single lab; no catalytic mutant confirmation","pmids":["34242623"],"is_preprint":false},{"year":2024,"finding":"SENP1 binds to HDAC2 and mediates its de-SUMOylation; SENP1-mediated de-SUMOylation of HDAC2 enhances EGFR transcription and activates the AKT signaling pathway to promote AML cell proliferation.","method":"Co-immunoprecipitation (SENP1–HDAC2), SUMO assays, ChIP-qPCR (HDAC2 at EGFR locus), shRNA/sgRNA knockdown","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and SUMO/ChIP assays in single lab; novel PTM (de-SUMOylation) of HDAC2 reported","pmids":["38822351"],"is_preprint":false},{"year":2022,"finding":"HDAC2 reduces histone H3K9 acetylation at the miR-205 promoter through an SP1-mediated pathway, suppressing miR-205 expression. miR-205 in turn directly targets and inhibits HDAC2 expression, forming a feedback regulatory loop that controls ECM production in tubular epithelial cells in diabetic kidney disease.","method":"ChIP (H3K9ac at miR-205 promoter), luciferase reporter assays (miR-205 promoter), siRNA knockdown, overexpression, db/db mouse model","journal":"Clinical science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase assays directly linking HDAC2 to miR-205 promoter histone modification; feedback loop validated by multiple methods; single lab","pmids":["35084460"],"is_preprint":false},{"year":2019,"finding":"Cytoplasmic binding between glucocorticoid receptor (GR) and HDAC2 was demonstrated in mesenchymal stem cells. VPA-mediated HDAC2 inhibition alters this GR–HDAC2 cytoplasmic interaction and leads to GR recruitment to the nGRE element of the osteocalcin (OC) promoter, downregulating OC expression.","method":"Co-immunoprecipitation (cytoplasmic GR–HDAC2), chromatin immunoprecipitation (ChIP of GR at OC nGRE), HDAC2 knockdown, in vivo bone formation assay (NOD/SCID mice)","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and ChIP in single lab; cytoplasmic localization of the complex is a notable finding; functional in vivo validation","pmids":["30841579"],"is_preprint":false},{"year":2016,"finding":"p21 and CK2 interaction (but not CK2 alone) enhances HDAC2 phosphorylation, which restricts KLF4 deacetylation by HDAC2 and prevents KLF4 from acting as an oncogene in bladder cancer cells. When p21 is absent, HDAC2 deacetylates KLF4, converting it from a tumor suppressor to a proliferation promoter.","method":"Co-immunoprecipitation (p21–CK2–HDAC2), phosphorylation assays, KLF4 acetylation assays, siRNA knockdown, luciferase reporter assays","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and acetylation assays placing HDAC2 phosphorylation in pathway; single lab","pmids":["26729194"],"is_preprint":false},{"year":2024,"finding":"Hypoxia-activated XBP1s forms a stable repressor complex with HDAC2 and EZH2. This complex binds the ΔNp63 promoter, mediating a switch from H3K27ac (normoxic state) to H3K27me3 (hypoxic state) to suppress ΔNp63α transcription and promote breast cancer metastasis. Knockdown of either HDAC2 or EZH2 restores H3K27ac and ΔNp63α expression.","method":"Co-immunoprecipitation (XBP1s–HDAC2–EZH2), ChIP (H3K27ac and H3K27me3 at ΔNp63 promoter), siRNA knockdown, pharmacological inhibition, in vivo metastasis models","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP of trimeric complex, ChIP for two histone marks at specific locus, in vivo metastasis validation; multiple orthogonal methods in single lab","pmids":["38413797"],"is_preprint":false}],"current_model":"HDAC2 is a class I histone deacetylase that functions both as a canonical histone deacetylase (regulating H3K56ac, H3K9ac, H3K27ac, H4ac at specific gene promoters) and as a modifier of non-histone substrates (Gata4, CIITA, FOXO3a, HNF-4α, eIF4E via sumoylation, FOXA3, METTL3 via delactylation, ACSL4 indirectly via SIRT3, KLF4); it is regulated post-translationally by phosphorylation (CK2 at mitosis), ubiquitination/deubiquitination (USP4, USP5, USP17, ARHGAP4, NEDDylation/SENP8), and SUMOylation (SENP1); it operates in multiple complexes including NuRD (with MTA1/2, MBD3, RBBP4/7), Sin3A, CoREST, and context-specific assemblies with Hopx/Gata4, Tet2/IκBζ, MYCN, XBP1s/EZH2, SMAD3/SKI, MIER3/Snail, and PACS-1, collectively controlling gene expression programs in DNA damage repair, inflammation resolution, cardiac development, neuronal plasticity, myelination, ciliogenesis, osteoclastogenesis, and tumor metastasis."},"narrative":{"mechanistic_narrative":"HDAC2 is a class I histone deacetylase that controls gene expression programs by erasing acetyl (and acyl) marks from chromatin and from non-histone substrates, operating largely within multiprotein corepressor assemblies [PMID:37488358, PMID:19372552]. As a chromatin enzyme it deacetylates histones at specific loci—removing H3K56ac at DNA double-strand breaks to promote nonhomologous end-joining and DNA repair [PMID:20802485], eliminating H3K27ac at the NLRP3 promoter to restrain BRD4–p65 recruitment and pyroptosis [PMID:38804602], and erasing H3K9 lactylation as a delactylase that limits VEGF-driven angiogenesis [PMID:38918851]. Its repressive function is delivered through context-specific complexes: the NuRD complex (MTA1/2, MBD3, RBBP4/7), whose stability depends on HDAC2 itself [PMID:37488358], and assemblies with Tet2/IκBζ at the Il6 promoter [PMID:26287468], MYCN at miR-183 [PMID:23625969], XBP1s/EZH2 at the ΔNp63 promoter where it drives an H3K27ac-to-H3K27me3 switch [PMID:38413797], SMAD3/SKI [PMID:37598220], MIER3/Snail at E-cadherin [PMID:34242623], and SP1 [PMID:37205635]. Beyond histones, HDAC2 deacetylates transcription factors—Gata4 (stabilized by Hopx) to restrain cardiac myocyte proliferation [PMID:20833366], CIITA to trigger its degradation [PMID:19041327], FOXO3a to repress p21 [PMID:25609639], HNF-4α [PMID:28202389], FOXA3 [PMID:35764883]—and exerts non-deacetylase activities including promotion of eIF4E sumoylation to stimulate cap-dependent translation [PMID:20421305] and delactylation of METTL3 [PMID:39950833]. HDAC2 abundance and activity are tightly post-translationally controlled by CK2 phosphorylation that governs HDAC1/HDAC2 dimerization across the cell cycle [PMID:23612983], by deubiquitination (USP4, USP5, USP17) [PMID:26411366, PMID:31727867, PMID:26617781], by NEDDylation/SENP8 [PMID:25655932], and by SENP1-mediated de-SUMOylation [PMID:38822351]. Through these activities HDAC2 functions in DNA damage signaling and the replication-stress checkpoint via PR130/PP2A control of ATM/CHK kinases [PMID:29472538], peripheral myelination with Sox10 [PMID:21423190], chronic pain through repression of Cacna2d1 and Kv1.2 in sensory neurons [PMID:36257688, PMID:31022463], tumor-associated macrophage polarization [PMID:37205635], and metastasis [PMID:38413797, PMID:35764883]. The HDAC1 and HDAC2 paralogs are synthetically lethal in cells with hemizygous deletion of the other [PMID:37488358].","teleology":[{"year":2010,"claim":"Established HDAC2 as a chromatin enzyme recruited directly to DNA lesions, defining a substrate-specific role (H3K56ac) in repair pathway choice rather than generic transcriptional repression.","evidence":"siRNA depletion, immunofluorescence localization to break