{"gene":"HDAC1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2022,"finding":"HDAC1 (and HDAC2/3) are histone delactylases: they cleave ε-N-L-lactyllysine (K(L-la)) and K(D-la) marks from histones in vitro, and de-L-lactylase activity of HDAC1 was confirmed in cells. HDAC1-3 also remove diverse short-chain acyl modifications beyond acetyl groups.","method":"In vitro enzymatic screen with zinc- and NAD-dependent HDACs; cellular validation of de-L-lactylase activity","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic in vitro biochemical screen plus orthogonal cellular confirmation, multiple labs/substrates tested","pmids":["35044827"],"is_preprint":false},{"year":2023,"finding":"HDAC1/2/3 (class I HDACs) are the primary histone desuccinylases: inhibition or depletion of HDAC1/2/3 markedly increases global histone succinylation, while ectopic expression of catalytically active HDAC1/2/3 reduces it. Reconstituted HDAC1/2/3 complexes show robust desuccinylase activity in vitro. Histone succinylation is enriched at gene promoters and positively correlates with transcriptional activity.","method":"In vitro desuccinylase assay with reconstituted complexes; gain- and loss-of-function cell experiments; active-site mutant controls; genomic landscape analysis (ChIP-seq)","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with catalytic mutants plus orthogonal cellular experiments and genomic analyses in single rigorous study","pmids":["37580347"],"is_preprint":false},{"year":2013,"finding":"FUS directly interacts with HDAC1 (co-immunoprecipitation). This FUS–HDAC1 interaction is required for proper DNA double-strand break (DSB) damage response signaling and repair in neurons. ALS-associated FUS mutants show diminished interaction with HDAC1 and are defective in DNA damage response.","method":"Co-immunoprecipitation; recruitment of FUS to DSB sites; analysis of familial ALS FUS mutants; DNA damage assays in neurons and ALS patient tissue","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional loss-of-function with defined phenotype and human patient validation","pmids":["24036913"],"is_preprint":false},{"year":2006,"finding":"HDAC1 serves as a coactivator for the glucocorticoid receptor (GR). A subfraction of HDAC1 becomes acetylated after GR association; acetylation of HDAC1 inactivates its deacetylase activity in vitro, and mutation of the critical acetylation sites abrogates HDAC1 function in vivo. HDAC1 on transcriptionally active chromatin shows low acetylation, while repressed chromatin-associated HDAC1 is highly acetylated.","method":"In vitro deacetylase activity assay of purified acetylated HDAC1; site-directed mutagenesis of acetylation sites; chromatin immunoprecipitation; in vivo reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay combined with mutagenesis and in vivo functional validation in single study","pmids":["16762839"],"is_preprint":false},{"year":2013,"finding":"Protein kinase CK2 phosphorylates HDAC1 and HDAC2 during mitosis, which is required for dissociation of the HDAC1/HDAC2 heterodimer. During metaphase, HDAC1 and HDAC2 dissociate from each other but each remains associated with corepressor complex components (Sin3, NuRD, CoREST) as homodimers. Enzymatic inhibition studies and mutational analyses confirmed that CK2-catalyzed phosphorylation is crucial for this dissociation.","method":"Kinase inhibition studies; site-directed mutagenesis of phosphorylation sites; co-immunoprecipitation during mitosis; cell fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis plus enzymatic inhibition plus Co-IP with multiple corepressor components, single lab","pmids":["23612983"],"is_preprint":false},{"year":2025,"finding":"UM171 acts as a molecular glue that induces high-affinity interaction between KBTBD4 (a CRL3 E3 ligase substrate receptor) and HDAC1/2, targeting HDAC1/2 for degradation within the LSD1-CoREST corepressor complex. Cryo-EM revealed an asymmetric assembly where a single UM171 molecule enables one KBTBD4 KELCH-repeat propeller to engage the HDAC1 catalytic domain (partially masking its active-site rim) while a second propeller strengthens binding cooperatively. Endogenous inositol hexakisphosphate acts as a second molecular glue stabilizing the interaction. Base editor scanning of KBTBD4 and HDAC1 confirmed the functional relevance of these interfaces.","method":"Cryo-EM structure determination; proteomics; chemical inhibitor studies; base editor scanning mutagenesis; co-immunoprecipitation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with mutagenesis (base editor scanning) and proteomics in a single rigorous study","pmids":["39939761"],"is_preprint":false},{"year":2018,"finding":"HDAC1/2 suppress expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase PP2A. This suppression sustains phosphorylation of checkpoint kinases ATM, CHK1, CHK2, as well as WEE1 and CDK1, during replicative stress. PR130 promotes dephosphorylation of ATM by PP2A; genetic elimination of PR130 altered S-phase checkpoint and DNA damage response.","method":"Genetic elimination of HDAC1/2 and PR130; kinase activity assays; checkpoint phosphorylation analysis; homologous recombination assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined molecular mechanism, multiple orthogonal readouts, single lab","pmids":["29472538"],"is_preprint":false},{"year":2021,"finding":"EGFR phosphorylates HDAC1 at tyrosine 72 (Tyr72), which is necessary for HDAC1 protein stability. This EGFR-mediated tyrosine phosphorylation mediates HDAC1's anti-apoptotic function. Prior work had established serine phosphorylation by CK2 promotes HDAC1 deacetylase activity; the EGFR pathway represents an alternative, distinct regulatory mechanism.","method":"Site-directed mutagenesis of Tyr72; EGFR activity modulation; apoptosis assays; protein stability measurements","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of specific phosphorylation site with functional readout, single lab, single study","pmids":["33976119"],"is_preprint":false},{"year":2017,"finding":"USP19, a deubiquitinase, physically interacts with HDAC1/2 and specifically regulates their K63-linked ubiquitination. USP19 translocates to the nucleus upon ionizing radiation and its activity is required for proper DNA damage response. Loss of USP19 leads to genomic instability through impaired HDAC1/2-dependent DNA damage repair.","method":"Co-immunoprecipitation; K63-linked ubiquitination assay; nuclear translocation by imaging; DNA damage assays after IR","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with specific ubiquitin linkage characterization plus functional DNA damage assays, single lab","pmids":["27517492"],"is_preprint":false},{"year":2018,"finding":"HDAC1 substrate profiling using a mutant-trapping strategy combined with mass spectrometry identified CDK1, AIFM1, MSH6, and RuvB-like 1 as HDAC1 substrates, revealing roles of HDAC1 beyond histone deacetylation.","method":"Proteomics-based substrate trapping using catalytically inactive HDAC1 mutant combined with mass spectrometry","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — innovative substrate-trapping method with MS, single lab, not fully validated by orthogonal approaches for each substrate","pmids":["30421914"],"is_preprint":false},{"year":2016,"finding":"Acetylation of HDAC1 (via acetyltransferases) attenuates HDAC1 activity and trans-represses HDAC2 activity through HDAC1/HDAC2 dimerization, converting the corepressor complex into an activator complex during erythropoiesis. During erythropoiesis, global HDAC activity is dramatically reduced, linked to HDAC1 acetylation.","method":"Biochemical analysis of HDAC1 acetylation; dimerization studies; HDAC activity assays during erythroid differentiation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reviewed and synthesized findings from multiple studies; acetylation-activity link supported by prior biochemical data (PMID 16762839)","pmids":["33187090"],"is_preprint":false},{"year":2008,"finding":"Atrophin (Drosophila)/RERE (vertebrate) recruits HDAC1/2 through its ELM2-SANT domains to form a complex with histone methyltransferase G9a. This complex co-occupies chromosomal loci in Drosophila to establish H3K9 methylation and gene repression, controlling wing vein and melanotic-mass cell fate decisions.","method":"Co-immunoprecipitation; chromosomal co-localization; Drosophila genetic interaction studies; histone modification assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genetic epistasis in Drosophila with functional phenotype, single lab","pmids":["18451879"],"is_preprint":false},{"year":2012,"finding":"Ets-1 transcription factor physically interacts with HDAC1 and co-expression of Ets-1 with HDAC1 synergistically represses IL-10 transcription in Th1 cells. Loss of Ets-1 reduces HDAC1 enrichment at Il10 regulatory regions with concomitant increased histone H3 acetylation.","method":"Co-immunoprecipitation; chromatin immunoprecipitation; luciferase reporter assay; Ets-1 knockout cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical interaction confirmed by Co-IP plus ChIP demonstrating functional occupancy, single lab","pmids":["22266280"],"is_preprint":false},{"year":2021,"finding":"BAP1 forms a trimeric protein complex with HMGB1 and HDAC1 that modulates HMGB1 acetylation and its secretion. Reduced BAP1 levels cause increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion, which promotes mesothelial cell transformation.","method":"Co-immunoprecipitation; ubiquitylation assays; HMGB1 acetylation measurement; cell transformation assays; patient serum analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of trimeric complex plus functional consequence via HDAC1 degradation and HMGB1 acetylation, single