{"gene":"HDAC7","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2008,"finding":"Crystal structures of human HDAC7 catalytic domain (cdHDAC7) and its complexes with two hydroxamate inhibitors revealed a class IIa-specific zinc binding motif adjacent to the active site, an enlarged active site pocket with different topology compared to class I/IIb HDACs, and a low but measurable intrinsic deacetylase activity inhibitable by known HDAC inhibitors.","method":"X-ray crystallography; in vitro deacetylase activity assay; inhibitor binding studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation (activity assay + inhibitor complexes) in a single rigorous study","pmids":["18285338"],"is_preprint":false},{"year":2001,"finding":"HDAC7 deacetylase activity in the cell nucleus depends on its interaction with the class I HDAC3; cytoplasmic HDAC7 not bound to HDAC3 is enzymatically inactive. The corepressors SMRT and N-CoR serve as mediators by binding class II HDACs and HDAC3 via two distinct repressor domains.","method":"Co-immunoprecipitation; fractionation; functional deacetylase assays; domain mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with fractionation and activity assays, multiple orthogonal methods in a single focused study","pmids":["11466315"],"is_preprint":false},{"year":2001,"finding":"HDAC7 directly interacts with MEF2 proteins (MEF2-A, -C, -D) via its N-terminal 121 amino acids (repression domain 1), and the MADS domain of MEF2 mediates this interaction; HDAC7-mediated MEF2 repression is independent of the C-terminal deacetylase domain. HDAC7 also interacts with CtBP and other class I/II HDACs. During myogenesis induced by serum withdrawal, HDAC7 translocates from nucleus to cytoplasm.","method":"GST pulldown; co-immunoprecipitation; reporter assays; domain-deletion mapping; fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (GST pulldown + Co-IP + domain mapping + live-cell localization) in a single rigorous study","pmids":["11279209"],"is_preprint":false},{"year":2003,"finding":"HDAC7 represses Nur77 transcription via MEF2D in CD4+CD8+ double-positive thymocytes. TCR activation triggers nuclear export of HDAC7, leading to Nur77 derepression and apoptosis. A triple serine mutant (S155A/S318A/S448A) of HDAC7 is not exported and suppresses TCR-mediated apoptosis; RNAi knockdown of HDAC7 increases TCR-mediated apoptosis.","method":"Reporter assays; site-directed mutagenesis; RNAi; fluorescence microscopy; thymocyte apoptosis assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis combined with RNAi and functional phenotype, replicated by multiple approaches in one study","pmids":["12753745"],"is_preprint":false},{"year":2004,"finding":"Protein kinase D1 (PKD1) is activated after TCR engagement, physically interacts with HDAC7, and phosphorylates three serines (Ser155, Ser318, Ser448) at its N-terminus, causing nuclear export of HDAC7 via a calcium-independent pathway. Kinase-inactive PKD1 blocked HDAC7 shuttling. PKD1 activation leads to Nur77 transcriptional activation via MEF2 binding sites.","method":"Co-immunoprecipitation; in vitro kinase assay; site-directed mutagenesis; dominant-negative PKD1; fluorescence microscopy; reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay + mutagenesis + dominant-negative rescue + nuclear export phenotype, multiple orthogonal methods","pmids":["15623513"],"is_preprint":false},{"year":2007,"finding":"Protein phosphatase 1β (PP1β) and myosin phosphatase targeting subunit 1 (MYPT1) associate with HDAC7 in thymocytes and dephosphorylate HDAC7, promoting its nuclear localization and repression of Nur77, thereby inhibiting apoptosis in CD4+CD8+ thymocytes. ROCK signaling pathway operates upstream via MYPT1.","method":"Co-immunoprecipitation; phosphatase assays; siRNA knockdown; fluorescence microscopy; apoptosis assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical phosphatase assay combined with Co-IP and functional apoptosis readout, multiple methods in a focused study","pmids":["17369396"],"is_preprint":false},{"year":2004,"finding":"HDAC7 localizes to the mitochondrial inner membrane space of prostate epithelial cells and undergoes cytoplasmic relocalization upon initiation of apoptosis.","method":"Subcellular fractionation; immunofluorescence microscopy; mitochondrial isolation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment with fractionation, single lab, single study","pmids":["15364908"],"is_preprint":false},{"year":2001,"finding":"HDAC7 interacts with the endothelin receptor A (ETA) as determined by yeast two-hybrid, GST pulldown, and co-immunoprecipitation. ET-1 stimulation causes internalization of ETA to a perinuclear compartment and simultaneous nuclear export of HDAC7 to the same compartment.","method":"Yeast two-hybrid; GST pulldown; co-immunoprecipitation; fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal interaction methods, single lab","pmids":["11262386"],"is_preprint":false},{"year":2008,"finding":"VEGF stimulates PKD1-dependent phosphorylation of HDAC7 at Ser178, Ser344, and Ser479 via a PLCγ/PKC/PKD1 pathway, causing cytoplasmic accumulation of HDAC7. A phosphorylation-deficient HDAC7 mutant inhibited VEGF-induced expression of MT1-MMP and MMP10 and suppressed endothelial cell migration, tube formation, and microvessel sprouting.","method":"Pharmacological inhibitors; siRNA; dominant-negative adenoviruses; western blotting; tube formation/migration assays; phosphomutant constructs","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative + siRNA + pharmacological) with functional in vitro and ex vivo readouts","pmids":["18617643"],"is_preprint":false},{"year":2010,"finding":"HDAC7 protects neurons from apoptosis by directly associating with the c-jun gene promoter and inhibiting c-jun transcription. This neuroprotection is independent of HDAC7's catalytic domain and cannot be blocked by chemical HDAC inhibitors.","method":"shRNA knockdown; forced expression; chromatin immunoprecipitation (ChIP); catalytic domain mutants; neuronal apoptosis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + domain-deletion mutants + RNAi/overexpression with phenotypic readout, single lab","pmids":["21118817"],"is_preprint":false},{"year":2011,"finding":"HDAC7 interacts with the transcription factor Mitf in RAW 264 osteoclast precursor cells and represses Mitf transcriptional activity; either the amino- or carboxyl-terminus of HDAC7 is sufficient for this repression. Knockdown of HDAC7 accelerates osteoclast differentiation, and the repression is insensitive to trichostatin A, indicating a deacetylation-independent mechanism.","method":"Co-immunoprecipitation; siRNA knockdown; reporter assays; domain-deletion analysis; osteoclast differentiation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + domain mapping + functional differentiation assay, single lab","pmids":["21324898"],"is_preprint":false},{"year":2009,"finding":"HDAC7 undergoes alternative splicing during ES cell differentiation toward smooth muscle cells (SMCs); the spliced form modulates the SRF-myocardin complex to promote SMC differentiation. PDGF enhanced this splicing and SMC differentiation.","method":"Western blot; immunofluorescence; overexpression in ES cells; SM22-LacZ transgenic embryonic cell culture; co-immunoprecipitation of SRF-myocardin complex","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with molecular (SRF-myocardin complex modulation) and phenotypic (SMC marker expression) readouts, single lab","pmids":["19174469"],"is_preprint":false},{"year":2010,"finding":"Sp1 binds the HDAC7 promoter at a minimal PDGF-BB-responsive element (−343 to −292 bp) containing a Sp1 site, activating HDAC7 transcription during SMC differentiation. Mutation of the Sp1 site abolishes PDGF-BB-induced HDAC7 promoter activity, and Sp1 knockdown abrogates PDGF-BB-induced HDAC7 upregulation and SMC gene expression.","method":"Promoter deletion analysis; luciferase reporter assay; site-directed mutagenesis; ChIP; siRNA knockdown; overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mapping with mutagenesis and ChIP, single lab","pmids":["20889501"],"is_preprint":false},{"year":2013,"finding":"In pre-B cells, HDAC7 interacts with transcription factor MEF2C and is recruited to MEF2 binding sites at promoters of macrophage-specific genes to repress them. Re-expression of HDAC7 during pre-B to macrophage transdifferentiation blocks induction of myeloid genes and suppresses phagocytosis and cytokine responses.","method":"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); microarray; overexpression/knockdown; phagocytosis and cytokine assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP + ChIP + functional phenotype with multiple orthogonal methods, single lab","pmids":["23696748"],"is_preprint":false},{"year":2012,"finding":"HDAC7 binds β-catenin in proliferating chondrocytes and suppresses β-catenin transcriptional activity and cyclin D1 expression. Stimulation of chondrocyte maturation causes HDAC7 translocation to the cytoplasm where it is degraded by the proteasome, releasing β-catenin to the nucleus. Postnatal conditional Hdac7 deletion in chondrocytes expands the proliferative zone.","method":"Co-immunoprecipitation; conditional knockout (tamoxifen-inducible Cre); adenoviral Cre deletion; nuclear/cytoplasmic fractionation; reporter assays; histology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP + conditional KO model + fractionation + functional proliferation assay, multiple orthogonal methods","pmids":["25389289"],"is_preprint":false},{"year":2012,"finding":"HDAC7 overexpression suppresses and HDAC7 deletion enhances osteoclastogenesis. Mechanistically, HDAC7 attenuates β-catenin function and cyclin D1 expression to reduce precursor proliferation; upon RANKL signaling, HDAC7 suppresses NFATc1 and prevents β-catenin downregulation to block differentiation. Conditional HDAC7 knockout in osteoclast lineage reduces bone mass due to elevated bone resorption.","method":"Conditional knockout mice; bone marrow differentiation assays; overexpression; western blot; reporter assay","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo + in vitro gain-/loss-of-function with molecular mechanism, multiple methods","pmids":["23204328"],"is_preprint":false},{"year":2013,"finding":"PP2A-Bα phosphatase controls HDAC7 activity; loss of PP2A-Bα abrogates HDAC7 transcriptional repression, leading to increased ArgBP2 expression, RhoA hyperactivation, and disruption of endothelial cytoskeletal dynamics and vascular lumen formation. This PP2A-Bα/HDAC7/ArgBP2 axis maintains vascular lumens.","method":"siRNA knockdown; zebrafish morpholino; reporter assays; western blot; RhoA activity assay; tubulogenesis assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell and in vivo (zebrafish) experiments with pathway epistasis, single lab","pmids":["23955003"],"is_preprint":false},{"year":2012,"finding":"HDAC7 silencing in HUVECs results in H3 histone acetylation at the AKAP12 promoter, increasing AKAP12 mRNA/protein levels; elevated AKAP12 mediates