sites, and H3K56ac assays with damage-sensitivity readouts","pmids":["20802485"],"confidence":"High","gaps":["Does not distinguish HDAC2-specific from HDAC1-specific contribution","Recruitment mechanism to break sites not defined"]},{"year":2010,"claim":"Showed HDAC2 acts on non-histone substrates, deacetylating the transcription factor Gata4 (with Hopx as a stabilizing cofactor) to constrain a developmental proliferation program.","evidence":"Reciprocal Co-IP, Hopx/Hdac2 knockout mice, luciferase reporters, and cardiac myocyte proliferation quantification","pmids":["20833366"],"confidence":"High","gaps":["Acetylation site on Gata4 not mapped","Whether deacetylation is direct or complex-mediated not fully resolved"]},{"year":2010,"claim":"Revealed a deacetylase-independent activity—HDAC2 promotes eIF4E sumoylation to drive cap-dependent translation—expanding its function beyond chromatin.","evidence":"In vitro sumoylation assays, Co-IP, and translational reporter assays","pmids":["20421305"],"confidence":"Medium","gaps":["Single lab","Mechanism by which HDAC2 enhances SUMO conjugation unclear"]},{"year":2013,"claim":"Defined cell-cycle post-translational control: CK2 phosphorylation governs HDAC1/HDAC2 dimer assembly and dissociation, redistributing the enzymes among Sin3, NuRD, and CoREST complexes.","evidence":"Phosphosite mutagenesis, kinase inhibitors, and Co-IP across cell cycle stages","pmids":["23612983"],"confidence":"High","gaps":["Functional consequence of mitotic dissociation on target genes not defined"]},{"year":2011,"claim":"Demonstrated a paralog-specific developmental role in which HDAC2 cooperates with Sox10 to activate the myelination transcriptional program.","evidence":"Schwann-cell-specific conditional knockout, immunofluorescence, and gene expression analysis","pmids":["21423190"],"confidence":"High","gaps":["Direct targets of HDAC2 in the myelination program not enumerated"]},{"year":2015,"claim":"Placed HDAC2 in inflammation resolution by showing Tet2 recruits it via IκBζ to deacetylate and repress the Il6 promoter independently of DNA methylation.","evidence":"Co-IP, ChIP, knockout mice, and LPS challenge","pmids":["26287468"],"confidence":"High","gaps":["Histone marks erased at Il6 not specified","Generality across inflammatory loci untested"]},{"year":2015,"claim":"Identified deubiquitination as a major control of HDAC2 abundance, with USP4 stabilizing HDAC2 to dampen p53 and NF-κB responses.","evidence":"Co-IP, ubiquitination assays, and p53 acetylation/apoptosis readouts","pmids":["26411366"],"confidence":"High","gaps":["Ubiquitin ligase opposing USP4 not identified"]},{"year":2015,"claim":"Showed promoter-selective repression of FOXO3a targets, with HDAC2 restraining p21 transcription and oxidative stress relieving repression via Ser394 phosphorylation.","evidence":"Co-IP, ChIP, Ser394 mutagenesis, and histone acetylation assays in neurons","pmids":["25609639"],"confidence":"High","gaps":["Kinase phosphorylating Ser394 under stress not identified","Basis of promoter selectivity unexplained"]},{"year":2015,"claim":"Connected HDAC2 to epigenetic reprogramming by demonstrating it supports DNMT3A2 nuclear localization required to establish genomic imprints.","evidence":"Co-IP, oocyte conditional knockout, and microinjection rescue with DNA methylation assays","pmids":["26586441"],"confidence":"High","gaps":["Whether the effect requires deacetylase activity not tested"]},{"year":2018,"claim":"Positioned HDAC1/HDAC2 in the replication-stress checkpoint by showing they repress PR130/PP2A to maintain ATM/CHK1/CHK2 phosphorylation and prevent mitotic catastrophe.","evidence":"Genetic elimination of HDAC1/2, PR130 epistasis, and PP2A activity/phosphorylation assays","pmids":["29472538"],"confidence":"High","gaps":["HDAC2-specific versus HDAC1-specific contribution not separated"]},{"year":2023,"claim":"Established HDAC2 as a structural determinant of NuRD integrity and chromatin accessibility, and revealed synthetic lethality with HDAC1 in paralog-deleted cells.","evidence":"dTAG-mediated degradation, ATAC-seq, NuRD proteomics, and in vivo tumor assays","pmids":["37488358"],"confidence":"High","gaps":["Mechanism by which HDAC2 loss destabilizes other NuRD subunits not defined"]},{"year":2024,"claim":"Extended HDAC2 catalysis to acyl marks, identifying it as an eraser of histone H3K9 lactylation and a delactylase of METTL3, linking metabolism to chromatin and RNA modification.","evidence":"CUT&Tag, m6A sequencing, Co-IP, and overexpression/inhibitor studies","pmids":["38918851","39950833"],"confidence":"Medium","gaps":["Direct catalytic delactylation versus complex-mediated effect not biochemically reconstituted","Single lab per substrate"]},{"year":2024,"claim":"Defined SUMO-based control of HDAC2 by SENP1, whose de-SUMOylation of HDAC2 promotes EGFR/AKT-driven leukemia proliferation.","evidence":"Co-IP, SUMO assays, and ChIP-qPCR at the EGFR locus with knockdown","pmids":["38822351"],"confidence":"Medium","gaps":["SUMO acceptor site on HDAC2 not mapped","Single lab"]},{"year":null,"claim":"How HDAC2 substrate and locus selectivity is encoded—which complex compositions, post-translational states, and acyl-mark specificities direct it to particular promoters and non-histone targets—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model linking complex composition to target selection","Relative contributions of deacetylase, delactylase, and non-catalytic functions not unified","HDAC2-specific versus HDAC1-shared activities incompletely separated genome-wide"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,8,16,24,26]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,17,27,33,35,41]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,28,31]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,27,31]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2,8,19,27]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[39]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[19,27,31,41]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,17,33,35]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,10,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,27,29]}],"complexes":["NuRD","Sin3","CoREST"],"partners":["HDAC1","MTA1","MTA2","MBD3","RBBP4","EZH2","SMAD3","SP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92769","full_name":"Histone deacetylase 2","aliases":["Protein deacylase HDAC2"],"length_aa":488,"mass_kda":55.4,"function":"Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (By similarity). Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR (PubMed:12724404). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). Component of the SIN3B complex that represses transcription and counteracts the histone acetyltransferase activity of EP300 through the recognition H3K27ac marks by PHF12 and the activity of the histone deacetylase HDAC2 (PubMed:37137925). Also deacetylates non-histone targets: deacetylates TSHZ3, thereby regulating its transcriptional repressor activity (PubMed:19343227). May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation (By similarity). Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A (PubMed:21965678). 