lab","pmids":["34815344"],"is_preprint":false},{"year":2023,"finding":"ENO2-derived phosphoenolpyruvate (PEP) selectively inhibits HDAC1 activity, increasing acetylation of β-catenin and activating the Wnt/β-catenin pathway in colorectal cancer cells. This identifies PEP as an endogenous metabolite inhibitor of HDAC1.","method":"In vitro HDAC1 enzymatic activity assay with PEP; β-catenin acetylation measurement; pathway activation assays; xenograft models","journal":"Nature metabolism","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro HDAC1 inhibition assay plus cellular functional consequences, single lab","pmids":["37667133"],"is_preprint":false},{"year":2025,"finding":"TRIM46 is a ubiquitin E3 ligase that targets HDAC1 for ubiquitination and proteasomal degradation. The TRIM46–HDAC1 axis regulates genes involved in DNA replication and repair, and TRIM46 overexpression promotes breast cancer cell proliferation and chemoresistance.","method":"Co-immunoprecipitation; ubiquitination assay; CRISPR/Cas9 homologous recombination to recreate SNP; in vitro and in vivo proliferation/chemoresistance assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus CRISPR-validated functional model, single lab","pmids":["34459501"],"is_preprint":false},{"year":2014,"finding":"HDAC1 is sufficient to activate FoxO transcription factors and induce muscle fiber atrophy in vivo, requiring its deacetylase activity. This involves deacetylation of FoxO3a and induction of atrophy genes including atrogin-1. Dominant-negative HDAC1 (deacetylase-dead) blocked these effects, establishing deacetylase activity as mechanistically required.","method":"In vivo expression of wild-type and dominant-negative HDAC1 plasmids; FoxO acetylation and activity assays; gene expression analysis; muscle fiber size measurements","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative mutant approach plus in vivo phenotype with defined molecular target (FoxO3a deacetylation), single lab","pmids":["24463822"],"is_preprint":false},{"year":2023,"finding":"HDAC1 and HDAC2 are synthetically lethal with each other when one paralog is hemizygously deleted (collateral synthetic lethality). Mechanistically, targeted degradation of HDAC2 in HDAC1-deficient neuroblastoma cells promotes degradation of NuRD complex subunits, diminishes chromatin accessibility at HDAC2-NuRD-bound sites, and impairs enhancer-associated transcription.","method":"dTAG-mediated protein degradation; genetic disruption; ATAC-seq; ChIP-seq; in vitro and in vivo tumor growth assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — dTAG rapid degradation plus genetic disruption plus chromatin profiling, multiple orthogonal approaches, mechanistic pathway defined","pmids":["37488358"],"is_preprint":false},{"year":2025,"finding":"Rapid HDAC1 degradation (via dTAG within 1 hour) in mouse ESCs lacking HDAC2 revealed that H2BK5 and H2BK11 are the most sensitive substrates for HDAC1. Upregulated genes showed increased H2BK5ac and H3K27ac at their TSS. Paradoxically, the most strongly downregulated genes showed decreased acetylation and chromatin accessibility at super-enhancers, demonstrating that HDAC1 is required to maintain histone acetylation at critical enhancer regions for the pluripotency gene network.","method":"dTAG rapid degradation system (<1 hour); histone acetylation mass spectrometry; RNA-seq time course; ATAC-seq; H3K27ac ChIP-seq","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — dTAG system with time-resolved multi-omics (RNA-seq, ATAC-seq, histone MS) in genetically defined ESC model lacking paralog","pmids":["39704107"],"is_preprint":false},{"year":2004,"finding":"Recombinant HDAC1 expressed in mammalian cells is only active as a multi-protein complex; the purified His-tagged HDAC1 preparation co-purifies with endogenous HDAC2 and HDAC3, demonstrating that HDAC1 requires complex formation for enzymatic activity. Removal of the His-tag increased activity 2–4 fold.","method":"Stable expression of His-tagged HDAC1 in mammalian cells; nickel affinity purification; Western blot identification of co-purifying HDACs; deacetylase activity assay","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with purification and co-purification analysis, single lab, foundational biochemical characterization","pmids":["15043985"],"is_preprint":false},{"year":2017,"finding":"The ELM2 domain of MIER1 and MIER2 (but not MIER3) is required for HDAC1 recruitment. MIER2, but not MIER3, co-immunoprecipitates with HDAC1 in a cell-line-dependent manner, and MIER2 complexes have associated deacetylase activity. A conserved tryptophan residue (W228) in the ELM2 domain is critical for HDAC1 recruitment.","method":"Co-immunoprecipitation; deacetylase activity assay; deletion analysis; site-directed mutagenesis of ELM2 domain","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus deacetylase activity assay plus site-directed mutagenesis, single lab","pmids":["28046085"],"is_preprint":false},{"year":2022,"finding":"HDAC1 deacetylates JAK1 at lysine 1109; HDAC1 inhibition by SAHA increases JAK1 acetylation at K1109, promoting its proteasomal degradation and reducing STAT3-driven FGL1 transcription. This was established by co-immunoprecipitation showing HDAC1 as an essential deacetylase of JAK1, and by mass spectrometry identification of the specific acetylation site.","method":"Co-immunoprecipitation; mass spectrometry identifying JAK1 K1109 acetylation; proteasomal degradation assay; ChIP for STAT3 at FGL1 promoter; RNA-seq","journal":"Journal for immunotherapy of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS site identification plus proteasomal degradation assay and transcriptional readout, single lab","pmids":["39384195"],"is_preprint":false},{"year":2025,"finding":"HDAC1 K412 lactylation is essential for regulation of ferroptosis resistance in colorectal cancer. HDAC inhibitors (SAHA and TSA) specifically diminish HDAC1 K412 lactylation, leading to increased H3K27 acetylation of FTO and ALKBH5, activation of these m6A erasers, reduced m6A modification of FSP1 mRNA, and its degradation, sensitizing cells to ferroptosis.","method":"Drug screening; mass spectrometry identification of HDAC1 K412 lactylation; ChIP for H3K27ac at FTO/ALKBH5; m6A quantification; in vivo xenograft models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific PTM identification by MS plus mechanistic ChIP and m6A assays plus in vivo validation, single lab","pmids":["39888307"],"is_preprint":false},{"year":2016,"finding":"HDAC1 and HDAC2 directly bind to the TP53 gene locus (demonstrated by ChIP) and contribute to maintaining mutant p53 expression in pancreatic cancer. MYC also directly binds the TP53 locus, and MYC recruitment drops upon HDAC inhibitor treatment, suggesting a class I HDAC-MYC cooperative mechanism at the TP53 gene.","method":"Chromatin immunoprecipitation (ChIP) for HDAC1, HDAC2, and MYC at TP53 gene; genetic siRNA knockdown; HDAC inhibitor treatment; RT-PCR and Western blot for mutant p53","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter occupancy plus genetic and pharmacological loss-of-function, single lab","pmids":["27721407"],"is_preprint":false},{"year":2022,"finding":"Inflammation-driven NF-κB signaling recruits HDAC1 (and HDAC3) to the antioxidant response element (ARE) in the Slc40a1 (ferroportin) promoter in macrophages. HDAC1 and HDAC3 recruitment is dependent on NF-κB signaling and leads to repression of ferroportin transcription, contributing to anemia of inflammation.","method":"Chromatin immunoprecipitation (ChIP) for HDAC1/3 at Slc40a1 ARE; pharmacological and targeted RNAi screens; NF-κB signaling inhibition","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter recruitment plus genetic/pharmacological epistasis, single lab","pmids":["39656097"],"is_preprint":false},{"year":2011,"finding":"In Schwann cells, HDAC1 controls Schwann cell survival by regulating levels of active β-catenin, while HDAC2 (not HDAC1) activates the transcriptional program of myelination in synergy with Sox10. These represent distinct, non-redundant primary functions of the two paralogs in peripheral nervous system myelination.","method":"Conditional mouse genetics (Schwann cell-specific ablation of Hdac1 and Hdac2); expression analysis of Sox10, Krox20; β-catenin activity measurement; histological analysis of sciatic nerves","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout mouse genetics with defined molecular pathway (β-catenin) and phenotypic readout, replicated across multiple genetic combinations","pmids":["21423190"],"is_preprint":false},{"year":2010,"finding":"HDAC1 and HDAC2 directly mediate the repressive transcriptional functions of p63 in epidermal progenitor cells: HDACs bind and are active at promoters of p63-repressed targets (p21, 14-3-3σ, p16/INK4a) in normal keratinocytes. Loss of both HDAC1 and HDAC2 leads to increased acetylation of p53, which opposes p63 functions, and p53 is required for HDAC inhibitor-mediated p21 expression.","method":"Conditional ectodermal knockout of Hdac1/2; ChIP for HDAC binding at target promoters; p53 acetylation measurement; p53 genetic requirement analysis in keratinocytes","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse genetics plus ChIP at target promoters plus genetic epistasis with p53, multiple orthogonal methods","pmids":["21093383"],"is_preprint":false},{"year":2016,"finding":"HDAC1 (and HDAC2) regulate global poly(A) RNA stability at the post-transcriptional level. Inhibition of HDAC1/2 induces widespread degradation of normally stable poly(A) RNA in mammalian and Drosophila cells. The mechanism involves CBP/p300-mediated acetylation of CAF1a (a catalytic subunit of the CCR4-CAF1-NOT deadenylase complex), which accelerates poly(A) RNA degradation.","method":"HDAC1/2 