PKC-dependent STAT3 phosphorylation. AKAP12 upregulation following HDAC7 knockdown is responsible for inhibition of endothelial migration and tube formation.","method":"siRNA; proteomics; ChIP; western blot; migration and tube formation assays","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + proteomics + functional rescue assays, single lab","pmids":["22584896"],"is_preprint":false},{"year":2014,"finding":"Deacetylation of HSP70 at K246 by HDAC1 and HDAC7 promotes cancer cell survival and therapy resistance by inhibiting autophagic cell death. miR-34a targets HDAC1 and HDAC7 to suppress this deacetylation.","method":"miRNA target validation (luciferase); site-directed mutagenesis of HSP70 K246; co-immunoprecipitation; western blot; cell survival and autophagy assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deacetylation site mutagenesis combined with functional autophagy and survival assays, single lab","pmids":["25173798"],"is_preprint":false},{"year":2017,"finding":"HDAC7 directly interacts with and deacetylates STAT3, reducing STAT3 acetylation and tyrosine phosphorylation. Loss of HDAC7 in mouse lung tumors or human cancer cell lines results in enhanced STAT3 acetylation/activation. The tumor-promoting effect of Hdac7 in K-Ras mice was reversed by dominant-negative Stat3.","method":"Co-immunoprecipitation; pulldown assay; western blot; in vivo mouse model (Hdac7+/-/K-Ras); dominant-negative rescue; deacetylation assay","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown + Co-IP + genetic epistasis (dnStat3 rescue), single lab","pmids":["29126425"],"is_preprint":false},{"year":2022,"finding":"HDAC7 deacetylates β-catenin at Lys49, reducing its phosphorylation at Ser45, which promotes β-catenin nuclear translocation and TCF4-dependent activation of FGF18. Deubiquitinase USP10 interacts with HDAC7 and stabilizes it by preventing its ubiquitin-proteasome degradation.","method":"Co-immunoprecipitation; western blot; lentiviral overexpression/knockdown; in vivo xenograft; luciferase reporter","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deacetylation and phosphorylation readouts + in vivo rescue, single lab","pmids":["35277183"],"is_preprint":false},{"year":2019,"finding":"ZNF326 activates HDAC7 transcription by binding to the HDAC7 promoter via its zinc-finger and transcriptional activation domains. Upregulated HDAC7 then deacetylates β-catenin at Lys49, decreasing its phosphorylation at Ser45, promoting β-catenin nuclear import and TCF4 binding to activate Wnt target genes.","method":"ChIP; dual-luciferase assay; GST pulldown; co-immunoprecipitation; western blot; site-directed mutagenesis","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + dual-luciferase + Co-IP + mutagenesis, single lab","pmids":["30691485"],"is_preprint":false},{"year":2015,"finding":"Ectopically expressed HDAC7 in leukemia/lymphoma cells localizes to the nucleus, interacts with MEF2C, HDAC3, and SMRT to downregulate c-Myc and induce apoptosis. Both the MEF2C-interaction domain and the catalytic domain of HDAC7 are required for reduced cell viability.","method":"Co-immunoprecipitation; overexpression; xenograft model; reporter assay; domain-deletion analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + domain mapping + in vivo xenograft, single lab","pmids":["25675295"],"is_preprint":false},{"year":2016,"finding":"In B cell progenitors, HDAC7 interacts with MEF2C and is recruited to promoters and enhancers of myeloid and T-lymphocyte genes; conditional HDAC7 knockout blocks early B cell development, causes lymphopenia, and leads to pro-B cell lineage promiscuity. HDAC7 absence leads to increased enrichment of active histone marks at target gene loci.","method":"Conditional knockout mouse model; ChIP-seq; co-immunoprecipitation; flow cytometry; gene expression analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo + ChIP-seq + Co-IP with defined developmental phenotype, multiple orthogonal methods","pmids":["27810920"],"is_preprint":false},{"year":2017,"finding":"Tonic LAT-mediated TCR signals constitutively export HDAC7 from the nucleus of naive CD4+ T cells, maintaining expression of HDAC7 target genes Nur77 and Irf4. Without tonic LAT signals, HDAC7 is nuclear, repressing Nur77 and Irf4.","method":"Genetic (LAT-deficient mice); nuclear export assays; gene expression profiling; functional T cell assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic LAT deficiency + target gene regulation, single lab","pmids":["28538176"],"is_preprint":false},{"year":2020,"finding":"SIK1 phosphorylates and stabilizes HDAC7 protein during cardiac stress; this HDAC7 stabilization is required for pathologic cardiomyocyte remodeling and c-Myc induction. HDAC7 acts as a prohypertrophic effector in the cytoplasm of cardiomyocytes, representing a functional departure from canonical nuclear MEF2 corepressor activity.","method":"Gain- and loss-of-function in rodent models and hiPSC-derived cardiomyocytes; western blot; co-immunoprecipitation; kinase assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — kinase-substrate relationship (SIK1→HDAC7 phosphorylation/stabilization) + in vivo rodent model + iPSC model, multiple orthogonal methods","pmids":["32106109"],"is_preprint":false},{"year":2010,"finding":"Nuclear-retained HDAC7 mutants inhibit C2C12 myocyte differentiation and reduce MHC and myogenin expression; this inhibition is partially relieved by a mutation disrupting HDAC7-MEF2 interaction. Phosphorylated HDAC7 (pS178) colocalizes with actin filaments in myocytes, and nuclear-retained HDAC7 causes defects in myocyte migration.","method":"Stable expression of HDAC7 mutants; immunofluorescence; phalloidin staining; differentiation and migration assays; site-directed mutagenesis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis + localization + functional differentiation/migration assays, single lab","pmids":["20621129"],"is_preprint":false},{"year":2006,"finding":"HDAC7 acts as a corepressor of androgen receptor (AR); in absence of AR ligand, HDAC7 is cytoplasmic, but androgen-occupied AR induces nuclear transfer of HDAC7. The deacetylase activity of HDAC7 is partly dispensable for AR repression, and PML-3 overexpression sequesters HDAC7 to PML-3 domains to relieve HDAC7-mediated AR repression.","method":"Fluorescence microscopy; co-immunoprecipitation; reporter assays; domain mutagenesis; PML-3 overexpression","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization + functional reporter + domain analysis, single lab","pmids":["16860317"],"is_preprint":false},{"year":2017,"finding":"HDAC7 is ubiquitinated by the E3 ligase CBX4 in hippocampal neurons after contextual fear conditioning (CFC) training, leading to HDAC7 ubiquitin-dependent degradation. Decreased HDAC7 levels correlate with increased Nur77 expression, which modulates CFC memory formation.","method":"Immunoprecipitation; western blot; hippocampal injection of siRNA; fear conditioning behavioral assay; ubiquitination assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — E3 ligase identified by IP + ubiquitination assay + behavioral phenotype, single lab","pmids":["28283560"],"is_preprint":false},{"year":2022,"finding":"HDAC7 interacts with IKKα and IKKβ to promote their deacetylation and activation, leading to NF-κB activation in astrocytes. Astrocyte-specific HDAC7 overexpression induces NF-κB-driven pro-inflammatory gene expression and anxiety-like behaviors in mice.","method":"Co-immunoprecipitation; western blot; AAV-mediated overexpression; siRNA knockdown; pharmacological inhibition; behavioral assays","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + in vivo overexpression with behavioral and molecular phenotypes, single lab","pmids":["35871708"],"is_preprint":false},{"year":2024,"finding":"Using a selective PROTAC degrader (B4), HDAC7 was shown to have a deacetylase-independent proinflammatory role in macrophages; HDAC7 directly interacts with the TRAF6-TAK1 complex, activating MAPK/NF-κB signaling downstream of TLR4 and driving production of specific proinflammatory cytokines.","method":"PROTAC-mediated targeted degradation; co-immunoprecipitation; western blot; cytokine assays; mouse LPS model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PROTAC degradation as selective tool + Co-IP for complex, single lab","pmids":["39049738"],"is_preprint":false},{"year":2023,"finding":"In macrophages, HDAC7 functions as a metabolic switch: LPS (distal danger) triggers HDAC7-dependent glycolysis and IL-1β production, while bacterial challenge (proximal danger) induces HDAC7-mediated pentose phosphate pathway engagement via 6PGD, generating NADPH/ROS for antimicrobial killing and D-ribulose-5-phosphate (RL5P) with antimicrobial and immunomodulatory activities. Hdac7 enzymatic activity is required for IL-1β production but acts enzyme-independently for metabolic reprogramming.","method":"Hdac7-deficient macrophages; enzyme-dead mutant reconstitution; extracellular acidification rate (ECAR) assay; cytokine assays; metabolomics; UPEC killing assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzyme-dead mutant reconstitution + metabolomics + multiple functional readouts, multiple orthogonal methods in single study","pmids":["36649417"],"is_preprint":false},{"year":2021,"finding":"TLR4/LPS-activated HDAC7 enzymatic activity in macrophages is required for production of specific inflammatory mediators (IL-1β, CCL2), while its metabolic glycolysis-reprogramming function is enzyme-independent. TLR-inducible class IIa HDAC activity is absent in Hdac7-deficient macrophages and requires MyD88 (except for TLR3 agonist).","method":"Hdac7-deficient mouse macrophages; enzyme-dead mutant reconstitution; ECAR assay; cytokine assays; MyD88-deficient cells","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzyme-dead mutant reconstitution + knockout macrophages + metabolic assays, single lab","pmids":["34811804"],"is_preprint":false},{"year":2021,"finding":"TGF-β signaling, in concert with HDAC7, suppresses expression of TCA cycle enzymes in renal cell carcinoma (RCC) by repressing PGC-1α. Pharmacologic inhibition of TGF-β restores TCA cycle enzyme expression and suppresses tumor growth in an orthotopic RCC model.","method":"Proteomics; gene expression analysis; PGC-1α overexpression; TGF-β inhibition in orthotopic model; metabolic flux analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with mechanistic rescue + metabolomics, single lab","pmids":["34609963"],"is_preprint":false},{"year":2022,"finding":"HDAC4, -5, and -7 dissociate from corepressor NCoR in the presence of acetyllysine-containing peptides (consistent with reader function). Mutation of a critical AR acetylation site regulated AR transcriptional activation through an HDAC7-NCoR-HDAC3 dissociation mechanism, providing evidence that HDAC7 can function as an epigenetic acetyllysine reader.","method":"NCoR dissociation assay with acetyllysine peptides; AR mutagenesis; reporter assay; co-immunoprecipitation","journal":"Cell chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acetyllysine