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) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation, delactylation and de-2-hydroxyisobutyrylation, respectively (PubMed:28497810, PubMed:29192674, PubMed:35044827)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q92769/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HDAC2","classification":"Not Classified","n_dependent_lines":43,"n_total_lines":1208,"dependency_fraction":0.03559602649006623},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000196591","cell_line_id":"CID001500","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"HDAC1","stoichiometry":10.0},{"gene":"MTA2","stoichiometry":10.0},{"gene":"MBD3","stoichiometry":10.0},{"gene":"GATAD2B","stoichiometry":10.0},{"gene":"CTBP1","stoichiometry":10.0},{"gene":"MTA1","stoichiometry":10.0},{"gene":"RCOR1","stoichiometry":10.0},{"gene":"KDM1A","stoichiometry":10.0},{"gene":"RBBP4","stoichiometry":10.0},{"gene":"CHD4","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001500","total_profiled":1310},"omim":[{"mim_id":"620100","title":"MIER FAMILY, MEMBER 3; MIER3","url":"https://www.omim.org/entry/620100"},{"mim_id":"620092","title":"MIER FAMILY, MEMBER 2; MIER2","url":"https://www.omim.org/entry/620092"},{"mim_id":"619942","title":"ZINC FINGER PROTEIN 541; ZNF541","url":"https://www.omim.org/entry/619942"},{"mim_id":"619505","title":"ZINC FINGER PROTEIN 431; ZNF431","url":"https://www.omim.org/entry/619505"},{"mim_id":"618764","title":"CDK2-ASSOCIATED CULLIN DOMAIN-CONTAINING PROTEIN 1; CACUL1","url":"https://www.omim.org/entry/618764"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HDAC2"},"hgnc":{"alias_symbol":["RPD3","YAF1","KDAC2"],"prev_symbol":[]},"alphafold":{"accession":"Q92769","domains":[{"cath_id":"3.40.800.20","chopping":"32-53_115-372","consensus_level":"high","plddt":97.5676,"start":32,"end":372}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92769","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92769-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92769-F1-predicted_aligned_error_v6.png","plddt_mean":85.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HDAC2","jax_strain_url":"https://www.jax.org/strain/search?query=HDAC2"},"sequence":{"accession":"Q92769","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92769.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92769/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92769"}},"corpus_meta":[{"pmid":"26287468","id":"PMC_26287468","title":"Tet2 is 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assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, and loss-of-function genetics with specific phenotypic readout in vivo; multiple orthogonal methods in a rigorous study\",\n      \"pmids\": [\"26287468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HDAC1 and HDAC2 are recruited to DNA double-strand break sites and regulate acetylation of histone H3 Lys56 (H3K56ac), promoting DNA repair by nonhomologous end-joining (NHEJ); depletion of both causes hypersensitivity to DNA-damaging agents and sustained DNA-damage signaling.\",\n      \"method\": \"siRNA knockdown, immunofluorescence localization to damage sites, H3K56 acetylation assays, cell survival assays with DNA-damaging agents\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization to damage sites with functional consequence, specific histone substrate (H3K56) identified, and multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"20802485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hdac2 physically interacts with the transcription factor Gata4 and mediates its deacetylation; this interaction is stabilized by Hopx. Hopx/Hdac2-mediated deacetylation of Gata4 impairs Gata4's ability to transactivate cell cycle genes, thereby restraining cardiac myocyte proliferation during embryonic development.\",\n      \"method\": \"Co-immunoprecipitation, mouse genetic knockout (Hopx and Hdac2), luciferase reporter assays, cardiac myocyte proliferation quantification\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo genetic loss-of-function, reporter assay, and identification of non-histone substrate (Gata4); multiple orthogonal methods\",\n      \"pmids\": [\"20833366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HDAC2 physically interacts with CIITA (MHC class II transactivator) in smooth muscle cells and macrophages, deacetylates CIITA, promotes its proteasomal degradation, decreases its recruitment to target promoters, and suppresses its transcriptional activity (MHC II activation and collagen repression). Enzyme-deficient HDAC2 does not promote CIITA degradation.\",\n      \"method\": \"Co-immunoprecipitation, HDAC inhibitor (TSA) treatment, siRNA knockdown, chromatin immunoprecipitation (ChIP), luciferase reporter assays, quantitative PCR\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, catalytic mutant analysis, and reporter assays identifying non-histone substrate CIITA with multiple orthogonal methods\",\n      \"pmids\": [\"19041327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP4 (ubiquitin-specific peptidase 4) directly interacts with and deubiquitinates HDAC2, leading to HDAC2 stabilization. Accumulated HDAC2 in USP4-overexpressing cells compromises p53 acetylation, p53 transcriptional activation, and apoptotic response to DNA damage, and also downregulates TNFα-induced NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, overexpression and knockdown experiments, p53 acetylation assays, apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct deubiquitination demonstrated, multiple downstream functional readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26411366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HDAC2 promotes sumoylation of eIF4E (eukaryotic translation initiation factor 4E) independent of its deacetylase activity, inducing formation of the active eIF4F complex and stimulating cap-dependent mRNA translation of a subset of eIF4E-responsive genes essential for cell proliferation and survival.\",\n      \"method\": \"In vitro sumoylation assays, co-immunoprecipitation, overexpression studies, translational reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel non-deacetylase enzymatic activity identified; sumoylation-promoting function demonstrated in cell-based assays; single lab\",\n      \"pmids\": [\"20421305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Protein kinase CK2-catalyzed phosphorylation of HDAC2 (and HDAC1) during mitosis promotes dissociation of HDAC1/HDAC2 heterodimers, leaving each enzyme as homodimers associated with Sin3, NuRD, and CoREST corepressor complex components. HDAC1/HDAC2 dimerization depends on phosphorylation in interphase, and phosphorylation by CK2 is required for their dissociation during metaphase.\",\n      \"method\": \"Kinase inhibitor studies, site-directed mutagenesis of phosphorylation sites, co-immunoprecipitation across cell cycle stages, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phosphorylation site mutagenesis combined with kinase inhibitor experiments and co-IP across cell cycle phases; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"23612983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Schwann cells, HDAC2 specifically activates the transcriptional program of myelination in synergy with Sox10. Ablation of Hdac2 in Schwann cells leads to massive Schwann cell loss and virtual absence of peripheral myelin, with greatly reduced Sox10 and Krox20 expression.