inhibition and knockdown; RNA stability assays; acetylation of CAF1a demonstrated; adipocyte differentiation model","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional loss-of-function in two organisms plus biochemical mechanism (CAF1a acetylation), single lab","pmids":["27635759"],"is_preprint":false},{"year":2019,"finding":"HDAC1 regulates β-cell proliferation by deacetylating histones at the Cdkn1b/p27 locus, thereby reducing p27 expression and allowing cell cycle progression from G1 to S phase. HDAC1 overexpression increases Cyclin A2, Cyclin B1, and E2F1 expression; overexpression of p27 blocks HDAC1-mediated β-cell proliferation.","method":"HDAC1 overexpression in primary rat islets and INS-1 cells; p27 overexpression rescue experiment; cell cycle analysis; gene expression analysis","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with rescue experiment establishing epistatic relationship, defined molecular target, single lab","pmids":["30322885"],"is_preprint":false},{"year":1996,"finding":"The human RPD3L1 gene (HDAC1) was cloned and found to be highly homologous (52% amino acid identity) to the yeast RPD3 transcription factor. The gene encodes a 482 amino acid protein and maps to chromosome band 1p34.1.","method":"cDNA cloning from human fetal lung library; sequence alignment; FISH chromosomal mapping; Northern blot expression analysis","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — definitive cloning and chromosomal mapping, foundational identification paper","pmids":["8646880"],"is_preprint":false},{"year":2014,"finding":"HDAC1 and Klf4 competitively bind to the promoter region of Klf4, with HDAC1 repressing Klf4 expression in myeloid leukemia. HDAC1 knockdown increases Klf4 expression and inhibits cell cycle progression; Klf4 overexpression can block the pro-proliferative effects of HDAC1 overexpression, and vice versa, establishing a mechanistic interplay.","method":"ChIP for HDAC1 and Klf4 at Klf4 promoter; knockdown and overexpression of HDAC1 and Klf4; rescue experiments in leukemia cell lines and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing promoter occupancy plus reciprocal rescue experiments in vitro and in vivo, single lab","pmids":["25341045"],"is_preprint":false},{"year":2021,"finding":"HDAC1 (but not HDAC2) controls the transcriptional identity and survival of glioma stem cells in a p53-dependent manner; HDAC1 loss is not compensated by HDAC2 in this context (unlike in normal neural stem cells). Knockdown of HDAC1 suppresses tumor growth in patient-derived xenograft models.","method":"shRNA knockdown of HDAC1 and HDAC2; cell-based and biochemical assays; RNA-seq; patient-derived xenograft models; p53 genetic manipulation","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific KD with transcriptomics and xenograft validation plus mechanistic p53 link, single lab","pmids":["34494550"],"is_preprint":false},{"year":2023,"finding":"HDAC1 inhibits beige adipocyte-mediated thermogenesis by regulating histone crotonylation (H3K18cr) and acetylation (H3K18ac) at the enhancers and promoters of Pgc1α and Ucp1 genes. Deletion of Hdac1 in beige adipocytes increases H3K18cr at these regulatory regions, promoting Pgc1α/Ucp1 transcription and thermogenesis.","method":"Conditional Hdac1 deletion in beige adipocytes; H3K18cr and H3K18ac ChIP-seq; gene expression analysis; energy expenditure measurement; MS275 HDAC inhibitor treatment","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with ChIP-seq for specific histone marks at defined loci plus functional metabolic phenotype, single lab","pmids":["37640195"],"is_preprint":false},{"year":2022,"finding":"TNFα + IFNγ stimulation promotes formation of a FRA1:c-JUN:HDAC1 complex at the AP1 response element of the filaggrin (FLG) promoter, which suppresses FLG expression in keratinocytes. Co-immunoprecipitation demonstrated HDAC1 interaction with FRA1:c-JUN; HDAC1 knockdown abrogated cytokine-induced FLG suppression.","method":"DNA affinity precipitation assay; co-immunoprecipitation; HDAC1 knockdown; luciferase reporter assay; mouse models of skin inflammation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical complex by Co-IP plus functional knockdown, in vitro and in vivo validation, single lab","pmids":["36067301"],"is_preprint":false},{"year":2019,"finding":"HDAC1 regulates anti-inflammatory effects of isoflurane in human monocytes by preventing NF-κB nuclear translocation. Co-immunoprecipitation showed that LPS decreased HDAC1/HDAC2 interaction, which was restored by isoflurane pretreatment. Gene silencing of HDAC1 (and HDAC2) blocked isoflurane-induced reduction of NF-κB nuclear translocation and proinflammatory cytokine production.","method":"Co-immunoprecipitation of HDAC1/2 interaction; siRNA gene silencing; NF-κB nuclear translocation assay; cytokine measurement in THP-1 cells and primary monocytes","journal":"Immunology and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing dynamic HDAC1/2 interaction plus siRNA knockdown with mechanistic readout, validated in primary cells, single lab","pmids":["31950542"],"is_preprint":false},{"year":2022,"finding":"DNTTIP1 recruits HDAC1 to the DUSP2 gene promoter, maintaining a deacetylated state of histone H3K27 and suppressing DUSP2 transcription. This leads to aberrant ERK pathway activation and elevated MMP2, promoting nasopharyngeal carcinoma metastasis.","method":"ChIP assay for HDAC1 at DUSP2 promoter; co-immunoprecipitation of DNTTIP1-HDAC1 interaction; luciferase reporter assays; in vitro and in vivo metastasis assays","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating HDAC1 recruitment by DNTTIP1 plus Co-IP plus functional in vivo validation, single lab","pmids":["35689852"],"is_preprint":false},{"year":2017,"finding":"SP1 recruits HDAC1 to the miR-326 gene promoter in osteosarcoma cells, causing histone deacetylation and transcriptional inhibition of miR-326. This was established by ChIP assay and DAPA, and the loss of miR-326 activates the SMO/Hedgehog pathway to promote proliferation and metastasis.","method":"ChIP assay for SP1/HDAC1 at miR-326 promoter; DNA affinity precipitation assay (DAPA); miR-326 expression after SP1/HDAC1 modulation; in vivo metastasis model","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating HDAC1 promoter recruitment plus functional downstream pathway analysis, single lab","pmids":["32743904"],"is_preprint":false}],"current_model":"HDAC1 is a class I zinc-dependent deacetylase that removes acetyl groups (and other short-chain acyl marks including lactyl, succinyl, and crotonyl groups) from lysine residues on histones and diverse non-histone substrates (FoxO3a, β-catenin, JAK1, HMGB1, p53, among others); its catalytic activity requires assembly into multi-protein corepressor complexes (Sin3, NuRD, CoREST) and is dynamically regulated by post-translational modifications—serine phosphorylation by CK2 promotes activity and dimer formation, acetylation of HDAC1 itself inactivates it and trans-represses its HDAC2 partner, tyrosine phosphorylation by EGFR stabilizes the protein, K412 lactylation modulates ferroptosis resistance, and K63-linked ubiquitination (regulated by USP19) controls its DNA-damage repair function; HDAC1 is recruited to specific genomic loci via interaction with transcription factors and corepressors (p63, Ets-1, FRA1:c-JUN, DNTTIP1, SP1, GFI1, Atrophin/RERE), where it represses target genes by histone deacetylation, while paradoxically also being required to maintain acetylation at super-enhancers critical for gene activation programs; it occupies a defined pathway position upstream of cell-cycle checkpoints (through PP2A/PR130 suppression) and downstream of environmental signals including metabolic intermediates (PEP) and inflammatory cues (NF-κB recruitment of HDAC1 to ferroportin promoter), with isoform-specific roles in Schwann cell survival (via β-catenin), T cell and dendritic cell development, muscle atrophy (via FoxO deacetylation), and neuronal differentiation that are only partially compensated by its paralog HDAC2."},"narrative":{"mechanistic_narrative":"HDAC1, the human ortholog of yeast RPD3 [PMID:8646880], is a class I zinc-dependent lysine deacylase that erases multiple short-chain acyl marks from histones—removing acetyl, succinyl [PMID:37580347], and L-/D-lactyl [PMID:35044827] groups—and is enzymatically active only when assembled into multi-protein corepressor complexes, co-purifying with HDAC2 and HDAC3 [PMID:15043985]. Beyond histones, it deacetylates non-histone substrates including CDK1, AIFM1, MSH6 and RuvB-like 1 [PMID:30421914], JAK1 (at K1109, controlling its proteasomal stability and STAT3-driven transcription) [PMID:39384195], FoxO3a (driving atrophy gene programs and muscle fiber atrophy) [PMID:24463822], β-catenin [PMID:37667133], and HMGB1 [PMID:34815344]. HDAC1 is recruited to specific genomic loci by transcription factors and corepressor scaffolds—p63 [PMID:21093383], Ets-1 [PMID:22266280], FRA1:c-JUN [PMID:36067301], DNTTIP1 [PMID:35689852], SP1 [PMID:32743904], Atrophin/RERE via ELM2-SANT domains [PMID:18451879], and MIER1/MIER2 ELM2 domains [PMID:28046085]—where it represses target genes through histone deacetylation, yet it is paradoxically also required to maintain histone acetylation at super-enhancers that drive activation programs such as the pluripotency network, with H2BK5 and H2BK11 being its most sensitive substrates [PMID:39704107]. Its activity is governed by post-translational modifications: CK2 phosphorylation promotes activity and controls mitotic dissociation of the HDAC1/HDAC2 heterodimer [PMID:23612983], EGFR-mediated Tyr72 phosphorylation stabilizes the protein and supports its anti-apoptotic function [PMID:33976119], self-acetylation inactivates HDAC1 and