peptide competition assay + mutagenesis + functional reporter, single lab","pmids":["35709754"],"is_preprint":false},{"year":2022,"finding":"In Tregs, wild-type HDAC7 regulates genes essential for Foxp3+ Treg function. Treg-specific conditional hemizygous deletion of HDAC7 increases EAE severity. The MS-protective HDAC7 R166H (R150H in mouse) variant confers enhanced Treg suppressive capacity in vitro and decreases EAE severity in vivo via transcriptomic alterations in brain-infiltrating Tregs.","method":"Treg-specific conditional knockout; knock-in mouse model; EAE model; in vitro Treg suppression assay; single-cell RNA-seq; transcriptomic analyses","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO + knock-in variant mouse + scRNA-seq + in vitro and in vivo functional assays, multiple orthogonal methods","pmids":["36516268"],"is_preprint":false},{"year":2024,"finding":"In Th17 cell differentiation, HDAC7 collaborates with transcription factor Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators (including Il2). Hdac7 is dispensable in other Th subtypes. Genetic or pharmacological inhibition of Hdac4/7 mitigates Th17-mediated intestinal inflammation in a colitis model.","method":"Conditional knockout (Hdac7 and Hdac4 in T cells); co-immunoprecipitation; ChIP; colitis mouse model; cytokine assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO + Co-IP + ChIP + in vivo colitis model, multiple orthogonal methods","pmids":["38657041"],"is_preprint":false},{"year":2022,"finding":"HDAC7 deficiency in pro-B cells induces TET2 expression, promoting DNA 5-hydroxymethylation and global chromatin de-condensation. HDAC7 loss also results in aberrant expression of microRNAs and LINE-1 transposable elements, revealing an HDAC7-TET2 epigenetic axis essential for early B cell development.","method":"Conditional knockout; 5-hmC profiling; histone mark analysis; microRNA/LINE-1 expression; chromatin conformation analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple epigenomic readouts, single lab","pmids":["35904805"],"is_preprint":false},{"year":2019,"finding":"In breast cancer stem-like cells, HDAC7 binds near transcription start sites and super-enhancers of oncogenes (c-MYC, CD44, etc.) and contributes to H3K27ac levels and transcriptional activation at these loci. HDAC1 or HDAC3 inhibition/knockdown leads to HDAC7 downregulation associated with decreased H3K27ac at super-enhancers.","method":"ChIP-seq; siRNA knockdown; western blot; gene expression analysis in CSC vs. non-CSC models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with knockdown experiments, single lab","pmids":["31375747"],"is_preprint":false},{"year":2010,"finding":"HDAC7 silencing in cancer cells causes G1/S arrest by suppressing c-Myc expression and increasing p21/p27. HDAC7 directly binds the c-Myc gene promoter, and its silencing decreases histone H3/H4 acetylation and RNA polymerase II occupancy at the c-Myc locus. Ectopic c-Myc expression reverses G1/S arrest and cellular senescence induced by HDAC7 knockdown.","method":"siRNA knockdown; ChIP; cell cycle analysis; overexpression rescue; western blot","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + functional rescue, single lab","pmids":["21120446"],"is_preprint":false},{"year":2023,"finding":"HDAC7 deacetylates FOXP1 in mesenchymal stem cells (MSCs); FOXP1 and HDAC7 cooperatively sustain MSC self-renewal and attenuate cellular senescence. Mutation of the FOXP1 acetylation site T172G (homologous to human T176G) profoundly augments MSC expansion capacity.","method":"Mass spectrometry; single and double knockout mice; site-directed mutagenesis (T176G); hESC-derived MSC overexpression; proliferation/senescence assays","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification of acetylation site + mutagenesis + KO model, single lab","pmids":["37507770"],"is_preprint":false},{"year":2025,"finding":"HDAC7 deacetylates TFEB at K310 in astrocytes, preventing TFEB nuclear translocation and reducing lysosomal biogenesis and tau clearance. Genetic or pharmacological inhibition of HDAC7 restores TFEB acetylation, enhances lysosomal biogenesis, and improves tau clearance and cognitive function in PS19 mice.","method":"Co-immunoprecipitation; mass spectrometry; immunoprecipitation; luciferase reporter; AAV-shRNA in PS19 mice; tau uptake/degradation assays; pharmacological inhibition (TMP195)","journal":"Molecular neurodegeneration","confidence":"High","confidence_rationale":"Tier 1 / Moderate — identification of deacetylation site by MS + mutagenesis + in vivo AAV genetic model + pharmacological validation, multiple orthogonal methods in single study","pmids":["39806423"],"is_preprint":false},{"year":2025,"finding":"HDAC7 deacetylates PINK1, suppressing phosphorylation of Parkin at Ser65 and inhibiting TOMM20/40 recruitment, thereby impairing PINK1-Parkin-dependent mitophagy in astrocytes. Astrocyte-specific HDAC7 knockout or pharmacological inhibition restores mitophagy, ATP release, and reverses depressive-like behaviors in mice.","method":"Co-immunoprecipitation; mass spectrometry; western blot; AAV-mediated astrocyte-specific KO; pharmacological inhibition; mitophagy assays; behavioral assays","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deacetylation substrate identified by Co-IP/MS + in vivo KO + functional mitophagy assay, single lab","pmids":["41286926"],"is_preprint":false},{"year":2013,"finding":"HDAC7 interacts with HDAC1, HDAC2, and HDAC7 (itself) via pulldown and co-immunoprecipitation, mediating transcriptional repression by Holocarboxylase synthetase (HCS) in a deacetylase/biotin-independent manner.","method":"In vitro pulldown; co-immunoprecipitation; GAL4-luciferase reporter assay","journal":"Molecular genetics and metabolism","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown, context is HCS biology, single lab","pmids":["24239178"],"is_preprint":false},{"year":2025,"finding":"HDAC7 promotes β-catenin deacetylation, phosphorylation modulation, and nuclear translocation in SCLC cells, forming a β-catenin/TCF/LEF1 complex that activates c-Myc and XPO1 transcription. This HDAC7/β-catenin/c-Myc/XPO1 axis drives SCLC proliferation.","method":"RNA sequencing; western blot; co-immunoprecipitation; xenograft and organoid models; ChIP","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ChIP + in vivo model, single lab","pmids":["39887933"],"is_preprint":false},{"year":2024,"finding":"TRIM28-mediated sumoylation of HDAC7 upregulates its protein levels; sumoylated HDAC7 mediates H3K27 deacetylation to inhibit SOX8, which facilitates JUN-dependent LGALS3 transcription to promote GBM mesenchymal transition and macrophage M2 polarization.","method":"Mass spectrum; RNA immunoprecipitation; co-immunoprecipitation; ChIP; gain/loss-of-function assays in vitro and in vivo","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + ChIP + mass spec for PTM identification, single lab","pmids":["39629136"],"is_preprint":false},{"year":2024,"finding":"FBXW7 interacts with HDAC7 via immunoprecipitation and promotes HDAC7 ubiquitination in glioblastoma cells; HDAC7 overexpression blocks FBXW7-induced apoptosis.","method":"Co-immunoprecipitation; ubiquitination assay; overexpression rescue; western blot","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP + ubiquitination assay, single lab","pmids":["34288252"],"is_preprint":false},{"year":2025,"finding":"HDAC7 reduces the acetylation level of Enolase 1 (ENO1), thereby enhancing malignant proliferation of ARID1A-deficient HCC cells. The transcription factor PU.1 (induced by ARID1A loss) drives HDAC7 transcription. Targeting HDAC7 inhibited ARID1A-deficient tumor xenograft growth.","method":"RNA-seq; ChIP; luciferase reporter; protein IP + mass spectrometry (identifying ENO1 as substrate); xenograft; western blot","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by IP/MS + ChIP/luciferase for transcriptional regulation + in vivo xenograft, single lab","pmids":["40536557"],"is_preprint":false},{"year":2014,"finding":"ROCK signaling via MYPT1 (myosin phosphatase) controls nucleocytoplasmic shuttling of HDAC7; inhibition of the ROCK pathway in iPSCs leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1.","method":"iPSC model; ROCK inhibition; immunofluorescence microscopy; reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment with functional readout, single lab","pmids":["25511694"],"is_preprint":false}],"current_model":"HDAC7 is a class IIa histone deacetylase with cryptically low intrinsic catalytic activity (due to a non-canonical active site) whose primary enzymatic activity in the nucleus depends on assembly with HDAC3/SMRT/N-CoR complexes; it functions as a transcriptional corepressor of MEF2 family transcription factors (via its N-terminal repression domain) and, in thymocytes, is regulated by PKD1-mediated phosphorylation of Ser155/Ser318/Ser448 to drive nuclear export and derepress Nur77/apoptosis, with myosin phosphatase (PP1β/MYPT1) acting as the opposing phosphatase to restore nuclear localization; beyond MEF2/Nur77 regulation, HDAC7 deacetylates non-histone substrates including STAT3, β-catenin (Lys49), HSP70 (K246), FOXP1, TFEB (K310), PINK1, and ENO1, and it acts as a deacetylase-independent scaffold interacting with TRAF6-TAK1, IKK, and β-catenin to regulate NF-κB and Wnt signaling; SIK1 phosphorylates and stabilizes cytoplasmic HDAC7 to drive cardiac hypertrophy, USP10 stabilizes HDAC7 via deubiquitination, and CBX4/FBXW7 promote its ubiquitin-dependent degradation; in macrophages, HDAC7 acts as a bifunctional immunometabolic switch coupling TLR4 signals to glycolysis (enzyme-independent) and to antimicrobial pentose phosphate pathway responses and inflammatory cytokine production (enzyme-dependent)."