\",\n      \"method\": \"Conditional genetic knockout (Schwann cell-specific Hdac1 and Hdac2 deletion), immunofluorescence, gene expression analysis\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional genetic deletion with clear and specific phenotypic readout; distinction from HDAC1 function demonstrated in same study\",\n      \"pmids\": [\"21423190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HDAC2 forms a physical complex with FOXO3a and selectively enriches at the p21 gene promoter (but not other FOXO3a targets), inhibiting FOXO3a-mediated p21 transcription. Oxidative stress reduces HDAC2–FOXO3a interaction (regulated by phosphorylation at HDAC2 Ser394), leading to increased H4K16 acetylation at the p21 promoter and upregulation of p21 expression in a p53-independent manner.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), site-directed mutagenesis (Ser394), histone acetylation assays, qRT-PCR, neuronal apoptosis assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP with histone mark quantification, and phosphorylation site mutagenesis; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"25609639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HDAC2 forms a complex with DNMT3A2 in mouse embryonic stem cells; loss of HDAC1 and HDAC2 in oocytes reduces nuclear-associated DNMT3A2 and causes global DNA hypomethylation and failure to establish genomic imprints. Injection of Hdac2 into double-mutant oocytes partially restores DNMT3A2 nuclear localization.\",\n      \"method\": \"Co-immunoprecipitation (DNMT3A2–HDAC2), oocyte-specific conditional knockout, microinjection rescue experiments, DNA methylation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, genetic rescue by microinjection, and DNA methylation phenotype in loss-of-function model; multiple orthogonal methods\",\n      \"pmids\": [\"26586441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC1 and HDAC2 suppress expression of PPP2R3A/PR130 (a regulatory subunit of the serine/threonine phosphatase PP2A). PR130 promotes dephosphorylation of ATM by PP2A. Loss of HDAC1/2 upregulates PR130, leading to dephosphorylation of checkpoint kinases ATM, CHK1, CHK2, and the kinases WEE1/CDK1, impairing S-phase checkpoint and promoting mitotic catastrophe upon replicative stress.\",\n      \"method\": \"Genetic elimination of HDAC1/HDAC2, PR130 knockout epistasis, phosphorylation assays, PP2A activity assays, cell fate/apoptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with PR130 null cells, phosphatase activity assays, and multiple cell fate readouts; mechanistic pathway placement across multiple orthogonal methods\",\n      \"pmids\": [\"29472538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LncRNA EPB41L4A-AS1 interacts with HDAC2 and NPM1 and sequesters HDAC2 in the nucleolus. Silencing EPB41L4A-AS1 reduces HDAC2–NPM1 interaction, releases HDAC2 from the nucleolus to the nucleoplasm, enhances HDAC2 occupancy on VHL and VDAC1 promoters, and accelerates glycolysis and glutaminolysis.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pulldown, RNA-FISH/immunofluorescence co-localization, ChIP, siRNA knockdown\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-protein interaction assays, co-localization, ChIP; lncRNA-mediated HDAC2 re-localization concept supported by multiple methods but single lab\",\n      \"pmids\": [\"30796006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HDAC2 promotes loss of primary cilia in pancreatic ductal adenocarcinoma cells by controlling Aurora A expression; inhibition or silencing of HDAC2 restores primary cilia formation and decreases Aurora A levels, acting independently of KRAS.\",\n      \"method\": \"siRNA silencing, pharmacological inhibition, immunofluorescence (cilia formation), Aurora A expression assays, KRAS epistasis experiments\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular target (Aurora A) and cellular phenotype (cilia formation); epistasis with KRAS; single lab\",\n      \"pmids\": [\"28028031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Lamin A/C forms a protein complex with HDAC2 and histone substrates in skin fibroblasts. This interaction is dynamically reduced at the onset of DNA damage and restored after DNA repair completion, paralleling modulation of p21 (CDKN1A) expression and global histone acetylation. LMNA mutations (progeria) disrupt this interplay, causing impaired lamin A/C–HDAC2 interaction and p21 accumulation during stress recovery.\",\n      \"method\": \"Co-immunoprecipitation, western blot, oxidative stress induction, comparison between normal and HGPS patient fibroblasts, gene expression analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP of endogenous complex, dynamic modulation shown across conditions, patient cell validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30109767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"USP17 interacts with HDAC2, deubiquitinates it, and stabilizes its protein level. In cigarette smoke extract-exposed airway epithelial cells and macrophages, HDAC2 is excessively ubiquitinated and degraded in the proteasome due to low USP17 expression; USP17 overexpression blocks HDAC2 destruction.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, USP17 overexpression, cigarette smoke extract exposure, proteasome inhibition\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ubiquitination assays in cell-based system; single lab, moderate methods, limited validation\",\n      \"pmids\": [\"26617781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NEDDylation (NEDD8 conjugation) targets HDAC2 for proteasomal degradation; HDAC2 is a substrate for NEDD8 conjugation potentiated by oxidized LDL. De-NEDDylating enzyme SENP8 and NEDD8 reciprocally regulate HDAC2 levels. HDAC2 reciprocally regulates Arginase2 transcription to modulate endothelial function.\",\n      \"method\": \"NEDD8 conjugation assays, ectopic expression of NEDD8/SENP8, pharmacological inhibition (MLN4924), Co-IP, mouse aortic ring functional assays\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct substrate modification assay (NEDDylation), reciprocal regulation with de-NEDDylating enzyme, functional vascular assay; single lab\",\n      \"pmids\": [\"25655932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HDAC2 deacetylates HNF-4α (hepatocyte nuclear factor 4α), disrupting its binding to the miR-101b promoter. Suppression of miR-101b upregulates its target AMPK, causing AD-like tau hyperphosphorylation, aggregation, and dendritic impairments.