trans-represses HDAC2 [PMID:16762839, PMID:33187090], and protein levels are set by competing ubiquitin ligases (KBTBD4 via the UM171 molecular glue [PMID:39939761], TRIM46 [PMID:34459501]) and the deubiquitinase USP19 [PMID:27517492]. Functionally, HDAC1 occupies pathway positions upstream of cell-cycle and DNA-damage checkpoints—suppressing the PP2A subunit PR130 to sustain ATM/CHK1/CHK2/WEE1/CDK1 phosphorylation [PMID:29472538] and partnering with FUS in double-strand-break repair [PMID:24036913]—and has isoform-specific, only partially HDAC2-compensated roles in Schwann cell survival via β-catenin [PMID:21423190], epidermal progenitor and keratinocyte programs [PMID:21093383], β-cell proliferation through the Cdkn1b/p27 locus [PMID:30322885], and glioma stem cell identity in a p53-dependent manner [PMID:34494550].","teleology":[{"year":1996,"claim":"Establishing the molecular identity of HDAC1 was the prerequisite for all mechanistic study—cloning revealed it as the human RPD3 counterpart, framing it as a transcriptional regulator.","evidence":"cDNA cloning, sequence alignment, and FISH mapping from human fetal lung library","pmids":["8646880"],"confidence":"High","gaps":["Cloning alone did not establish enzymatic activity or substrates","No complex membership defined"]},{"year":2004,"claim":"Resolved whether HDAC1 is an autonomous enzyme—showing it is catalytically active only within multi-protein complexes, co-purifying with HDAC2/HDAC3.","evidence":"Nickel-affinity purification of His-tagged HDAC1 from mammalian cells with deacetylase activity assays","pmids":["15043985"],"confidence":"Medium","gaps":["Did not define which corepressor complex confers activity","Tag effect on activity not fully resolved mechanistically"]},{"year":2006,"claim":"Identified a built-in inhibitory switch—acetylation of HDAC1 itself inactivates its deacetylase activity, allowing context-dependent conversion between repression and coactivation.","evidence":"In vitro deacetylase assay of purified acetylated HDAC1, acetylation-site mutagenesis, ChIP, and reporter assays in a GR system","pmids":["16762839"],"confidence":"High","gaps":["Acetyltransferase responsible not defined here","Generalizability beyond GR context unaddressed"]},{"year":2008,"claim":"Defined how HDAC1 is targeted to chromatin—Atrophin/RERE recruits it through ELM2-SANT domains into a G9a-containing repressive complex to establish H3K9 methylation.","evidence":"Co-IP, chromosomal co-localization, and Drosophila genetic interaction with histone modification assays","pmids":["18451879"],"confidence":"Medium","gaps":["Direct vs indirect HDAC1-G9a contact not resolved","Vertebrate validation limited"]},{"year":2011,"claim":"Demonstrated non-redundant paralog roles in vivo—HDAC1 controls Schwann cell survival via β-catenin while HDAC2 drives myelination, refuting simple functional equivalence.","evidence":"Schwann cell-specific conditional knockout mouse genetics with β-catenin activity and histological readouts","pmids":["21423190"],"confidence":"High","gaps":["Mechanism linking HDAC1 to β-catenin levels not fully defined","Degree of compensation context-specific"]},{"year":2013,"claim":"Linked HDAC1 directly to genome maintenance and mitotic regulation—FUS-HDAC1 interaction supports DSB repair, and CK2 phosphorylation drives mitotic heterodimer dissociation.","evidence":"Co-IP, DSB recruitment, ALS mutant analysis (FUS); kinase inhibition and phospho-site mutagenesis during mitosis (CK2)","pmids":["24036913","23612983"],"confidence":"High","gaps":["Whether HDAC1 deacetylase activity per se is required at DSBs not isolated","Functional consequence of homodimer state during metaphase incompletely mapped"]},{"year":2018,"claim":"Expanded the HDAC1 substrate landscape beyond histones and positioned it within checkpoint signaling—substrate trapping identified protein targets, and HDAC1/2 were shown to suppress PR130/PP2A to sustain checkpoint kinase phosphorylation.","evidence":"Catalytically-dead mutant substrate trapping with MS (substrates); genetic elimination of HDAC1/2 and PR130 with checkpoint phosphorylation and HR assays","pmids":["30421914","29472538"],"confidence":"Medium","gaps":["Individual trapped substrates not each orthogonally validated","Direct deacetylation sites for checkpoint factors not mapped"]},{"year":2022,"claim":"Established HDAC1 as a histone delactylase and broad short-chain de-acylase, redefining it as a multi-mark eraser rather than a pure deacetylase.","evidence":"In vitro enzymatic screen with cellular validation of de-L-lactylase activity","pmids":["35044827"],"confidence":"High","gaps":["Genomic distribution of lactyl marks regulated by HDAC1 not mapped here","Physiological consequences cell-type-specific"]},{"year":2023,"claim":"Showed HDAC1 governs metabolite- and acyl-mark-linked transcription—it is a primary desuccinylase, is inhibited by the glycolytic intermediate PEP to activate Wnt/β-catenin, and shows collateral synthetic lethality with HDAC2 through NuRD-dependent enhancer transcription.","evidence":"Reconstituted desuccinylase assays and ChIP-seq; in vitro PEP inhibition with β-catenin acetylation and xenografts; dTAG degradation with ATAC-seq/ChIP-seq","pmids":["37580347","37667133","37488358"],"confidence":"High","gaps":["How succinyl-mark removal integrates with deacetylation at single loci unclear","Breadth of metabolite-sensing inhibition beyond PEP unknown"]},{"year":2025,"claim":"Defined the structural basis of pharmacological HDAC1 degradation and uncovered PTM-linked metabolic control—UM171 acts as a molecular glue recruiting KBTBD4 to HDAC1/2, while K412 lactylation tunes ferroptosis resistance.","evidence":"Cryo-EM with base editor scanning and proteomics (KBTBD4); MS site mapping with ChIP and m6A assays in vivo (K412 lactylation)","pmids":["39939761","39888307"],"confidence":"High","gaps":["Endogenous physiological trigger for K412 lactylation not defined","Selectivity of glue-induced degradation across complexes incompletely mapped"]},{"year":null,"claim":"It remains unresolved how HDAC1 mechanistically maintains, rather than removes, histone acetylation at super-enhancers, and how its choice between repressive and activating chromatin states is encoded by complex composition and its own PTMs.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model reconciling repressor vs enhancer-maintenance functions","Rules selecting corepressor complex (Sin3/NuRD/CoREST) at a given locus undefined","Integration of competing ubiquitination inputs (KBTBD4, TRIM46, USP19) into net abundance not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,9,16,21]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,26,12,35,36]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,26,18]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[23,24,32,35,36]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[18,11,26,1]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[12,23,24,35,36,30]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,6,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,6,28]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[25,26,16]}],"complexes":["Sin3","NuRD","CoREST","LSD1-CoREST"],"partners":["HDAC2","HDAC3","FUS","USP19","KBTBD4","DNTTIP1","MIER2","BAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13547","full_name":"Histone deacetylase 1","aliases":["Protein deacetylase HDAC1","Protein deacylase HDAC1"],"length_aa":482,"mass_kda":55.1,"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:16762839, PubMed:17704056, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:16762839, PubMed:17704056). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:16762839, PubMed:17704056). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). As part of the SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription (PubMed:21041482). Also functions as a deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3, STAT3, ZNF76 and TSHZ3 (PubMed:12837748, PubMed:16285960, PubMed:16337145, PubMed:16478997, PubMed:17996965, PubMed:19343227). Deacetylates SP proteins, SP1 and SP3, and regulates their function (PubMed:12837748, PubMed:16478997). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (PubMed:19081374). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (PubMed:19081374). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (PubMed:19343227). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (PubMed:17000776). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (PubMed:17996965). 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). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer (By similarity). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (By similarity). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase and delactylase by mediating decrotonylation ((2E)-butenoyl) and delactylation (lactoyl) of histones, respectively (PubMed:28497810, PubMed:35044827)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13547/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HDAC1","classification":"Not Classified","n_dependent_lines":62,"n_total_lines":1208,"dependency_fraction":0.05132450331125828},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000116478","cell_line_id":"CID001499","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"CHD4","stoichiometry":10.0},{"gene":"RBBP4","stoichiometry":10.0},{"gene":"HDAC2","stoichiometry":10.0},{"gene":"RBBP7","stoichiometry":10.0},{"gene":"GATAD2B","stoichiometry":10.0},{"gene":"MBD3","stoichiometry":10.0},{"gene":"MTA2","stoichiometry":10.0},{"gene":"RCOR1","stoichiometry":4.0},{"gene":"SIN3A","stoichiometry":4.0},{"gene":"CTBP1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001499","total_profiled":1310},"omim":[{"mim_id":"621447","title":"ZINC FINGER PROTEIN 787; ZNF787","url":"https://www.omim.org/entry/621447"},{"mim_id":"621074","title":"MITOTIC DEACETYLASE-ASSOCIATED SANT DOMAIN PROTEIN; MIDEAS","url":"https://www.omim.org/entry/621074"},{"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":"619943","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 19; KCTD19","url":"https://www.omim.org/entry/619943"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HDAC1"},"hgnc":{"alias_symbol":["HD1","GON-10","KDAC1"],"prev_symbol":["RPD3L1"]},"alphafold":{"accession":"Q13547","domains":[{"cath_id":"3.40.800.20","chopping":"10-371","consensus_level":"high","plddt":97.3673,"start":10,"end":371}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13547","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13547-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13547-F1-predicted_aligned_error_v6.png","plddt_mean":86.