},"narrative":{"mechanistic_narrative":"HDAC7 is a class IIa histone deacetylase that functions principally as a signal-responsive transcriptional corepressor, with its biological output dictated by phosphorylation-controlled nucleocytoplasmic shuttling and by non-catalytic scaffolding activities [PMID:11279209, PMID:15623513]. Its catalytic domain adopts a class IIa-specific architecture with an enlarged active-site pocket and only low intrinsic deacetylase activity [PMID:18285338], and its robust nuclear enzymatic function depends on assembly with HDAC3 through the SMRT/N-CoR corepressors [PMID:11466315]. HDAC7 represses transcription by binding MEF2 family factors (MEF2A/C/D) through its N-terminal repression domain in a manner independent of the catalytic domain [PMID:11279209], a module deployed across thymocyte selection where it silences Nur77 [PMID:12753745], B-lymphoid and myeloid lineage decisions [PMID:23696748, PMID:27810920], and Th17 and Treg programs [PMID:36516268, PMID:38657041]. Activation signals relocalize HDAC7 out of the nucleus: PKD1, activated downstream of the TCR or VEGF receptor, phosphorylates conserved N-terminal serines (Ser155/Ser318/Ser448, or Ser178/Ser344/Ser479) to drive cytoplasmic export and derepression of target genes [PMID:15623513, PMID:18617643], while opposing phosphatases (PP1β/MYPT1, PP2A-Bα) and the ROCK pathway restore nuclear localization and repression [PMID:17369396, PMID:23955003]. Beyond MEF2 corepression, HDAC7 deacetylates an expanding set of non-histone substrates—STAT3 [PMID:29126425], β-catenin at Lys49 [PMID:35277183, PMID:30691485], HSP70 at K246 [PMID:25173798], FOXP1 [PMID:37507770], TFEB at K310 [PMID:39806423], PINK1 [PMID:41286926], and ENO1 [PMID:40536557]—thereby controlling tumor signaling, lysosomal biogenesis, mitophagy, and stem-cell senescence. It also acts as a deacetylase-independent scaffold, engaging the TRAF6-TAK1 complex and IKKα/β to drive MAPK/NF-κB inflammatory signaling [PMID:35871708, PMID:39049738], and in macrophages serves as a bifunctional immunometabolic switch coupling TLR4 signals to enzyme-independent glycolytic reprogramming and enzyme-dependent inflammatory cytokine and pentose-phosphate-pathway responses [PMID:36649417, PMID:34811804]. HDAC7 protein abundance is set by competing ubiquitin and SUMO machinery: USP10 stabilizes it by deubiquitination [PMID:35277183], CBX4 and FBXW7 promote its degradation [PMID:28283560], SIK1 phosphorylates and stabilizes cytoplasmic HDAC7 to drive cardiac hypertrophy [PMID:32106109], and TRIM28-mediated sumoylation elevates its levels [PMID:39629136].","teleology":[{"year":2001,"claim":"Established the founding mechanism of HDAC7 as a MEF2 corepressor and revealed that its repressive output is structurally separable from its catalytic domain.","evidence":"GST pulldown, Co-IP, reporter assays and domain mapping in mammalian cells","pmids":["11279209","11466315"],"confidence":"High","gaps":["Did not resolve how nuclear export is triggered physiologically","In vitro deacetylase activity of HDAC7 itself not quantified"]},{"year":2003,"claim":"Placed HDAC7-MEF2 repression in a physiological circuit by showing it gates Nur77-dependent thymocyte apoptosis, with nuclear export as the regulatory event.","evidence":"Reporter assays, triple-serine mutant, RNAi and thymocyte apoptosis assays","pmids":["12753745"],"confidence":"High","gaps":["Kinase responsible for the export-driving phosphorylation not identified","Opposing phosphatase unknown"]},{"year":2004,"claim":"Identified PKD1 as the TCR-activated kinase that phosphorylates HDAC7 N-terminal serines to drive nuclear export, defining the signal-to-localization link.","evidence":"In vitro kinase assay, site-directed mutagenesis, dominant-negative PKD1, microscopy","pmids":["15623513"],"confidence":"High","gaps":["Did not identify the export receptor/14-3-3 machinery","Reversal mechanism not addressed"]},{"year":2007,"claim":"Closed the regulatory loop by identifying PP1β/MYPT1 as the phosphatase that dephosphorylates HDAC7 to restore nuclear repression, with ROCK upstream.","evidence":"Co-IP, phosphatase assays, siRNA and thymocyte apoptosis readouts","pmids":["17369396"],"confidence":"High","gaps":["Direct versus indirect dephosphorylation not fully dissected","Other phosphatases not excluded"]},{"year":2008,"claim":"Defined the class IIa-specific active-site architecture and confirmed low but genuine intrinsic deacetylase activity, explaining why HDAC7 relies on partner enzymes.","evidence":"X-ray crystallography of the catalytic domain with inhibitor complexes plus in vitro activity assay","pmids":["18285338"],"confidence":"High","gaps":["Physiological substrate of the isolated catalytic domain not defined","Full-length and complex-bound structures not solved"]},{"year":2008,"claim":"Generalized the PKD1-HDAC7 shuttling module beyond immunity to VEGF-driven angiogenic gene expression in endothelial cells.","evidence":"PLCγ/PKC/PKD1 pathway dissection, phosphomutants, dominant-negatives, tube formation and sprouting assays","pmids":["18617643"],"confidence":"High","gaps":["Direct transcriptional targets at MT1-MMP/MMP10 loci not mapped by ChIP","Role of catalytic activity not isolated"]},{"year":2013,"claim":"Extended MEF2 corepression to lineage commitment, showing HDAC7-MEF2C represses myeloid genes to enforce B-lymphoid identity.","evidence":"Co-IP, ChIP, microarray and functional transdifferentiation assays in pre-B cells","pmids":["23696748"],"confidence":"High","gaps":["Catalytic dependence of repression not resolved","Recruitment to specific enhancers versus promoters not separated"]},{"year":2016,"claim":"Demonstrated in vivo that HDAC7-MEF2C occupancy enforces early B cell development and prevents lineage promiscuity, linking loss to altered active histone marks.","evidence":"Conditional knockout mouse, ChIP-seq, Co-IP and flow cytometry","pmids":["27810920"],"confidence":"High","gaps":["Mechanism connecting HDAC7 loss to gain of active marks not biochemically defined","Catalytic requirement not tested in vivo"]},{"year":2017,"claim":"Identified non-histone substrate deacetylation as a distinct HDAC7 mechanism by showing it directly deacetylates STAT3 to restrain its activation in lung tumors.","evidence":"Co-IP, pulldown, deacetylation assay, Hdac7+/-/K-Ras mouse model with dominant-negative STAT3 rescue","pmids":["29126425"],"confidence":"Medium","gaps":["Acetyl-lysine site on STAT3 not mapped","Direct enzyme-substrate kinetics not established"]},{"year":2020,"claim":"Revealed a cytoplasmic, MEF2-independent role: SIK1 phosphorylates and stabilizes HDAC7 as a prohypertrophic effector driving cardiomyocyte remodeling.","evidence":"Gain/loss-of-function in rodents and hiPSC-cardiomyocytes, kinase assay, Co-IP","pmids":["32106109"],"confidence":"High","gaps":["Cytoplasmic effector mechanism (substrate or scaffold) not fully defined","Phosphosite mediating stabilization not specified here"]},{"year":2022,"claim":"Connected HDAC7 to Wnt signaling and its own stability control, showing it deacetylates β-catenin at Lys49 to promote nuclear translocation while USP10 stabilizes HDAC7.","evidence":"Co-IP, deacetylation/phosphorylation readouts, lentiviral knockdown and xenograft","pmids":["35277183","30691485"],"confidence":"Medium","gaps":["Direct versus indirect effect on β-catenin Ser45 phosphorylation not resolved","Reciprocal deubiquitination kinetics not quantified"]},{"year":2022,"claim":"Defined deacetylase-independent scaffolding of NF-κB signaling, with HDAC7 deacetylating and activating IKKα/β to drive astrocyte inflammation.","evidence":"Co-IP, AAV overexpression, siRNA, pharmacological inhibition and behavioral assays","pmids":["35871708"],"confidence":"Medium","gaps":["IKK acetyl-lysine sites not mapped","Distinction between scaffold and catalytic contribution incomplete"]},{"year":2023,"claim":"Resolved HDAC7 as a bifunctional immunometabolic switch in macrophages, separating enzyme-independent glycolytic reprogramming from enzyme-dependent inflammatory and antimicrobial outputs.","evidence":"Hdac7-deficient macrophages with enzyme-dead reconstitution, ECAR, metabolomics, cytokine and bacterial killing assays","pmids":["36649417","34811804"],"confidence":"High","gaps":["Molecular target of the enzyme-independent glycolytic function not identified","Direct metabolic-enzyme substrates of HDAC7 not defined"]},{"year":2024,"claim":"Identified the TRAF6-TAK1 complex as a direct deacetylase-independent partner coupling HDAC7 to TLR4-driven MAPK/NF-κB cytokine production, validated by selective PROTAC degradation.","evidence":"PROTAC degrader B4, Co-IP, cytokine assays and mouse LPS model","pmids":["39049738"],"confidence":"Medium","gaps":["Stoichiometry and binding interface with TRAF6-TAK1 not defined","Single lab, no reciprocal structural validation"]},{"year":2025,"claim":"Expanded the non-histone substrate repertoire into proteostasis and organelle quality control, with HDAC7 deacetylating TFEB (K310), PINK1 and ENO1 to suppress lysosomal biogenesis, mitophagy and metabolism.","evidence":"Co-IP, mass spectrometry, site mutagenesis, AAV genetic models and pharmacological inhibition","pmids":["39806423","41286926","40536557"],"confidence":"Medium","gaps":["Direct enzymatic specificity versus complex-dependent activity not separated for each substrate","In vitro reconstitution of deacetylation reactions not shown"]},{"year":null,"claim":"It remains unresolved how a single low-activity catalytic domain achieves the broad non-histone substrate selectivity observed, and which substrates require complex-assembled versus intrinsic HDAC7 activity.","evidence":"No reconstituted enzyme-substrate study in the corpus reconciles intrinsic catalytic weakness with the documented deacetylation events","pmids":[],"confidence":"Medium","gaps":["No structure of HDAC7 bound to a non-histone substrate","Substrate-recognition determinants undefined","Quantitative contribution of HDAC3-complex activity to each reported substrate unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,19,20,18,40,41,42,47]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,3,13,23,9,39]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[34]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[30,29]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,4,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,4,14,25,27]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,13,23,36]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[31,32,30,35,36]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[29,30,20,21]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[38,37,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[31,33]}],"complexes":["SMRT/N-CoR-HDAC3 corepressor complex"],"partners":["MEF2C","HDAC3","PKD1","MYPT1","CTNNB1","STAT3","TRAF6","IKBKB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WUI4","full_name":"Histone deacetylase 7","aliases":["Histone deacetylase 7A","HD7a","Protein deacetylase HDAC7"],"length_aa":952,"mass_kda":102.9,"function":"Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (By similarity). 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). Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C (By similarity). During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene (PubMed:12239305). Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565). Serves as a corepressor of RARA, causing its deacetylation and inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758). Also acetylates non-histone proteins, such as ALKBH5 (PubMed:37369679)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8WUI4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HDAC7","classification":"Not Classified","n_dependent_lines":60,"n_total_lines":1208,"dependency_fraction":0.04966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HDAC7","total_profiled":1310},"omim":[{"mim_id":"614312","title":"ZINC FINGER MYND-CONTAINING PROTEIN 15; ZMYND15","url":"https://www.omim.org/entry/614312"},{"mim_id":"608544","title":"HISTONE DEACETYLASE 10; HDAC10","url":"https://www.omim.org/entry/608544"},{"mim_id":"606542","title":"HISTONE DEACETYLASE 7A; HDAC7A","url":"https://www.omim.org/entry/606542"},{"mim_id":"605314","title":"HISTONE DEACETYLASE 4; HDAC4","url":"https://www.omim.org/entry/605314"},{"mim_id":"300688","title":"BCL6 COREPRESSOR-LIKE 1; BCORL1","url":"https://www.omim.org/entry/300688"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HDAC7"},"hgnc":{"alias_symbol":["DKFZP586J0917"],"prev_symbol":["HDAC7A"]},"alphafold":{"accession":"Q8WUI4","domains":[{"cath_id":"3.40.800.20","chopping":"521-535_542-912","consensus_level":"medium","plddt":93.0396,"start":521,"end":912}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUI4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUI4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WUI4-F1-predicted_aligned_error_v6.png","plddt_mean":62.