\",\n      \"method\": \"Overexpression/knockdown of HDAC2, HNF-4α deacetylation assays, chromatin immunoprecipitation, miRNA mimic/siRNA rescue experiments in AD mouse model\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — non-histone substrate deacetylation (HNF-4α) demonstrated with downstream pathway placement; in vivo rescue; single lab\",\n      \"pmids\": [\"28202389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MYCN recruits HDAC2 to the miR-183 promoter in neuroblastoma cells; HDAC2 depletion enhances H4 pan-acetylation at the miR-183 promoter and induces miR-183 transcription. MYCN and HDAC2 thus co-repress miR-183, a tumor suppressive microRNA.\",\n      \"method\": \"Co-immunoprecipitation (MYCN–HDAC2 complexes), chromatin immunoprecipitation (ChIP) at miR-183 promoter, HDAC2 knockdown/overexpression, H4 acetylation assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP of MYCN–HDAC2 complex, ChIP, histone modification assay, and gain/loss-of-function; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"23625969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HDAC1 and HDAC2 directly bind to the TP53 gene locus together with MYC; inhibition of HDAC1/HDAC2 with HDAC inhibitors reduces MYC recruitment to the TP53 gene and decreases mutant p53 mRNA and protein expression in pancreatic cancer cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of HDAC1, HDAC2, and MYC at TP53 locus, HDAC inhibitor treatment, genetic elimination of HDAC1/HDAC2, qRT-PCR, western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter occupancy of HDAC2, genetic KO combined with pharmacological inhibition; single lab, multiple methods\",\n      \"pmids\": [\"27721407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC2 controls chromatin accessibility at HDAC2–NuRD complex-bound genomic sites; targeted degradation of HDAC2 in HDAC1-deficient neuroblastoma cells prompts degradation of several NuRD complex subunits (MTA1, MTA2, MBD3, RBBP4/7) and impairs control of enhancer-associated transcription. HDAC1 and HDAC2 are synthetically lethal in cells with hemizygous deletion of the other paralog.\",\n      \"method\": \"dTAG-mediated targeted protein degradation, CRISPR genetic disruption, chromatin accessibility (ATAC-seq), proteomics, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — dTAG degradation with chromatin accessibility profiling, proteomic NuRD complex analysis, in vivo validation, and genetic epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"37488358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PACS-1 accumulates in the nucleus during cell cycle progression and interacts with HDAC2 (and HDAC3) to regulate chromatin dynamics by maintaining histone acetylation status. PACS-1 knockdown causes proteasome-mediated degradation of HDAC2 and HDAC3, elevated H3K9ac and H4K16ac, and increased replication stress-induced DNA damage.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, histone acetylation assays, γH2AX assays, cell cycle fractionation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP of endogenous complex, loss-of-function with histone modification readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31988453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC2 constitutively enriches at the Cacna2d1 (α2δ-1) gene promoter in dorsal root ganglion (DRG) neurons to repress its transcription. Nerve injury reduces HDAC2 enrichment at this promoter, causing histone hyperacetylation, α2δ-1 upregulation, and increased NMDA receptor synaptic trafficking/activity in the spinal cord, promoting chronic pain. Conditional knockout or knockdown of Hdac2 in DRG neurons phenocopies nerve injury and is reversed by gabapentin or α2δ-1 knockout.\",\n      \"method\": \"Conditional knockout (DRG-specific Hdac2 deletion), ChIP (HDAC2 at Cacna2d1 promoter), siRNA knockdown, electrophysiology, behavioral pain assays, epistasis with Cacna2d1 knockout mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic KO, ChIP, epistasis with Cacna2d1 KO, electrophysiology, and behavioral rescue in vivo; multiple orthogonal methods with mechanistic clarity\",\n      \"pmids\": [\"36257688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC2, but not HDAC1, co-localizes with Kv1.2 in NF200-positive large neurons of the DRG; HDAC2 siRNA (not HDAC1 siRNA) treatment relieves mechanical/thermal hypersensitivity and upregulates Kv1.2 expression in a CCI neuropathic pain model, establishing HDAC2 as a selective regulator of Kv1.2 gene expression in primary sensory neurons.\",\n      \"method\": \"siRNA knockdown (HDAC1 vs HDAC2), immunofluorescence co-localization, intrathecal injection, western blot, qRT-PCR, behavioral pain assays\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA-based loss-of-function with specific phenotypic readout; HDAC1 vs HDAC2 specificity demonstrated; single lab\",\n      \"pmids\": [\"31022463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"During RANKL-induced osteoclastogenesis, HDAC2 activates Akt; Akt directly phosphorylates and inactivates FoxO1 (a negative regulator of osteoclastogenesis that reduces reactive oxygen species). HDAC2 deletion decreases Akt activation and increases FoxO1 activity, suppressing osteoclastogenesis.\",\n      \"method\": \"Lentiviral overexpression/deletion in bone marrow macrophages, western blot (Akt phosphorylation, FoxO1 activity), osteoclast differentiation assays, bone resorption assays\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic loss- and gain-of-function with Akt/FoxO1 pathway intermediary measurements; single lab with pathway placement\",\n      \"pmids\": [\"26962001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC2 promotes FOXA3 deacetylation by interacting with FOXA3, stabilized by lncRNA DACT3-AS1. Deacetylated FOXA3 is downregulated, relieving its transcriptional repression of PKM2, thereby upregulating PKM2 to promote HCC metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, RIP, western blot, overexpression/knockdown, in vivo metastasis assays\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and ChIP support the HDAC2–FOXA3 interaction; single lab with multiple methods\",\n      \"pmids\": [\"35764883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"UBIQUITIN-SPECIFIC PROTEASE 5 (USP5) interacts with and deubiquitinates HDAC2, protecting it from ubiquitin-mediated proteasomal degradation. USP5 knockdown reduces HDAC2 levels and increases p27 (cell cycle inhibitor) expression, suppressing ovarian cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown, xenograft tumor models, western blot\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay establishing deubiquitination; functional rescue experiments; single lab\",\n      \"pmids\": [\"31727867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC2 mediates delactylation of METTL3 (m6A methyltransferase), facilitating METTL3 interaction with WTAP and increasing m6A modification of DNA damage repair transcripts, thereby promoting cisplatin resistance in triple-negative breast cancer.\",\n      \"method\": \"Co-immunoprecipitation, m6A sequencing, HDAC2 inhibitor (Tucidinostat) treatment, western blot, in vitro and in vivo cisplatin resistance assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, m6A modification assays, pharmacological and genetic manipulation; novel non-histone substrate (METTL3 delactylation); single lab\",\n      \"pmids\": [\"39950833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC2 suppresses chromatin accessibility at the NLRP3 promoter by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of a BRD4–phospho-p65 complex to enhance NLRP3 transcription, enabling NLRP3/GSDMD-mediated pyroptosis in colorectal cancer cells.