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HDAC1","jax_strain_url":"https://www.jax.org/strain/search?query=HDAC1"},"sequence":{"accession":"Q13547","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13547.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13547/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13547"}},"corpus_meta":[{"pmid":"35044827","id":"PMC_35044827","title":"Class I 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(K(L-la)) and K(D-la) marks from histones in vitro, and de-L-lactylase activity of HDAC1 was confirmed in cells. HDAC1-3 also remove diverse short-chain acyl modifications beyond acetyl groups.\",\n      \"method\": \"In vitro enzymatic screen with zinc- and NAD-dependent HDACs; cellular validation of de-L-lactylase activity\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic in vitro biochemical screen plus orthogonal cellular confirmation, multiple labs/substrates tested\",\n      \"pmids\": [\"35044827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC1/2/3 (class I HDACs) are the primary histone desuccinylases: inhibition or depletion of HDAC1/2/3 markedly increases global histone succinylation, while ectopic expression of catalytically active HDAC1/2/3 reduces it. Reconstituted HDAC1/2/3 complexes show robust desuccinylase activity in vitro. Histone succinylation is enriched at gene promoters and positively correlates with transcriptional activity.\",\n      \"method\": \"In vitro desuccinylase assay with reconstituted complexes; gain- and loss-of-function cell experiments; active-site mutant controls; genomic landscape analysis (ChIP-seq)\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with catalytic mutants plus orthogonal cellular experiments and genomic analyses in single rigorous study\",\n      \"pmids\": [\"37580347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FUS directly interacts with HDAC1 (co-immunoprecipitation). This FUS–HDAC1 interaction is required for proper DNA double-strand break (DSB) damage response signaling and repair in neurons. ALS-associated FUS mutants show diminished interaction with HDAC1 and are defective in DNA damage response.\",\n      \"method\": \"Co-immunoprecipitation; recruitment of FUS to DSB sites; analysis of familial ALS FUS mutants; DNA damage assays in neurons and ALS patient tissue\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional loss-of-function with defined phenotype and human patient validation\",\n      \"pmids\": [\"24036913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HDAC1 serves as a coactivator for the glucocorticoid receptor (GR). A subfraction of HDAC1 becomes acetylated after GR association; acetylation of HDAC1 inactivates its deacetylase activity in vitro, and mutation of the critical acetylation sites abrogates HDAC1 function in vivo. HDAC1 on transcriptionally active chromatin shows low acetylation, while repressed chromatin-associated HDAC1 is highly acetylated.\",\n      \"method\": \"In vitro deacetylase activity assay of purified acetylated HDAC1; site-directed mutagenesis of acetylation sites; chromatin immunoprecipitation; in vivo reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay combined with mutagenesis and in vivo functional validation in single study\",\n      \"pmids\": [\"16762839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Protein kinase CK2 phosphorylates HDAC1 and HDAC2 during mitosis, which is required for dissociation of the HDAC1/HDAC2 heterodimer. During metaphase, HDAC1 and HDAC2 dissociate from each other but each remains associated with corepressor complex components (Sin3, NuRD, CoREST) as homodimers. Enzymatic inhibition studies and mutational analyses confirmed that CK2-catalyzed phosphorylation is crucial for this dissociation.\",\n      \"method\": \"Kinase inhibition studies; site-directed mutagenesis of phosphorylation sites; co-immunoprecipitation during mitosis; cell fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis plus enzymatic inhibition plus Co-IP with multiple corepressor components, single lab\",\n      \"pmids\": [\"23612983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UM171 acts as a molecular glue that induces high-affinity interaction between KBTBD4 (a CRL3 E3 ligase substrate receptor) and HDAC1/2, targeting HDAC1/2 for degradation within the LSD1-CoREST corepressor complex. Cryo-EM revealed an asymmetric assembly where a single UM171 molecule enables one KBTBD4 KELCH-repeat propeller to engage the HDAC1 catalytic domain (partially masking its active-site rim) while a second propeller strengthens binding cooperatively. Endogenous inositol hexakisphosphate acts as a second molecular glue stabilizing the interaction. Base editor scanning of KBTBD4 and HDAC1 confirmed the functional relevance of these interfaces.\",\n      \"method\": \"Cryo-EM structure determination; proteomics; chemical inhibitor studies; base editor scanning mutagenesis; co-immunoprecipitation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with mutagenesis (base editor scanning) and proteomics in a single rigorous study\",\n      \"pmids\": [\"39939761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC1/2 suppress expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase PP2A. This suppression sustains phosphorylation of checkpoint kinases ATM, CHK1, CHK2, as well as WEE1 and CDK1, during replicative stress. PR130 promotes dephosphorylation of ATM by PP2A; genetic elimination of PR130 altered S-phase checkpoint and DNA damage response.\",\n      \"method\": \"Genetic elimination of HDAC1/2 and PR130; kinase activity assays; checkpoint phosphorylation analysis; homologous recombination assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined molecular mechanism, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"29472538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EGFR phosphorylates HDAC1 at tyrosine 72 (Tyr72), which is necessary for HDAC1 protein stability. This EGFR-mediated tyrosine phosphorylation mediates HDAC1's anti-apoptotic function. Prior work had established serine phosphorylation by CK2 promotes HDAC1 deacetylase activity; the EGFR pathway represents an alternative, distinct regulatory mechanism.\",\n      \"method\": \"Site-directed mutagenesis of Tyr72; EGFR activity modulation; apoptosis assays; protein stability measurements\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of specific phosphorylation site with functional readout, single lab, single study\",\n      \"pmids\": [\"33976119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"USP19, a deubiquitinase, physically interacts with HDAC1/2 and specifically regulates their K63-linked ubiquitination. USP19 translocates to the nucleus upon ionizing radiation and its activity is required for proper DNA damage response. Loss of USP19 leads to genomic instability through impaired HDAC1/2-dependent DNA damage repair.\",\n      \"method\": \"Co-immunoprecipitation; K63-linked ubiquitination assay; nuclear translocation by imaging; DNA damage assays after IR\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with specific ubiquitin linkage characterization plus functional DNA damage assays, single lab\",\n      \"pmids\": [\"27517492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC1 substrate profiling using a mutant-trapping strategy combined with mass spectrometry identified CDK1, AIFM1, MSH6, and RuvB-like 1 as HDAC1 substrates, revealing roles of HDAC1 beyond histone deacetylation.\",\n      \"method\": \"Proteomics-based substrate trapping using catalytically inactive HDAC1 mutant combined with mass spectrometry\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — innovative substrate-trapping method with MS, single lab, not fully validated by orthogonal approaches for each substrate\",\n      \"pmids\": [\"30421914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Acetylation of HDAC1 (via acetyltransferases) attenuates HDAC1 activity and trans-represses HDAC2 activity through HDAC1/HDAC2 dimerization, converting the corepressor complex into an activator complex during erythropoiesis. During erythropoiesis, global HDAC activity is dramatically reduced, linked to HDAC1 acetylation.\",\n      \"method\": \"Biochemical analysis of HDAC1 acetylation; dimerization studies; HDAC activity assays during erythroid differentiation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reviewed and synthesized findings from multiple studies; acetylation-activity link supported by prior biochemical data (PMID 16762839)\",\n      \"pmids\": [\"33187090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Atrophin (Drosophila)/RERE (vertebrate) recruits HDAC1/2 through its ELM2-SANT domains to form a complex with histone methyltransferase G9a. This complex co-occupies chromosomal loci in Drosophila to establish H3K9 methylation and gene repression, controlling wing vein and melanotic-mass cell fate decisions.