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HDAC7","jax_strain_url":"https://www.jax.org/strain/search?query=HDAC7"},"sequence":{"accession":"Q8WUI4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WUI4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WUI4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WUI4"}},"corpus_meta":[{"pmid":"18285338","id":"PMC_18285338","title":"Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18285338","citation_count":226,"is_preprint":false},{"pmid":"11466315","id":"PMC_11466315","title":"Human HDAC7 histone deacetylase activity is associated with HDAC3 in vivo.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11466315","citation_count":193,"is_preprint":false},{"pmid":"12753745","id":"PMC_12753745","title":"HDAC7, a thymus-specific class II histone deacetylase, regulates Nur77 transcription and TCR-mediated apoptosis.","date":"2003","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12753745","citation_count":190,"is_preprint":false},{"pmid":"11279209","id":"PMC_11279209","title":"A dynamic role for HDAC7 in MEF2-mediated muscle differentiation.","date":"2001","source":"The Journal of biological 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deacetylase activity inhibitable by known HDAC inhibitors.\",\n      \"method\": \"X-ray crystallography; in vitro deacetylase activity assay; inhibitor binding studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation (activity assay + inhibitor complexes) in a single rigorous study\",\n      \"pmids\": [\"18285338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HDAC7 deacetylase activity in the cell nucleus depends on its interaction with the class I HDAC3; cytoplasmic HDAC7 not bound to HDAC3 is enzymatically inactive. The corepressors SMRT and N-CoR serve as mediators by binding class II HDACs and HDAC3 via two distinct repressor domains.\",\n      \"method\": \"Co-immunoprecipitation; fractionation; functional deacetylase assays; domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with fractionation and activity assays, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"11466315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HDAC7 directly interacts with MEF2 proteins (MEF2-A, -C, -D) via its N-terminal 121 amino acids (repression domain 1), and the MADS domain of MEF2 mediates this interaction; HDAC7-mediated MEF2 repression is independent of the C-terminal deacetylase domain. HDAC7 also interacts with CtBP and other class I/II HDACs. During myogenesis induced by serum withdrawal, HDAC7 translocates from nucleus to cytoplasm.\",\n      \"method\": \"GST pulldown; co-immunoprecipitation; reporter assays; domain-deletion mapping; fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (GST pulldown + Co-IP + domain mapping + live-cell localization) in a single rigorous study\",\n      \"pmids\": [\"11279209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HDAC7 represses Nur77 transcription via MEF2D in CD4+CD8+ double-positive thymocytes. TCR activation triggers nuclear export of HDAC7, leading to Nur77 derepression and apoptosis. A triple serine mutant (S155A/S318A/S448A) of HDAC7 is not exported and suppresses TCR-mediated apoptosis; RNAi knockdown of HDAC7 increases TCR-mediated apoptosis.\",\n      \"method\": \"Reporter assays; site-directed mutagenesis; RNAi; fluorescence microscopy; thymocyte apoptosis assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis combined with RNAi and functional phenotype, replicated by multiple approaches in one study\",\n      \"pmids\": [\"12753745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Protein kinase D1 (PKD1) is activated after TCR engagement, physically interacts with HDAC7, and phosphorylates three serines (Ser155, Ser318, Ser448) at its N-terminus, causing nuclear export of HDAC7 via a calcium-independent pathway. Kinase-inactive PKD1 blocked HDAC7 shuttling. PKD1 activation leads to Nur77 transcriptional activation via MEF2 binding sites.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase assay; site-directed mutagenesis; dominant-negative PKD1; fluorescence microscopy; reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay + mutagenesis + dominant-negative rescue + nuclear export phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"15623513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Protein phosphatase 1β (PP1β) and myosin phosphatase targeting subunit 1 (MYPT1) associate with HDAC7 in thymocytes and dephosphorylate HDAC7, promoting its nuclear localization and repression of Nur77, thereby inhibiting apoptosis in CD4+CD8+ thymocytes. ROCK signaling pathway operates upstream via MYPT1.\",\n      \"method\": \"Co-immunoprecipitation; phosphatase assays; siRNA knockdown; fluorescence microscopy; apoptosis assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical phosphatase assay combined with Co-IP and functional apoptosis readout, multiple methods in a focused study\",\n      \"pmids\": [\"17369396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HDAC7 localizes to the mitochondrial inner membrane space of prostate epithelial cells and undergoes cytoplasmic relocalization upon initiation of apoptosis.\",\n      \"method\": \"Subcellular fractionation; immunofluorescence microscopy; mitochondrial isolation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment with fractionation, single lab, single study\",\n      \"pmids\": [\"15364908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"HDAC7 interacts with the endothelin receptor A (ETA) as determined by yeast two-hybrid, GST pulldown, and co-immunoprecipitation. ET-1 stimulation causes internalization of ETA to a perinuclear compartment and simultaneous nuclear export of HDAC7 to the same compartment.\",\n      \"method\": \"Yeast two-hybrid; GST pulldown; co-immunoprecipitation; fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal interaction methods, single lab\",\n      \"pmids\": [\"11262386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VEGF stimulates PKD1-dependent phosphorylation of HDAC7 at Ser178, Ser344, and Ser479 via a PLCγ/PKC/PKD1 pathway, causing cytoplasmic accumulation of HDAC7. A phosphorylation-deficient HDAC7 mutant inhibited VEGF-induced expression of MT1-MMP and MMP10 and suppressed endothelial cell migration, tube formation, and microvessel sprouting.\",\n      \"method\": \"Pharmacological inhibitors; siRNA; dominant-negative adenoviruses; western blotting; tube formation/migration assays; phosphomutant constructs\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (dominant-negative + siRNA + pharmacological) with functional in vitro and ex vivo readouts\",\n      \"pmids\": [\"18617643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HDAC7 protects neurons from apoptosis by directly associating with the c-jun gene promoter and inhibiting c-jun transcription. This neuroprotection is independent of HDAC7's catalytic domain and cannot be blocked by chemical HDAC inhibitors.\",\n      \"method\": \"shRNA knockdown; forced expression; chromatin immunoprecipitation (ChIP); catalytic domain mutants; neuronal apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + domain-deletion mutants + RNAi/overexpression with phenotypic readout, single lab\",\n      \"pmids\": [\"21118817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HDAC7 interacts with the transcription factor Mitf in RAW 264 osteoclast precursor cells and represses Mitf transcriptional activity; either the amino- or carboxyl-terminus of HDAC7 is sufficient for this repression. Knockdown of HDAC7 accelerates osteoclast differentiation, and the repression is insensitive to trichostatin A, indicating a deacetylation-independent mechanism.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; reporter assays; domain-deletion analysis; osteoclast differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + domain mapping + functional differentiation assay, single lab\",\n      \"pmids\": [\"21324898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HDAC7 undergoes alternative splicing during ES cell differentiation toward smooth muscle cells (SMCs); the spliced form modulates the SRF-myocardin complex to promote SMC differentiation. PDGF enhanced this splicing and SMC differentiation.\",\n      \"method\": \"Western blot; immunofluorescence; overexpression in ES cells; SM22-LacZ transgenic embryonic cell culture; co-immunoprecipitation of SRF-myocardin complex\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with molecular (SRF-myocardin complex modulation) and phenotypic (SMC marker expression) readouts, single lab\",\n      \"pmids\": [\"19174469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Sp1 binds the HDAC7 promoter at a minimal PDGF-BB-responsive element (−343 to −292 bp) containing a Sp1 site, activating HDAC7 transcription during SMC differentiation. Mutation of the Sp1 site abolishes PDGF-BB-induced HDAC7 promoter activity, and Sp1 knockdown abrogates PDGF-BB-induced HDAC7 upregulation and SMC gene expression.\",\n      \"method\": \"Promoter deletion analysis; luciferase reporter assay; site-directed mutagenesis; ChIP; siRNA knockdown; overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mapping with mutagenesis and ChIP, single lab\",\n      \"pmids\": [\"20889501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In pre-B cells, HDAC7 interacts with transcription factor MEF2C and is recruited to MEF2 binding sites at promoters of macrophage-specific genes to repress them. Re-expression of HDAC7 during pre-B to macrophage transdifferentiation blocks induction of myeloid genes and suppresses phagocytosis and cytokine responses.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); microarray; overexpression/knockdown; phagocytosis and cytokine assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP + ChIP + functional phenotype with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23696748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HDAC7 binds β-catenin in proliferating chondrocytes and suppresses β-catenin transcriptional activity and cyclin D1 expression. Stimulation of chondrocyte maturation causes HDAC7 translocation to the cytoplasm where it is degraded by the proteasome, releasing β-catenin to the nucleus. Postnatal conditional Hdac7 deletion in chondrocytes expands the proliferative zone.