\",\n      \"method\": \"ATAC-seq, RNA-seq, ChIP-qPCR (H3K27ac, BRD4, p65), CRISPR knockout, western blot, xenograft models\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ATAC-seq and ChIP-qPCR directly linking HDAC2 to chromatin state and transcription factor recruitment at a specific locus; genetic KO with in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"38804602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC2 acts as an eraser of H3K9 lactylation (H3K9la); hyperlactylation of H3K9 inhibits HDAC2 expression, creating a feedback loop that drives VEGF-induced angiogenesis. HDAC2 overexpression decreases H3K9 lactylation and suppresses angiogenesis in endothelial cells.\",\n      \"method\": \"CUT&Tag (H3K9la chromatin mapping), pharmacological glycolysis inhibition, HDAC2 overexpression, in vivo angiogenesis assays\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&Tag chromatin mapping with functional validation; identifies novel substrate (H3K9la); single lab with multiple methods\",\n      \"pmids\": [\"38918851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC2 regulates the M2-like tumor-associated macrophage phenotype via histone H3 acetylation and through the transcription factor SP1. Myeloid-specific deletion of Hdac2 or pharmacological class I HDAC inhibition shifts macrophages from M2-like to M1-like, alters T-cell infiltration, and reduces tumor growth and angiogenesis in murine lung cancer models.\",\n      \"method\": \"Conditional myeloid Hdac2 knockout (four murine cancer models), pharmacological inhibition, histone acetylation assays, SP1 ChIP/co-IP, coculture systems, tumor growth assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic KO in four independent models, ChIP/co-IP for HDAC2-SP1 interaction, multiple in vivo and in vitro readouts; replicated across models\",\n      \"pmids\": [\"37205635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPV1-mediated glucocorticoid receptor (GR) signaling induces HDAC2 expression in the hippocampus. In Trpv1-deficient mice, GR-mediated HDAC2 expression and activity are reduced, altering HDAC2-regulated cell-cycle- and neuroplasticity-related gene expression. Hippocampal HDAC2 knockdown phenocopies TRPV1 deficiency, and HDAC2 overexpression blocks the stress-resilient behavioral effects of TRPV1 deficiency.\",\n      \"method\": \"Trpv1 knockout mice, hippocampal siRNA knockdown, HDAC2 overexpression (viral), chronic unpredictable stress behavioral assays, western blot\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic and viral manipulation with behavioral readout and epistasis demonstration; single lab\",\n      \"pmids\": [\"28402861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HDAC2 selectively deacetylates histones at chromatin, and its siRNA depletion (but not HDAC1 or HDAC6 depletion) leads to reduced expression of heterochromatin maintenance proteins, chromatin decondensation, and sensitization of breast cancer cells to topoisomerase inhibitor-induced apoptosis. HDAC2 expression correlates with HDAC inhibitor-induced histone acetylation in surrogate tissue.\",\n      \"method\": \"siRNA knockdown (HDAC1, HDAC2, HDAC6), morphological chromatin analysis, heterochromatin protein assays, apoptosis assays with topoisomerase inhibitors\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — isoform-specific siRNA knockdown demonstrating specific role of HDAC2 vs paralogs; single lab; functional phenotype with molecular readout\",\n      \"pmids\": [\"19372552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC2 enhances ACSL4 acetylation indirectly by inhibiting transcription of the deacetylase SIRT3. Separately, HAT1 directly promotes ACSL4 acetylation at lysine 383. ACSL4 acetylation inhibits FBXO10-mediated K48-linked ubiquitination, stabilizing ACSL4 and promoting ferroptosis-sensitive properties in nasopharyngeal carcinoma.\",\n      \"method\": \"Co-IP, acetylation assays (ACSL4-K383), ubiquitination assays, HDAC2 overexpression/knockdown, SIRT3 expression assays, in vitro and in vivo radiosensitivity assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — indirect mechanism (HDAC2 inhibits SIRT3 transcription to increase ACSL4 acetylation); co-IP and acetylation assays; single lab\",\n      \"pmids\": [\"40050614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC2 forms a co-repressor complex with SMAD3 and SKI (TGF-β pathway proteins) in brain tumor stem cells (BTSCs), maintaining chromatin accessibility required for BTSC self-renewal and growth. Disruption of the HDAC2–SMAD3–SKI axis via pharmacological inhibition or genetic loss-of-function reduces tumorigenic potential in vitro and in orthotopic xenograft models.\",\n      \"method\": \"Pharmacological HDAC inhibition, genetic loss and gain of function, chromatin accessibility assays, co-immunoprecipitation, BTSC self-renewal assays, orthotopic xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of endogenous complex, chromatin accessibility, in vivo xenograft validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37598220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HDAC2 maintains HIF-1α protein stability in oral squamous cell carcinoma cells via direct physical interaction; HDAC2 overexpression prevents VHL-mediated ubiquitination of HIF-1α, while HDAC2 knockdown reduces HIF-1α levels and impairs cell invasion/migration. Co-immunoprecipitation confirmed direct interaction of HIF-1α with VHL as modulated by HDAC2.\",\n      \"method\": \"Co-immunoprecipitation (HDAC2–HIF-1α, HIF-1α–VHL), protein synthesis/degradation inhibitor studies, shRNA knockdown, overexpression, in vivo tumor models\",\n      \"journal\": \"Journal of oral pathology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP supports HDAC2–HIF-1α interaction; mechanism of VHL interaction modulation inferred; single lab\",\n      \"pmids\": [\"21332579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HDAC2 directly binds to the LAPTM4B promoter at four distinct sites to activate its transcription, promoting autophagy in hepatocellular carcinoma. HDAC2 binding at LAPTM4B was confirmed by ChIP, establishing LAPTM4B as a direct HDAC2 transcriptional target.