\",\n      \"method\": \"Co-immunoprecipitation; chromosomal co-localization; Drosophila genetic interaction studies; histone modification assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genetic epistasis in Drosophila with functional phenotype, single lab\",\n      \"pmids\": [\"18451879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ets-1 transcription factor physically interacts with HDAC1 and co-expression of Ets-1 with HDAC1 synergistically represses IL-10 transcription in Th1 cells. Loss of Ets-1 reduces HDAC1 enrichment at Il10 regulatory regions with concomitant increased histone H3 acetylation.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation; luciferase reporter assay; Ets-1 knockout cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical interaction confirmed by Co-IP plus ChIP demonstrating functional occupancy, single lab\",\n      \"pmids\": [\"22266280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAP1 forms a trimeric protein complex with HMGB1 and HDAC1 that modulates HMGB1 acetylation and its secretion. Reduced BAP1 levels cause increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion, which promotes mesothelial cell transformation.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitylation assays; HMGB1 acetylation measurement; cell transformation assays; patient serum analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of trimeric complex plus functional consequence via HDAC1 degradation and HMGB1 acetylation, single lab\",\n      \"pmids\": [\"34815344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ENO2-derived phosphoenolpyruvate (PEP) selectively inhibits HDAC1 activity, increasing acetylation of β-catenin and activating the Wnt/β-catenin pathway in colorectal cancer cells. This identifies PEP as an endogenous metabolite inhibitor of HDAC1.\",\n      \"method\": \"In vitro HDAC1 enzymatic activity assay with PEP; β-catenin acetylation measurement; pathway activation assays; xenograft models\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro HDAC1 inhibition assay plus cellular functional consequences, single lab\",\n      \"pmids\": [\"37667133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM46 is a ubiquitin E3 ligase that targets HDAC1 for ubiquitination and proteasomal degradation. The TRIM46–HDAC1 axis regulates genes involved in DNA replication and repair, and TRIM46 overexpression promotes breast cancer cell proliferation and chemoresistance.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; CRISPR/Cas9 homologous recombination to recreate SNP; in vitro and in vivo proliferation/chemoresistance assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay plus CRISPR-validated functional model, single lab\",\n      \"pmids\": [\"34459501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HDAC1 is sufficient to activate FoxO transcription factors and induce muscle fiber atrophy in vivo, requiring its deacetylase activity. This involves deacetylation of FoxO3a and induction of atrophy genes including atrogin-1. Dominant-negative HDAC1 (deacetylase-dead) blocked these effects, establishing deacetylase activity as mechanistically required.\",\n      \"method\": \"In vivo expression of wild-type and dominant-negative HDAC1 plasmids; FoxO acetylation and activity assays; gene expression analysis; muscle fiber size measurements\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative mutant approach plus in vivo phenotype with defined molecular target (FoxO3a deacetylation), single lab\",\n      \"pmids\": [\"24463822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC1 and HDAC2 are synthetically lethal with each other when one paralog is hemizygously deleted (collateral synthetic lethality). Mechanistically, targeted degradation of HDAC2 in HDAC1-deficient neuroblastoma cells promotes degradation of NuRD complex subunits, diminishes chromatin accessibility at HDAC2-NuRD-bound sites, and impairs enhancer-associated transcription.\",\n      \"method\": \"dTAG-mediated protein degradation; genetic disruption; ATAC-seq; ChIP-seq; in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dTAG rapid degradation plus genetic disruption plus chromatin profiling, multiple orthogonal approaches, mechanistic pathway defined\",\n      \"pmids\": [\"37488358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Rapid HDAC1 degradation (via dTAG within 1 hour) in mouse ESCs lacking HDAC2 revealed that H2BK5 and H2BK11 are the most sensitive substrates for HDAC1. Upregulated genes showed increased H2BK5ac and H3K27ac at their TSS. Paradoxically, the most strongly downregulated genes showed decreased acetylation and chromatin accessibility at super-enhancers, demonstrating that HDAC1 is required to maintain histone acetylation at critical enhancer regions for the pluripotency gene network.\",\n      \"method\": \"dTAG rapid degradation system (<1 hour); histone acetylation mass spectrometry; RNA-seq time course; ATAC-seq; H3K27ac ChIP-seq\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — dTAG system with time-resolved multi-omics (RNA-seq, ATAC-seq, histone MS) in genetically defined ESC model lacking paralog\",\n      \"pmids\": [\"39704107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Recombinant HDAC1 expressed in mammalian cells is only active as a multi-protein complex; the purified His-tagged HDAC1 preparation co-purifies with endogenous HDAC2 and HDAC3, demonstrating that HDAC1 requires complex formation for enzymatic activity. Removal of the His-tag increased activity 2–4 fold.\",\n      \"method\": \"Stable expression of His-tagged HDAC1 in mammalian cells; nickel affinity purification; Western blot identification of co-purifying HDACs; deacetylase activity assay\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with purification and co-purification analysis, single lab, foundational biochemical characterization\",\n      \"pmids\": [\"15043985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The ELM2 domain of MIER1 and MIER2 (but not MIER3) is required for HDAC1 recruitment. MIER2, but not MIER3, co-immunoprecipitates with HDAC1 in a cell-line-dependent manner, and MIER2 complexes have associated deacetylase activity. A conserved tryptophan residue (W228) in the ELM2 domain is critical for HDAC1 recruitment.\",\n      \"method\": \"Co-immunoprecipitation; deacetylase activity assay; deletion analysis; site-directed mutagenesis of ELM2 domain\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus deacetylase activity assay plus site-directed mutagenesis, single lab\",\n      \"pmids\": [\"28046085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC1 deacetylates JAK1 at lysine 1109; HDAC1 inhibition by SAHA increases JAK1 acetylation at K1109, promoting its proteasomal degradation and reducing STAT3-driven FGL1 transcription. This was established by co-immunoprecipitation showing HDAC1 as an essential deacetylase of JAK1, and by mass spectrometry identification of the specific acetylation site.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry identifying JAK1 K1109 acetylation; proteasomal degradation assay; ChIP for STAT3 at FGL1 promoter; RNA-seq\",\n      \"journal\": \"Journal for immunotherapy of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS site identification plus proteasomal degradation assay and transcriptional readout, single lab\",\n      \"pmids\": [\"39384195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC1 K412 lactylation is essential for regulation of ferroptosis resistance in colorectal cancer. HDAC inhibitors (SAHA and TSA) specifically diminish HDAC1 K412 lactylation, leading to increased H3K27 acetylation of FTO and ALKBH5, activation of these m6A erasers, reduced m6A modification of FSP1 mRNA, and its degradation, sensitizing cells to ferroptosis.\",\n      \"method\": \"Drug screening; mass spectrometry identification of HDAC1 K412 lactylation; ChIP for H3K27ac at FTO/ALKBH5; m6A quantification; in vivo xenograft models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific PTM identification by MS plus mechanistic ChIP and m6A assays plus in vivo validation, single lab\",\n      \"pmids\": [\"39888307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HDAC1 and HDAC2 directly bind to the TP53 gene locus (demonstrated by ChIP) and contribute to maintaining mutant p53 expression in pancreatic cancer. MYC also directly binds the TP53 locus, and MYC recruitment drops upon HDAC inhibitor treatment, suggesting a class I HDAC-MYC cooperative mechanism at the TP53 gene.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for HDAC1, HDAC2, and MYC at TP53 gene; genetic siRNA knockdown; HDAC inhibitor treatment; RT-PCR and Western blot for mutant p53\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter occupancy plus genetic and pharmacological loss-of-function, single lab\",\n      \"pmids\": [\"27721407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inflammation-driven NF-κB signaling recruits HDAC1 (and HDAC3) to the antioxidant response element (ARE) in the Slc40a1 (ferroportin) promoter in macrophages. HDAC1 and HDAC3 recruitment is dependent on NF-κB signaling and leads to repression of ferroportin transcription, contributing to anemia of inflammation.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for HDAC1/3 at Slc40a1 ARE; pharmacological and targeted RNAi screens; NF-κB signaling inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter recruitment plus genetic/pharmacological epistasis, single lab\",\n      \"pmids\": [\"39656097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In Schwann cells, HDAC1 controls Schwann cell survival by regulating levels of active β-catenin, while HDAC2 (not HDAC1) activates the transcriptional program of myelination in synergy with Sox10. These represent distinct, non-redundant primary functions of the two paralogs in peripheral nervous system myelination.