\",\n      \"method\": \"Co-immunoprecipitation; conditional knockout (tamoxifen-inducible Cre); adenoviral Cre deletion; nuclear/cytoplasmic fractionation; reporter assays; histology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP + conditional KO model + fractionation + functional proliferation assay, multiple orthogonal methods\",\n      \"pmids\": [\"25389289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HDAC7 overexpression suppresses and HDAC7 deletion enhances osteoclastogenesis. Mechanistically, HDAC7 attenuates β-catenin function and cyclin D1 expression to reduce precursor proliferation; upon RANKL signaling, HDAC7 suppresses NFATc1 and prevents β-catenin downregulation to block differentiation. Conditional HDAC7 knockout in osteoclast lineage reduces bone mass due to elevated bone resorption.\",\n      \"method\": \"Conditional knockout mice; bone marrow differentiation assays; overexpression; western blot; reporter assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo + in vitro gain-/loss-of-function with molecular mechanism, multiple methods\",\n      \"pmids\": [\"23204328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PP2A-Bα phosphatase controls HDAC7 activity; loss of PP2A-Bα abrogates HDAC7 transcriptional repression, leading to increased ArgBP2 expression, RhoA hyperactivation, and disruption of endothelial cytoskeletal dynamics and vascular lumen formation. This PP2A-Bα/HDAC7/ArgBP2 axis maintains vascular lumens.\",\n      \"method\": \"siRNA knockdown; zebrafish morpholino; reporter assays; western blot; RhoA activity assay; tubulogenesis assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell and in vivo (zebrafish) experiments with pathway epistasis, single lab\",\n      \"pmids\": [\"23955003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HDAC7 silencing in HUVECs results in H3 histone acetylation at the AKAP12 promoter, increasing AKAP12 mRNA/protein levels; elevated AKAP12 mediates PKC-dependent STAT3 phosphorylation. AKAP12 upregulation following HDAC7 knockdown is responsible for inhibition of endothelial migration and tube formation.\",\n      \"method\": \"siRNA; proteomics; ChIP; western blot; migration and tube formation assays\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + proteomics + functional rescue assays, single lab\",\n      \"pmids\": [\"22584896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Deacetylation of HSP70 at K246 by HDAC1 and HDAC7 promotes cancer cell survival and therapy resistance by inhibiting autophagic cell death. miR-34a targets HDAC1 and HDAC7 to suppress this deacetylation.\",\n      \"method\": \"miRNA target validation (luciferase); site-directed mutagenesis of HSP70 K246; co-immunoprecipitation; western blot; cell survival and autophagy assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deacetylation site mutagenesis combined with functional autophagy and survival assays, single lab\",\n      \"pmids\": [\"25173798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC7 directly interacts with and deacetylates STAT3, reducing STAT3 acetylation and tyrosine phosphorylation. Loss of HDAC7 in mouse lung tumors or human cancer cell lines results in enhanced STAT3 acetylation/activation. The tumor-promoting effect of Hdac7 in K-Ras mice was reversed by dominant-negative Stat3.\",\n      \"method\": \"Co-immunoprecipitation; pulldown assay; western blot; in vivo mouse model (Hdac7+/-/K-Ras); dominant-negative rescue; deacetylation assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown + Co-IP + genetic epistasis (dnStat3 rescue), single lab\",\n      \"pmids\": [\"29126425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC7 deacetylates β-catenin at Lys49, reducing its phosphorylation at Ser45, which promotes β-catenin nuclear translocation and TCF4-dependent activation of FGF18. Deubiquitinase USP10 interacts with HDAC7 and stabilizes it by preventing its ubiquitin-proteasome degradation.\",\n      \"method\": \"Co-immunoprecipitation; western blot; lentiviral overexpression/knockdown; in vivo xenograft; luciferase reporter\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deacetylation and phosphorylation readouts + in vivo rescue, single lab\",\n      \"pmids\": [\"35277183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZNF326 activates HDAC7 transcription by binding to the HDAC7 promoter via its zinc-finger and transcriptional activation domains. Upregulated HDAC7 then deacetylates β-catenin at Lys49, decreasing its phosphorylation at Ser45, promoting β-catenin nuclear import and TCF4 binding to activate Wnt target genes.\",\n      \"method\": \"ChIP; dual-luciferase assay; GST pulldown; co-immunoprecipitation; western blot; site-directed mutagenesis\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + dual-luciferase + Co-IP + mutagenesis, single lab\",\n      \"pmids\": [\"30691485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ectopically expressed HDAC7 in leukemia/lymphoma cells localizes to the nucleus, interacts with MEF2C, HDAC3, and SMRT to downregulate c-Myc and induce apoptosis. Both the MEF2C-interaction domain and the catalytic domain of HDAC7 are required for reduced cell viability.\",\n      \"method\": \"Co-immunoprecipitation; overexpression; xenograft model; reporter assay; domain-deletion analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + domain mapping + in vivo xenograft, single lab\",\n      \"pmids\": [\"25675295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In B cell progenitors, HDAC7 interacts with MEF2C and is recruited to promoters and enhancers of myeloid and T-lymphocyte genes; conditional HDAC7 knockout blocks early B cell development, causes lymphopenia, and leads to pro-B cell lineage promiscuity. HDAC7 absence leads to increased enrichment of active histone marks at target gene loci.\",\n      \"method\": \"Conditional knockout mouse model; ChIP-seq; co-immunoprecipitation; flow cytometry; gene expression analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo + ChIP-seq + Co-IP with defined developmental phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"27810920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tonic LAT-mediated TCR signals constitutively export HDAC7 from the nucleus of naive CD4+ T cells, maintaining expression of HDAC7 target genes Nur77 and Irf4. Without tonic LAT signals, HDAC7 is nuclear, repressing Nur77 and Irf4.\",\n      \"method\": \"Genetic (LAT-deficient mice); nuclear export assays; gene expression profiling; functional T cell assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic LAT deficiency + target gene regulation, single lab\",\n      \"pmids\": [\"28538176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIK1 phosphorylates and stabilizes HDAC7 protein during cardiac stress; this HDAC7 stabilization is required for pathologic cardiomyocyte remodeling and c-Myc induction. HDAC7 acts as a prohypertrophic effector in the cytoplasm of cardiomyocytes, representing a functional departure from canonical nuclear MEF2 corepressor activity.\",\n      \"method\": \"Gain- and loss-of-function in rodent models and hiPSC-derived cardiomyocytes; western blot; co-immunoprecipitation; kinase assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — kinase-substrate relationship (SIK1→HDAC7 phosphorylation/stabilization) + in vivo rodent model + iPSC model, multiple orthogonal methods\",\n      \"pmids\": [\"32106109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nuclear-retained HDAC7 mutants inhibit C2C12 myocyte differentiation and reduce MHC and myogenin expression; this inhibition is partially relieved by a mutation disrupting HDAC7-MEF2 interaction. Phosphorylated HDAC7 (pS178) colocalizes with actin filaments in myocytes, and nuclear-retained HDAC7 causes defects in myocyte migration.\",\n      \"method\": \"Stable expression of HDAC7 mutants; immunofluorescence; phalloidin staining; differentiation and migration assays; site-directed mutagenesis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis + localization + functional differentiation/migration assays, single lab\",\n      \"pmids\": [\"20621129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HDAC7 acts as a corepressor of androgen receptor (AR); in absence of AR ligand, HDAC7 is cytoplasmic, but androgen-occupied AR induces nuclear transfer of HDAC7. The deacetylase activity of HDAC7 is partly dispensable for AR repression, and PML-3 overexpression sequesters HDAC7 to PML-3 domains to relieve HDAC7-mediated AR repression.\",\n      \"method\": \"Fluorescence microscopy; co-immunoprecipitation; reporter assays; domain mutagenesis; PML-3 overexpression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization + functional reporter + domain analysis, single lab\",\n      \"pmids\": [\"16860317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HDAC7 is ubiquitinated by the E3 ligase CBX4 in hippocampal neurons after contextual fear conditioning (CFC) training, leading to HDAC7 ubiquitin-dependent degradation. Decreased HDAC7 levels correlate with increased Nur77 expression, which modulates CFC memory formation.\",\n      \"method\": \"Immunoprecipitation; western blot; hippocampal injection of siRNA; fear conditioning behavioral assay; ubiquitination assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — E3 ligase identified by IP + ubiquitination assay + behavioral phenotype, single lab\",\n      \"pmids\": [\"28283560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC7 interacts with IKKα and IKKβ to promote their deacetylation and activation, leading to NF-κB activation in astrocytes. Astrocyte-specific HDAC7 overexpression induces NF-κB-driven pro-inflammatory gene expression and anxiety-like behaviors in mice.\",\n      \"method\": \"Co-immunoprecipitation; western blot; AAV-mediated overexpression; siRNA knockdown; pharmacological inhibition; behavioral assays\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + in vivo overexpression with behavioral and molecular phenotypes, single lab\",\n      \"pmids\": [\"35871708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Using a selective PROTAC degrader (B4), HDAC7 was shown to have a deacetylase-independent proinflammatory role in macrophages; HDAC7 directly interacts with the TRAF6-TAK1 complex, activating MAPK/NF-κB signaling downstream of TLR4 and driving production of specific proinflammatory cytokines.\",\n      \"method\": \"PROTAC-mediated targeted degradation; co-immunoprecipitation; western blot; cytokine assays; mouse LPS model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PROTAC degradation as selective tool + Co-IP for complex, single lab\",\n      \"pmids\": [\"39049738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In macrophages, HDAC7 functions as a metabolic switch: LPS (distal danger) triggers HDAC7-dependent glycolysis and IL-1β production, while bacterial challenge (proximal danger) induces HDAC7-mediated pentose phosphate pathway engagement via 6PGD, generating NADPH/ROS for antimicrobial killing and D-ribulose-5-phosphate (RL5P) with antimicrobial and immunomodulatory activities. Hdac7 enzymatic activity is required for IL-1β production but acts enzyme-independently for metabolic reprogramming.