\",\n      \"method\": \"ChIP (HDAC2 at LAPTM4B promoter), promoter binding site mapping, knockdown/overexpression, autophagy assays, in vivo xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with multiple binding site mapping and functional validation; single lab with in vivo validation\",\n      \"pmids\": [\"39147759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MIER3 interacts with HDAC1, HDAC2, and Snail to form a co-repressor complex that binds the E-cadherin promoter and mediates its deacetylation, promoting epithelial-mesenchymal transition in breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (MIER3–HDAC1/HDAC2–Snail), chromatin immunoprecipitation (ChIP at E-cadherin promoter), western blot, in vitro migration/invasion assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP of multi-protein complex and ChIP at target promoter; single lab; no catalytic mutant confirmation\",\n      \"pmids\": [\"34242623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SENP1 binds to HDAC2 and mediates its de-SUMOylation; SENP1-mediated de-SUMOylation of HDAC2 enhances EGFR transcription and activates the AKT signaling pathway to promote AML cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation (SENP1–HDAC2), SUMO assays, ChIP-qPCR (HDAC2 at EGFR locus), shRNA/sgRNA knockdown\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and SUMO/ChIP assays in single lab; novel PTM (de-SUMOylation) of HDAC2 reported\",\n      \"pmids\": [\"38822351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC2 reduces histone H3K9 acetylation at the miR-205 promoter through an SP1-mediated pathway, suppressing miR-205 expression. miR-205 in turn directly targets and inhibits HDAC2 expression, forming a feedback regulatory loop that controls ECM production in tubular epithelial cells in diabetic kidney disease.\",\n      \"method\": \"ChIP (H3K9ac at miR-205 promoter), luciferase reporter assays (miR-205 promoter), siRNA knockdown, overexpression, db/db mouse model\",\n      \"journal\": \"Clinical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase assays directly linking HDAC2 to miR-205 promoter histone modification; feedback loop validated by multiple methods; single lab\",\n      \"pmids\": [\"35084460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cytoplasmic binding between glucocorticoid receptor (GR) and HDAC2 was demonstrated in mesenchymal stem cells. VPA-mediated HDAC2 inhibition alters this GR–HDAC2 cytoplasmic interaction and leads to GR recruitment to the nGRE element of the osteocalcin (OC) promoter, downregulating OC expression.\",\n      \"method\": \"Co-immunoprecipitation (cytoplasmic GR–HDAC2), chromatin immunoprecipitation (ChIP of GR at OC nGRE), HDAC2 knockdown, in vivo bone formation assay (NOD/SCID mice)\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and ChIP in single lab; cytoplasmic localization of the complex is a notable finding; functional in vivo validation\",\n      \"pmids\": [\"30841579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"p21 and CK2 interaction (but not CK2 alone) enhances HDAC2 phosphorylation, which restricts KLF4 deacetylation by HDAC2 and prevents KLF4 from acting as an oncogene in bladder cancer cells. When p21 is absent, HDAC2 deacetylates KLF4, converting it from a tumor suppressor to a proliferation promoter.\",\n      \"method\": \"Co-immunoprecipitation (p21–CK2–HDAC2), phosphorylation assays, KLF4 acetylation assays, siRNA knockdown, luciferase reporter assays\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and acetylation assays placing HDAC2 phosphorylation in pathway; single lab\",\n      \"pmids\": [\"26729194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hypoxia-activated XBP1s forms a stable repressor complex with HDAC2 and EZH2. This complex binds the ΔNp63 promoter, mediating a switch from H3K27ac (normoxic state) to H3K27me3 (hypoxic state) to suppress ΔNp63α transcription and promote breast cancer metastasis. Knockdown of either HDAC2 or EZH2 restores H3K27ac and ΔNp63α expression.\",\n      \"method\": \"Co-immunoprecipitation (XBP1s–HDAC2–EZH2), ChIP (H3K27ac and H3K27me3 at ΔNp63 promoter), siRNA knockdown, pharmacological inhibition, in vivo metastasis models\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP of trimeric complex, ChIP for two histone marks at specific locus, in vivo metastasis validation; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"38413797\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HDAC2 is a class I histone deacetylase that functions both as a canonical histone deacetylase (regulating H3K56ac, H3K9ac, H3K27ac, H4ac at specific gene promoters) and as a modifier of non-histone substrates (Gata4, CIITA, FOXO3a, HNF-4α, eIF4E via sumoylation, FOXA3, METTL3 via delactylation, ACSL4 indirectly via SIRT3, KLF4); it is regulated post-translationally by phosphorylation (CK2 at mitosis), ubiquitination/deubiquitination (USP4, USP5, USP17, ARHGAP4, NEDDylation/SENP8), and SUMOylation (SENP1); it operates in multiple complexes including NuRD (with MTA1/2, MBD3, RBBP4/7), Sin3A, CoREST, and context-specific assemblies with Hopx/Gata4, Tet2/IκBζ, MYCN, XBP1s/EZH2, SMAD3/SKI, MIER3/Snail, and PACS-1, collectively controlling gene expression programs in DNA damage repair, inflammation resolution, cardiac development, neuronal plasticity, myelination, ciliogenesis, osteoclastogenesis, and tumor metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HDAC2 is a class I histone deacetylase that controls gene expression programs by erasing acetyl (and acyl) marks from chromatin and from non-histone substrates, operating largely within multiprotein corepressor assemblies [#19, #31]. As a chromatin enzyme it deacetylates histones at specific loci\\u2014removing H3K56ac at DNA double-strand breaks to promote nonhomologous end-joining and DNA repair [#1], eliminating H3K27ac at the NLRP3 promoter to restrain BRD4\\u2013p65 recruitment and pyroptosis [#27], and erasing H3K9 lactylation as a delactylase that limits VEGF-driven angiogenesis [#28]. Its repressive function is delivered through context-specific complexes: the NuRD complex (MTA1/2, MBD3, RBBP4/7), whose stability depends on HDAC2 itself [#19], and assemblies with Tet2/I\\u03baB\\u03b6 at the Il6 promoter [#0], MYCN at miR-183 [#17], XBP1s/EZH2 at the \\u0394Np63 promoter where it drives an H3K27ac-to-H3K27me3 switch [#41], SMAD3/SKI [#33], MIER3/Snail at E-cadherin [#36], and SP1 [#29]. Beyond histones, HDAC2 deacetylates transcription factors\\u2014Gata4 (stabilized by Hopx) to restrain cardiac myocyte proliferation [#2], CIITA to trigger its degradation [#3], FOXO3a to repress p21 [#8], HNF-4\\u03b1 [#16], FOXA3 [#24]\\u2014and exerts non-deacetylase activities including promotion of eIF4E sumoylation to stimulate cap-dependent translation [#5] and delactylation of METTL3 [#26]. HDAC2 abundance and activity are tightly post-translationally controlled by CK2 phosphorylation that governs HDAC1/HDAC2 dimerization across the cell cycle [#6], by deubiquitination (USP4, USP5, USP17) [#4, #25, #14], by NEDDylation/SENP8 [#15], and by SENP1-mediated de-SUMOylation [#37]. Through these activities HDAC2 functions in DNA damage signaling and the replication-stress checkpoint via PR130/PP2A control of ATM/CHK kinases [#10], peripheral myelination with Sox10 [#7], chronic pain through repression of Cacna2d1 and Kv1.2 in sensory neurons [#21, #22], tumor-associated macrophage polarization [#29], and metastasis [#41, #24]. The HDAC1 and HDAC2 paralogs are synthetically lethal in cells with hemizygous deletion of the other [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established HDAC2 as a chromatin enzyme recruited directly to DNA lesions, defining a substrate-specific role (H3K56ac) in repair pathway choice rather than generic transcriptional repression.