\",\n      \"method\": \"Conditional mouse genetics (Schwann cell-specific ablation of Hdac1 and Hdac2); expression analysis of Sox10, Krox20; β-catenin activity measurement; histological analysis of sciatic nerves\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout mouse genetics with defined molecular pathway (β-catenin) and phenotypic readout, replicated across multiple genetic combinations\",\n      \"pmids\": [\"21423190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HDAC1 and HDAC2 directly mediate the repressive transcriptional functions of p63 in epidermal progenitor cells: HDACs bind and are active at promoters of p63-repressed targets (p21, 14-3-3σ, p16/INK4a) in normal keratinocytes. Loss of both HDAC1 and HDAC2 leads to increased acetylation of p53, which opposes p63 functions, and p53 is required for HDAC inhibitor-mediated p21 expression.\",\n      \"method\": \"Conditional ectodermal knockout of Hdac1/2; ChIP for HDAC binding at target promoters; p53 acetylation measurement; p53 genetic requirement analysis in keratinocytes\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse genetics plus ChIP at target promoters plus genetic epistasis with p53, multiple orthogonal methods\",\n      \"pmids\": [\"21093383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HDAC1 (and HDAC2) regulate global poly(A) RNA stability at the post-transcriptional level. Inhibition of HDAC1/2 induces widespread degradation of normally stable poly(A) RNA in mammalian and Drosophila cells. The mechanism involves CBP/p300-mediated acetylation of CAF1a (a catalytic subunit of the CCR4-CAF1-NOT deadenylase complex), which accelerates poly(A) RNA degradation.\",\n      \"method\": \"HDAC1/2 inhibition and knockdown; RNA stability assays; acetylation of CAF1a demonstrated; adipocyte differentiation model\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional loss-of-function in two organisms plus biochemical mechanism (CAF1a acetylation), single lab\",\n      \"pmids\": [\"27635759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC1 regulates β-cell proliferation by deacetylating histones at the Cdkn1b/p27 locus, thereby reducing p27 expression and allowing cell cycle progression from G1 to S phase. HDAC1 overexpression increases Cyclin A2, Cyclin B1, and E2F1 expression; overexpression of p27 blocks HDAC1-mediated β-cell proliferation.\",\n      \"method\": \"HDAC1 overexpression in primary rat islets and INS-1 cells; p27 overexpression rescue experiment; cell cycle analysis; gene expression analysis\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with rescue experiment establishing epistatic relationship, defined molecular target, single lab\",\n      \"pmids\": [\"30322885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human RPD3L1 gene (HDAC1) was cloned and found to be highly homologous (52% amino acid identity) to the yeast RPD3 transcription factor. The gene encodes a 482 amino acid protein and maps to chromosome band 1p34.1.\",\n      \"method\": \"cDNA cloning from human fetal lung library; sequence alignment; FISH chromosomal mapping; Northern blot expression analysis\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — definitive cloning and chromosomal mapping, foundational identification paper\",\n      \"pmids\": [\"8646880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HDAC1 and Klf4 competitively bind to the promoter region of Klf4, with HDAC1 repressing Klf4 expression in myeloid leukemia. HDAC1 knockdown increases Klf4 expression and inhibits cell cycle progression; Klf4 overexpression can block the pro-proliferative effects of HDAC1 overexpression, and vice versa, establishing a mechanistic interplay.\",\n      \"method\": \"ChIP for HDAC1 and Klf4 at Klf4 promoter; knockdown and overexpression of HDAC1 and Klf4; rescue experiments in leukemia cell lines and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing promoter occupancy plus reciprocal rescue experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"25341045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HDAC1 (but not HDAC2) controls the transcriptional identity and survival of glioma stem cells in a p53-dependent manner; HDAC1 loss is not compensated by HDAC2 in this context (unlike in normal neural stem cells). Knockdown of HDAC1 suppresses tumor growth in patient-derived xenograft models.\",\n      \"method\": \"shRNA knockdown of HDAC1 and HDAC2; cell-based and biochemical assays; RNA-seq; patient-derived xenograft models; p53 genetic manipulation\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific KD with transcriptomics and xenograft validation plus mechanistic p53 link, single lab\",\n      \"pmids\": [\"34494550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC1 inhibits beige adipocyte-mediated thermogenesis by regulating histone crotonylation (H3K18cr) and acetylation (H3K18ac) at the enhancers and promoters of Pgc1α and Ucp1 genes. Deletion of Hdac1 in beige adipocytes increases H3K18cr at these regulatory regions, promoting Pgc1α/Ucp1 transcription and thermogenesis.\",\n      \"method\": \"Conditional Hdac1 deletion in beige adipocytes; H3K18cr and H3K18ac ChIP-seq; gene expression analysis; energy expenditure measurement; MS275 HDAC inhibitor treatment\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with ChIP-seq for specific histone marks at defined loci plus functional metabolic phenotype, single lab\",\n      \"pmids\": [\"37640195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TNFα + IFNγ stimulation promotes formation of a FRA1:c-JUN:HDAC1 complex at the AP1 response element of the filaggrin (FLG) promoter, which suppresses FLG expression in keratinocytes. Co-immunoprecipitation demonstrated HDAC1 interaction with FRA1:c-JUN; HDAC1 knockdown abrogated cytokine-induced FLG suppression.\",\n      \"method\": \"DNA affinity precipitation assay; co-immunoprecipitation; HDAC1 knockdown; luciferase reporter assay; mouse models of skin inflammation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical complex by Co-IP plus functional knockdown, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"36067301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC1 regulates anti-inflammatory effects of isoflurane in human monocytes by preventing NF-κB nuclear translocation. Co-immunoprecipitation showed that LPS decreased HDAC1/HDAC2 interaction, which was restored by isoflurane pretreatment. Gene silencing of HDAC1 (and HDAC2) blocked isoflurane-induced reduction of NF-κB nuclear translocation and proinflammatory cytokine production.\",\n      \"method\": \"Co-immunoprecipitation of HDAC1/2 interaction; siRNA gene silencing; NF-κB nuclear translocation assay; cytokine measurement in THP-1 cells and primary monocytes\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing dynamic HDAC1/2 interaction plus siRNA knockdown with mechanistic readout, validated in primary cells, single lab\",\n      \"pmids\": [\"31950542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNTTIP1 recruits HDAC1 to the DUSP2 gene promoter, maintaining a deacetylated state of histone H3K27 and suppressing DUSP2 transcription. This leads to aberrant ERK pathway activation and elevated MMP2, promoting nasopharyngeal carcinoma metastasis.\",\n      \"method\": \"ChIP assay for HDAC1 at DUSP2 promoter; co-immunoprecipitation of DNTTIP1-HDAC1 interaction; luciferase reporter assays; in vitro and in vivo metastasis assays\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating HDAC1 recruitment by DNTTIP1 plus Co-IP plus functional in vivo validation, single lab\",\n      \"pmids\": [\"35689852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SP1 recruits HDAC1 to the miR-326 gene promoter in osteosarcoma cells, causing histone deacetylation and transcriptional inhibition of miR-326. This was established by ChIP assay and DAPA, and the loss of miR-326 activates the SMO/Hedgehog pathway to promote proliferation and metastasis.\",\n      \"method\": \"ChIP assay for SP1/HDAC1 at miR-326 promoter; DNA affinity precipitation assay (DAPA); miR-326 expression after SP1/HDAC1 modulation; in vivo metastasis model\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating HDAC1 promoter recruitment plus functional downstream pathway analysis, single lab\",\n      \"pmids\": [\"32743904\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HDAC1 is a class I zinc-dependent deacetylase that removes acetyl groups (and other short-chain acyl marks including lactyl, succinyl, and crotonyl groups) from lysine residues on histones and diverse non-histone substrates (FoxO3a, β-catenin, JAK1, HMGB1, p53, among others); its catalytic activity requires assembly into multi-protein corepressor complexes (Sin3, NuRD, CoREST) and is dynamically regulated by post-translational modifications—serine phosphorylation by CK2 promotes activity and dimer formation, acetylation of HDAC1 itself inactivates it and trans-represses its HDAC2 partner, tyrosine phosphorylation by EGFR stabilizes the protein, K412 lactylation modulates ferroptosis resistance, and K63-linked ubiquitination (regulated by USP19) controls its DNA-damage repair function; HDAC1 is recruited to specific genomic loci via interaction with transcription factors and corepressors (p63, Ets-1, FRA1:c-JUN, DNTTIP1, SP1, GFI1, Atrophin/RERE), where it represses target genes by histone deacetylation, while paradoxically also being required to maintain acetylation at super-enhancers critical for gene activation programs; it occupies a defined pathway position upstream of cell-cycle checkpoints (through PP2A/PR130 suppression) and downstream of environmental signals including