\",\n      \"method\": \"Hdac7-deficient macrophages; enzyme-dead mutant reconstitution; extracellular acidification rate (ECAR) assay; cytokine assays; metabolomics; UPEC killing assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzyme-dead mutant reconstitution + metabolomics + multiple functional readouts, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36649417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TLR4/LPS-activated HDAC7 enzymatic activity in macrophages is required for production of specific inflammatory mediators (IL-1β, CCL2), while its metabolic glycolysis-reprogramming function is enzyme-independent. TLR-inducible class IIa HDAC activity is absent in Hdac7-deficient macrophages and requires MyD88 (except for TLR3 agonist).\",\n      \"method\": \"Hdac7-deficient mouse macrophages; enzyme-dead mutant reconstitution; ECAR assay; cytokine assays; MyD88-deficient cells\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzyme-dead mutant reconstitution + knockout macrophages + metabolic assays, single lab\",\n      \"pmids\": [\"34811804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TGF-β signaling, in concert with HDAC7, suppresses expression of TCA cycle enzymes in renal cell carcinoma (RCC) by repressing PGC-1α. Pharmacologic inhibition of TGF-β restores TCA cycle enzyme expression and suppresses tumor growth in an orthotopic RCC model.\",\n      \"method\": \"Proteomics; gene expression analysis; PGC-1α overexpression; TGF-β inhibition in orthotopic model; metabolic flux analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with mechanistic rescue + metabolomics, single lab\",\n      \"pmids\": [\"34609963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC4, -5, and -7 dissociate from corepressor NCoR in the presence of acetyllysine-containing peptides (consistent with reader function). Mutation of a critical AR acetylation site regulated AR transcriptional activation through an HDAC7-NCoR-HDAC3 dissociation mechanism, providing evidence that HDAC7 can function as an epigenetic acetyllysine reader.\",\n      \"method\": \"NCoR dissociation assay with acetyllysine peptides; AR mutagenesis; reporter assay; co-immunoprecipitation\",\n      \"journal\": \"Cell chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acetyllysine peptide competition assay + mutagenesis + functional reporter, single lab\",\n      \"pmids\": [\"35709754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Tregs, wild-type HDAC7 regulates genes essential for Foxp3+ Treg function. Treg-specific conditional hemizygous deletion of HDAC7 increases EAE severity. The MS-protective HDAC7 R166H (R150H in mouse) variant confers enhanced Treg suppressive capacity in vitro and decreases EAE severity in vivo via transcriptomic alterations in brain-infiltrating Tregs.\",\n      \"method\": \"Treg-specific conditional knockout; knock-in mouse model; EAE model; in vitro Treg suppression assay; single-cell RNA-seq; transcriptomic analyses\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO + knock-in variant mouse + scRNA-seq + in vitro and in vivo functional assays, multiple orthogonal methods\",\n      \"pmids\": [\"36516268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Th17 cell differentiation, HDAC7 collaborates with transcription factor Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators (including Il2). Hdac7 is dispensable in other Th subtypes. Genetic or pharmacological inhibition of Hdac4/7 mitigates Th17-mediated intestinal inflammation in a colitis model.\",\n      \"method\": \"Conditional knockout (Hdac7 and Hdac4 in T cells); co-immunoprecipitation; ChIP; colitis mouse model; cytokine assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO + Co-IP + ChIP + in vivo colitis model, multiple orthogonal methods\",\n      \"pmids\": [\"38657041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC7 deficiency in pro-B cells induces TET2 expression, promoting DNA 5-hydroxymethylation and global chromatin de-condensation. HDAC7 loss also results in aberrant expression of microRNAs and LINE-1 transposable elements, revealing an HDAC7-TET2 epigenetic axis essential for early B cell development.\",\n      \"method\": \"Conditional knockout; 5-hmC profiling; histone mark analysis; microRNA/LINE-1 expression; chromatin conformation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple epigenomic readouts, single lab\",\n      \"pmids\": [\"35904805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In breast cancer stem-like cells, HDAC7 binds near transcription start sites and super-enhancers of oncogenes (c-MYC, CD44, etc.) and contributes to H3K27ac levels and transcriptional activation at these loci. HDAC1 or HDAC3 inhibition/knockdown leads to HDAC7 downregulation associated with decreased H3K27ac at super-enhancers.\",\n      \"method\": \"ChIP-seq; siRNA knockdown; western blot; gene expression analysis in CSC vs. non-CSC models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with knockdown experiments, single lab\",\n      \"pmids\": [\"31375747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HDAC7 silencing in cancer cells causes G1/S arrest by suppressing c-Myc expression and increasing p21/p27. HDAC7 directly binds the c-Myc gene promoter, and its silencing decreases histone H3/H4 acetylation and RNA polymerase II occupancy at the c-Myc locus. Ectopic c-Myc expression reverses G1/S arrest and cellular senescence induced by HDAC7 knockdown.\",\n      \"method\": \"siRNA knockdown; ChIP; cell cycle analysis; overexpression rescue; western blot\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + functional rescue, single lab\",\n      \"pmids\": [\"21120446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC7 deacetylates FOXP1 in mesenchymal stem cells (MSCs); FOXP1 and HDAC7 cooperatively sustain MSC self-renewal and attenuate cellular senescence. Mutation of the FOXP1 acetylation site T172G (homologous to human T176G) profoundly augments MSC expansion capacity.\",\n      \"method\": \"Mass spectrometry; single and double knockout mice; site-directed mutagenesis (T176G); hESC-derived MSC overexpression; proliferation/senescence assays\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification of acetylation site + mutagenesis + KO model, single lab\",\n      \"pmids\": [\"37507770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC7 deacetylates TFEB at K310 in astrocytes, preventing TFEB nuclear translocation and reducing lysosomal biogenesis and tau clearance. Genetic or pharmacological inhibition of HDAC7 restores TFEB acetylation, enhances lysosomal biogenesis, and improves tau clearance and cognitive function in PS19 mice.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry; immunoprecipitation; luciferase reporter; AAV-shRNA in PS19 mice; tau uptake/degradation assays; pharmacological inhibition (TMP195)\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — identification of deacetylation site by MS + mutagenesis + in vivo AAV genetic model + pharmacological validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"39806423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC7 deacetylates PINK1, suppressing phosphorylation of Parkin at Ser65 and inhibiting TOMM20/40 recruitment, thereby impairing PINK1-Parkin-dependent mitophagy in astrocytes. Astrocyte-specific HDAC7 knockout or pharmacological inhibition restores mitophagy, ATP release, and reverses depressive-like behaviors in mice.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry; western blot; AAV-mediated astrocyte-specific KO; pharmacological inhibition; mitophagy assays; behavioral assays\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deacetylation substrate identified by Co-IP/MS + in vivo KO + functional mitophagy assay, single lab\",\n      \"pmids\": [\"41286926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC7 interacts with HDAC1, HDAC2, and HDAC7 (itself) via pulldown and co-immunoprecipitation, mediating transcriptional repression by Holocarboxylase synthetase (HCS) in a deacetylase/biotin-independent manner.\",\n      \"method\": \"In vitro pulldown; co-immunoprecipitation; GAL4-luciferase reporter assay\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown, context is HCS biology, single lab\",\n      \"pmids\": [\"24239178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC7 promotes β-catenin deacetylation, phosphorylation modulation, and nuclear translocation in SCLC cells, forming a β-catenin/TCF/LEF1 complex that activates c-Myc and XPO1 transcription. This HDAC7/β-catenin/c-Myc/XPO1 axis drives SCLC proliferation.\",\n      \"method\": \"RNA sequencing; western blot; co-immunoprecipitation; xenograft and organoid models; ChIP\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ChIP + in vivo model, single lab\",\n      \"pmids\": [\"39887933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM28-mediated sumoylation of HDAC7 upregulates its protein levels; sumoylated HDAC7 mediates H3K27 deacetylation to inhibit SOX8, which facilitates JUN-dependent LGALS3 transcription to promote GBM mesenchymal transition and macrophage M2 polarization.\",\n      \"method\": \"Mass spectrum; RNA immunoprecipitation; co-immunoprecipitation; ChIP; gain/loss-of-function assays in vitro and in vivo\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + ChIP + mass spec for PTM identification, single lab\",\n      \"pmids\": [\"39629136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FBXW7 interacts with HDAC7 via immunoprecipitation and promotes HDAC7 ubiquitination in glioblastoma cells; HDAC7 overexpression blocks FBXW7-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; overexpression rescue; western blot\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP + ubiquitination assay, single lab\",\n      \"pmids\": [\"34288252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC7 reduces the acetylation level of Enolase 1 (ENO1), thereby enhancing malignant proliferation of ARID1A-deficient HCC cells. The transcription factor PU.1 (induced by ARID1A loss) drives HDAC7 transcription. Targeting HDAC7 inhibited ARID1A-deficient tumor xenograft growth.\",\n      \"method\": \"RNA-seq; ChIP; luciferase reporter; protein IP + mass spectrometry (identifying ENO1 as substrate); xenograft; western blot\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by IP/MS + ChIP/luciferase for transcriptional regulation + in vivo xenograft, single lab\",\n      \"pmids\": [\"40536557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ROCK signaling via MYPT1 (myosin phosphatase) controls nucleocytoplasmic shuttling of HDAC7; inhibition of the ROCK pathway in iPSCs leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1.