\",\n      \"evidence\": \"siRNA depletion, immunofluorescence localization to break sites, and H3K56ac assays with damage-sensitivity readouts\",\n      \"pmids\": [\"20802485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not distinguish HDAC2-specific from HDAC1-specific contribution\", \"Recruitment mechanism to break sites not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed HDAC2 acts on non-histone substrates, deacetylating the transcription factor Gata4 (with Hopx as a stabilizing cofactor) to constrain a developmental proliferation program.\",\n      \"evidence\": \"Reciprocal Co-IP, Hopx/Hdac2 knockout mice, luciferase reporters, and cardiac myocyte proliferation quantification\",\n      \"pmids\": [\"20833366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetylation site on Gata4 not mapped\", \"Whether deacetylation is direct or complex-mediated not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a deacetylase-independent activity\\u2014HDAC2 promotes eIF4E sumoylation to drive cap-dependent translation\\u2014expanding its function beyond chromatin.\",\n      \"evidence\": \"In vitro sumoylation assays, Co-IP, and translational reporter assays\",\n      \"pmids\": [\"20421305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which HDAC2 enhances SUMO conjugation unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined cell-cycle post-translational control: CK2 phosphorylation governs HDAC1/HDAC2 dimer assembly and dissociation, redistributing the enzymes among Sin3, NuRD, and CoREST complexes.\",\n      \"evidence\": \"Phosphosite mutagenesis, kinase inhibitors, and Co-IP across cell cycle stages\",\n      \"pmids\": [\"23612983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of mitotic dissociation on target genes not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated a paralog-specific developmental role in which HDAC2 cooperates with Sox10 to activate the myelination transcriptional program.\",\n      \"evidence\": \"Schwann-cell-specific conditional knockout, immunofluorescence, and gene expression analysis\",\n      \"pmids\": [\"21423190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct targets of HDAC2 in the myelination program not enumerated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed HDAC2 in inflammation resolution by showing Tet2 recruits it via I\\u03baB\\u03b6 to deacetylate and repress the Il6 promoter independently of DNA methylation.\",\n      \"evidence\": \"Co-IP, ChIP, knockout mice, and LPS challenge\",\n      \"pmids\": [\"26287468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Histone marks erased at Il6 not specified\", \"Generality across inflammatory loci untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified deubiquitination as a major control of HDAC2 abundance, with USP4 stabilizing HDAC2 to dampen p53 and NF-\\u03baB responses.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and p53 acetylation/apoptosis readouts\",\n      \"pmids\": [\"26411366\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase opposing USP4 not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed promoter-selective repression of FOXO3a targets, with HDAC2 restraining p21 transcription and oxidative stress relieving repression via Ser394 phosphorylation.\",\n      \"evidence\": \"Co-IP, ChIP, Ser394 mutagenesis, and histone acetylation assays in neurons\",\n      \"pmids\": [\"25609639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase phosphorylating Ser394 under stress not identified\", \"Basis of promoter selectivity unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected HDAC2 to epigenetic reprogramming by demonstrating it supports DNMT3A2 nuclear localization required to establish genomic imprints.\",\n      \"evidence\": \"Co-IP, oocyte conditional knockout, and microinjection rescue with DNA methylation assays\",\n      \"pmids\": [\"26586441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the effect requires deacetylase activity not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioned HDAC1/HDAC2 in the replication-stress checkpoint by showing they repress PR130/PP2A to maintain ATM/CHK1/CHK2 phosphorylation and prevent mitotic catastrophe.\",\n      \"evidence\": \"Genetic elimination of HDAC1/2, PR130 epistasis, and PP2A activity/phosphorylation assays\",\n      \"pmids\": [\"29472538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HDAC2-specific versus HDAC1-specific contribution not separated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established HDAC2 as a structural determinant of NuRD integrity and chromatin accessibility, and revealed synthetic lethality with HDAC1 in paralog-deleted cells.\",\n      \"evidence\": \"dTAG-mediated degradation, ATAC-seq, NuRD proteomics, and in vivo tumor assays\",\n      \"pmids\": [\"37488358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which HDAC2 loss destabilizes other NuRD subunits not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended HDAC2 catalysis to acyl marks, identifying it as an eraser of histone H3K9 lactylation and a delactylase of METTL3, linking metabolism to chromatin and RNA modification.\",\n      \"evidence\": \"CUT&Tag, m6A sequencing, Co-IP, and overexpression/inhibitor studies\",\n      \"pmids\": [\"38918851\", \"39950833\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalytic delactylation versus complex-mediated effect not biochemically reconstituted\", \"Single lab per substrate\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined SUMO-based control of HDAC2 by SENP1, whose de-SUMOylation of HDAC2 promotes EGFR/AKT-driven leukemia proliferation.\",\n      \"evidence\": \"Co-IP, SUMO assays, and ChIP-qPCR at the EGFR locus with knockdown\",\n      \"pmids\": [\"38822351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO acceptor site on HDAC2 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HDAC2 substrate and locus selectivity is encoded\\u2014which complex compositions, post-translational states, and acyl-mark specificities direct it to particular promoters and non-histone targets\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking complex composition to target selection\", \"Relative contributions of deacetylase, delactylase, and non-catalytic functions not unified\", \"HDAC2-specific versus HDAC1-shared activities incompletely separated genome-wide\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 8, 16, 24, 26]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 17, 27, 33, 35, 41]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 28, 31]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 27, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2, 8, 19, 27]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [39]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [19, 27, 31, 41]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 17, 33, 35]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 10, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 27, 29]}\n    ],\n    \"complexes\": [\"NuRD\", \"Sin3\", \"CoREST\"],\n    \"partners\": [\"HDAC1\", \"MTA1\", \"MTA2\", \"MBD3\", \"RBBP4\", \"EZH2\", \"SMAD3\", \"SP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}