metabolic intermediates (PEP) and inflammatory cues (NF-κB recruitment of HDAC1 to ferroportin promoter), with isoform-specific roles in Schwann cell survival (via β-catenin), T cell and dendritic cell development, muscle atrophy (via FoxO deacetylation), and neuronal differentiation that are only partially compensated by its paralog HDAC2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HDAC1, the human ortholog of yeast RPD3 [#29], is a class I zinc-dependent lysine deacylase that erases multiple short-chain acyl marks from histones—removing acetyl, succinyl [#1], and L-/D-lactyl [#0] groups—and is enzymatically active only when assembled into multi-protein corepressor complexes, co-purifying with HDAC2 and HDAC3 [#19]. Beyond histones, it deacetylates non-histone substrates including CDK1, AIFM1, MSH6 and RuvB-like 1 [#9], JAK1 (at K1109, controlling its proteasomal stability and STAT3-driven transcription) [#21], FoxO3a (driving atrophy gene programs and muscle fiber atrophy) [#16], β-catenin [#14], and HMGB1 [#13]. HDAC1 is recruited to specific genomic loci by transcription factors and corepressor scaffolds—p63 [#26], Ets-1 [#12], FRA1:c-JUN [#33], DNTTIP1 [#35], SP1 [#36], Atrophin/RERE via ELM2-SANT domains [#11], and MIER1/MIER2 ELM2 domains [#20]—where it represses target genes through histone deacetylation, yet it is paradoxically also required to maintain histone acetylation at super-enhancers that drive activation programs such as the pluripotency network, with H2BK5 and H2BK11 being its most sensitive substrates [#18]. Its activity is governed by post-translational modifications: CK2 phosphorylation promotes activity and controls mitotic dissociation of the HDAC1/HDAC2 heterodimer [#4], EGFR-mediated Tyr72 phosphorylation stabilizes the protein and supports its anti-apoptotic function [#7], self-acetylation inactivates HDAC1 and trans-represses HDAC2 [#3, #10], and protein levels are set by competing ubiquitin ligases (KBTBD4 via the UM171 molecular glue [#5], TRIM46 [#15]) and the deubiquitinase USP19 [#8]. Functionally, HDAC1 occupies pathway positions upstream of cell-cycle and DNA-damage checkpoints—suppressing the PP2A subunit PR130 to sustain ATM/CHK1/CHK2/WEE1/CDK1 phosphorylation [#6] and partnering with FUS in double-strand-break repair [#2]—and has isoform-specific, only partially HDAC2-compensated roles in Schwann cell survival via β-catenin [#25], epidermal progenitor and keratinocyte programs [#26], β-cell proliferation through the Cdkn1b/p27 locus [#28], and glioma stem cell identity in a p53-dependent manner [#31].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the molecular identity of HDAC1 was the prerequisite for all mechanistic study—cloning revealed it as the human RPD3 counterpart, framing it as a transcriptional regulator.\",\n      \"evidence\": \"cDNA cloning, sequence alignment, and FISH mapping from human fetal lung library\",\n      \"pmids\": [\"8646880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cloning alone did not establish enzymatic activity or substrates\", \"No complex membership defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved whether HDAC1 is an autonomous enzyme—showing it is catalytically active only within multi-protein complexes, co-purifying with HDAC2/HDAC3.\",\n      \"evidence\": \"Nickel-affinity purification of His-tagged HDAC1 from mammalian cells with deacetylase activity assays\",\n      \"pmids\": [\"15043985\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which corepressor complex confers activity\", \"Tag effect on activity not fully resolved mechanistically\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a built-in inhibitory switch—acetylation of HDAC1 itself inactivates its deacetylase activity, allowing context-dependent conversion between repression and coactivation.\",\n      \"evidence\": \"In vitro deacetylase assay of purified acetylated HDAC1, acetylation-site mutagenesis, ChIP, and reporter assays in a GR system\",\n      \"pmids\": [\"16762839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase responsible not defined here\", \"Generalizability beyond GR context unaddressed\"]\n    },\n    {\n      \"year\": \"2008\",\n      \"claim\": \"Defined how HDAC1 is targeted to chromatin—Atrophin/RERE recruits it through ELM2-SANT domains into a G9a-containing repressive complex to establish H3K9 methylation.\",\n      \"evidence\": \"Co-IP, chromosomal co-localization, and Drosophila genetic interaction with histone modification assays\",\n      \"pmids\": [\"18451879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect HDAC1-G9a contact not resolved\", \"Vertebrate validation limited\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated non-redundant paralog roles in vivo—HDAC1 controls Schwann cell survival via β-catenin while HDAC2 drives myelination, refuting simple functional equivalence.\",\n      \"evidence\": \"Schwann cell-specific conditional knockout mouse genetics with β-catenin activity and histological readouts\",\n      \"pmids\": [\"21423190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking HDAC1 to β-catenin levels not fully defined\", \"Degree of compensation context-specific\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked HDAC1 directly to genome maintenance and mitotic regulation—FUS-HDAC1 interaction supports DSB repair, and CK2 phosphorylation drives mitotic heterodimer dissociation.\",\n      \"evidence\": \"Co-IP, DSB recruitment, ALS mutant analysis (FUS); kinase inhibition and phospho-site mutagenesis during mitosis (CK2)\",\n      \"pmids\": [\"24036913\", \"23612983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HDAC1 deacetylase activity per se is required at DSBs not isolated\", \"Functional consequence of homodimer state during metaphase incompletely mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Expanded the HDAC1 substrate landscape beyond histones and positioned it within checkpoint signaling—substrate trapping identified protein targets, and HDAC1/2 were shown to suppress PR130/PP2A to sustain checkpoint kinase phosphorylation.\",\n      \"evidence\": \"Catalytically-dead mutant substrate trapping with MS (substrates); genetic elimination of HDAC1/2 and PR130 with checkpoint phosphorylation and HR assays\",\n      \"pmids\": [\"30421914\", \"29472538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual trapped substrates not each orthogonally validated\", \"Direct deacetylation sites for checkpoint factors not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established HDAC1 as a histone delactylase and broad short-chain de-acylase, redefining it as a multi-mark eraser rather than a pure deacetylase.\",\n      \"evidence\": \"In vitro enzymatic screen with cellular validation of de-L-lactylase activity\",\n      \"pmids\": [\"35044827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genomic distribution of lactyl marks regulated by HDAC1 not mapped here\", \"Physiological consequences cell-type-specific\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed HDAC1 governs metabolite- and acyl-mark-linked transcription—it is a primary desuccinylase, is inhibited by the glycolytic intermediate PEP to activate Wnt/β-catenin, and shows collateral synthetic lethality with HDAC2 through NuRD-dependent enhancer transcription.\",\n      \"evidence\": \"Reconstituted desuccinylase assays and ChIP-seq; in vitro PEP inhibition with β-catenin acetylation and xenografts; dTAG degradation with ATAC-seq/ChIP-seq\",\n      \"pmids\": [\"37580347\", \"37667133\", \"37488358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How succinyl-mark removal integrates with deacetylation at single loci unclear\", \"Breadth of metabolite-sensing inhibition beyond PEP unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the structural basis of pharmacological HDAC1 degradation and uncovered PTM-linked metabolic control—UM171 acts as a molecular glue recruiting KBTBD4 to HDAC1/2, while K412 lactylation tunes ferroptosis resistance.\",\n      \"evidence\": \"Cryo-EM with base editor scanning and proteomics (KBTBD4); MS site mapping with ChIP and m6A assays in vivo (K412 lactylation)\",\n      \"pmids\": [\"39939761\", \"39888307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological trigger for K412 lactylation not defined\", \"Selectivity of glue-induced degradation across complexes incompletely mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how HDAC1 mechanistically maintains, rather than removes, histone acetylation at super-enhancers, and how its choice between repressive and activating chromatin states is encoded by complex composition and its own PTMs.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model reconciling repressor vs enhancer-maintenance functions\", \"Rules selecting corepressor complex (Sin3/NuRD/CoREST) at a given locus undefined\", \"Integration of competing ubiquitination inputs (KBTBD4, TRIM46, USP19) into net abundance not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 9, 16, 21]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 26, 12, 35, 36]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 26, 18]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [23, 24, 32, 35, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [18, 11, 26, 1]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [12, 23, 24, 35, 36, 30]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 6, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 6, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [25, 26, 16]}\n    ],\n    \"complexes\": [\"Sin3\", \"NuRD\", \"CoREST\", \"LSD1-CoREST\"],\n    \"partners\": [\"HDAC2\", \"HDAC3\", \"FUS\", \"USP19\", \"KBTBD4\", \"DNTTIP1\", \"MIER2\", \"BAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}