\",\n      \"method\": \"iPSC model; ROCK inhibition; immunofluorescence microscopy; reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment with functional readout, single lab\",\n      \"pmids\": [\"25511694\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HDAC7 is a class IIa histone deacetylase with cryptically low intrinsic catalytic activity (due to a non-canonical active site) whose primary enzymatic activity in the nucleus depends on assembly with HDAC3/SMRT/N-CoR complexes; it functions as a transcriptional corepressor of MEF2 family transcription factors (via its N-terminal repression domain) and, in thymocytes, is regulated by PKD1-mediated phosphorylation of Ser155/Ser318/Ser448 to drive nuclear export and derepress Nur77/apoptosis, with myosin phosphatase (PP1β/MYPT1) acting as the opposing phosphatase to restore nuclear localization; beyond MEF2/Nur77 regulation, HDAC7 deacetylates non-histone substrates including STAT3, β-catenin (Lys49), HSP70 (K246), FOXP1, TFEB (K310), PINK1, and ENO1, and it acts as a deacetylase-independent scaffold interacting with TRAF6-TAK1, IKK, and β-catenin to regulate NF-κB and Wnt signaling; SIK1 phosphorylates and stabilizes cytoplasmic HDAC7 to drive cardiac hypertrophy, USP10 stabilizes HDAC7 via deubiquitination, and CBX4/FBXW7 promote its ubiquitin-dependent degradation; in macrophages, HDAC7 acts as a bifunctional immunometabolic switch coupling TLR4 signals to glycolysis (enzyme-independent) and to antimicrobial pentose phosphate pathway responses and inflammatory cytokine production (enzyme-dependent).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HDAC7 is a class IIa histone deacetylase that functions principally as a signal-responsive transcriptional corepressor, with its biological output dictated by phosphorylation-controlled nucleocytoplasmic shuttling and by non-catalytic scaffolding activities [#2, #4]. Its catalytic domain adopts a class IIa-specific architecture with an enlarged active-site pocket and only low intrinsic deacetylase activity [#0], and its robust nuclear enzymatic function depends on assembly with HDAC3 through the SMRT/N-CoR corepressors [#1]. HDAC7 represses transcription by binding MEF2 family factors (MEF2A/C/D) through its N-terminal repression domain in a manner independent of the catalytic domain [#2], a module deployed across thymocyte selection where it silences Nur77 [#3], B-lymphoid and myeloid lineage decisions [#13, #23], and Th17 and Treg programs [#35, #36]. Activation signals relocalize HDAC7 out of the nucleus: PKD1, activated downstream of the TCR or VEGF receptor, phosphorylates conserved N-terminal serines (Ser155/Ser318/Ser448, or Ser178/Ser344/Ser479) to drive cytoplasmic export and derepression of target genes [#4, #8], while opposing phosphatases (PP1\\u03b2/MYPT1, PP2A-B\\u03b1) and the ROCK pathway restore nuclear localization and repression [#5, #16]. Beyond MEF2 corepression, HDAC7 deacetylates an expanding set of non-histone substrates\\u2014STAT3 [#19], \\u03b2-catenin at Lys49 [#20, #21], HSP70 at K246 [#18], FOXP1 [#40], TFEB at K310 [#41], PINK1 [#42], and ENO1 [#47]\\u2014thereby controlling tumor signaling, lysosomal biogenesis, mitophagy, and stem-cell senescence. It also acts as a deacetylase-independent scaffold, engaging the TRAF6-TAK1 complex and IKK\\u03b1/\\u03b2 to drive MAPK/NF-\\u03baB inflammatory signaling [#29, #30], and in macrophages serves as a bifunctional immunometabolic switch coupling TLR4 signals to enzyme-independent glycolytic reprogramming and enzyme-dependent inflammatory cytokine and pentose-phosphate-pathway responses [#31, #32]. HDAC7 protein abundance is set by competing ubiquitin and SUMO machinery: USP10 stabilizes it by deubiquitination [#20], CBX4 and FBXW7 promote its degradation [#28], SIK1 phosphorylates and stabilizes cytoplasmic HDAC7 to drive cardiac hypertrophy [#25], and TRIM28-mediated sumoylation elevates its levels [#45].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the founding mechanism of HDAC7 as a MEF2 corepressor and revealed that its repressive output is structurally separable from its catalytic domain.\",\n      \"evidence\": \"GST pulldown, Co-IP, reporter assays and domain mapping in mammalian cells\",\n      \"pmids\": [\"11279209\", \"11466315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how nuclear export is triggered physiologically\", \"In vitro deacetylase activity of HDAC7 itself not quantified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed HDAC7-MEF2 repression in a physiological circuit by showing it gates Nur77-dependent thymocyte apoptosis, with nuclear export as the regulatory event.\",\n      \"evidence\": \"Reporter assays, triple-serine mutant, RNAi and thymocyte apoptosis assays\",\n      \"pmids\": [\"12753745\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for the export-driving phosphorylation not identified\", \"Opposing phosphatase unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified PKD1 as the TCR-activated kinase that phosphorylates HDAC7 N-terminal serines to drive nuclear export, defining the signal-to-localization link.\",\n      \"evidence\": \"In vitro kinase assay, site-directed mutagenesis, dominant-negative PKD1, microscopy\",\n      \"pmids\": [\"15623513\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the export receptor/14-3-3 machinery\", \"Reversal mechanism not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Closed the regulatory loop by identifying PP1\\u03b2/MYPT1 as the phosphatase that dephosphorylates HDAC7 to restore nuclear repression, with ROCK upstream.\",\n      \"evidence\": \"Co-IP, phosphatase assays, siRNA and thymocyte apoptosis readouts\",\n      \"pmids\": [\"17369396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect dephosphorylation not fully dissected\", \"Other phosphatases not excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the class IIa-specific active-site architecture and confirmed low but genuine intrinsic deacetylase activity, explaining why HDAC7 relies on partner enzymes.\",\n      \"evidence\": \"X-ray crystallography of the catalytic domain with inhibitor complexes plus in vitro activity assay\",\n      \"pmids\": [\"18285338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate of the isolated catalytic domain not defined\", \"Full-length and complex-bound structures not solved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Generalized the PKD1-HDAC7 shuttling module beyond immunity to VEGF-driven angiogenic gene expression in endothelial cells.\",\n      \"evidence\": \"PLC\\u03b3/PKC/PKD1 pathway dissection, phosphomutants, dominant-negatives, tube formation and sprouting assays\",\n      \"pmids\": [\"18617643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets at MT1-MMP/MMP10 loci not mapped by ChIP\", \"Role of catalytic activity not isolated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended MEF2 corepression to lineage commitment, showing HDAC7-MEF2C represses myeloid genes to enforce B-lymphoid identity.\",\n      \"evidence\": \"Co-IP, ChIP, microarray and functional transdifferentiation assays in pre-B cells\",\n      \"pmids\": [\"23696748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic dependence of repression not resolved\", \"Recruitment to specific enhancers versus promoters not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated in vivo that HDAC7-MEF2C occupancy enforces early B cell development and prevents lineage promiscuity, linking loss to altered active histone marks.\",\n      \"evidence\": \"Conditional knockout mouse, ChIP-seq, Co-IP and flow cytometry\",\n      \"pmids\": [\"27810920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting HDAC7 loss to gain of active marks not biochemically defined\", \"Catalytic requirement not tested in vivo\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified non-histone substrate deacetylation as a distinct HDAC7 mechanism by showing it directly deacetylates STAT3 to restrain its activation in lung tumors.\",\n      \"evidence\": \"Co-IP, pulldown, deacetylation assay, Hdac7+/-/K-Ras mouse model with dominant-negative STAT3 rescue\",\n      \"pmids\": [\"29126425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Acetyl-lysine site on STAT3 not mapped\", \"Direct enzyme-substrate kinetics not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a cytoplasmic, MEF2-independent role: SIK1 phosphorylates and stabilizes HDAC7 as a prohypertrophic effector driving cardiomyocyte remodeling.\",\n      \"evidence\": \"Gain/loss-of-function in rodents and hiPSC-cardiomyocytes, kinase assay, Co-IP\",\n      \"pmids\": [\"32106109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic effector mechanism (substrate or scaffold) not fully defined\", \"Phosphosite mediating stabilization not specified here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected HDAC7 to Wnt signaling and its own stability control, showing it deacetylates \\u03b2-catenin at Lys49 to promote nuclear translocation while USP10 stabilizes HDAC7.\",\n      \"evidence\": \"Co-IP, deacetylation/phosphorylation readouts, lentiviral knockdown and xenograft\",\n      \"pmids\": [\"35277183\", \"30691485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect effect on \\u03b2-catenin Ser45 phosphorylation not resolved\", \"Reciprocal deubiquitination kinetics not quantified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined deacetylase-independent scaffolding of NF-\\u03baB signaling, with HDAC7 deacetylating and activating IKK\\u03b1/\\u03b2 to drive astrocyte inflammation.\",\n      \"evidence\": \"Co-IP, AAV overexpression, siRNA, pharmacological inhibition and behavioral assays\",\n      \"pmids\": [\"35871708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IKK acetyl-lysine sites not mapped\", \"Distinction between scaffold and catalytic contribution incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved HDAC7 as a bifunctional immunometabolic switch in macrophages, separating enzyme-independent glycolytic reprogramming from enzyme-dependent inflammatory and antimicrobial outputs.\",\n      \"evidence\": \"Hdac7-deficient macrophages with enzyme-dead reconstitution, ECAR, metabolomics, cytokine and bacterial killing assays\",\n      \"pmids\": [\"36649417\", \"34811804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of the enzyme-independent glycolytic function not identified\", \"Direct metabolic-enzyme substrates of HDAC7 not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified the TRAF6-TAK1 complex as a direct deacetylase-independent partner coupling HDAC7 to TLR4-driven MAPK/NF-\\u03baB cytokine production, validated by selective PROTAC degradation.\",\n      \"evidence\": \"PROTAC degrader B4, Co-IP, cytokine assays and mouse LPS model\",\n      \"pmids\": [\"39049738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and binding interface with TRAF6-TAK1 not defined\", \"Single lab, no reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the non-histone substrate repertoire into proteostasis and organelle quality control, with HDAC7 deacetylating TFEB (K310), PINK1 and ENO1 to suppress lysosomal biogenesis, mitophagy and metabolism.\",\n      \"evidence\": \"Co-IP, mass spectrometry, site mutagenesis, AAV genetic models and pharmacological inhibition\",\n      \"pmids\": [\"39806423\", \"41286926\", \"40536557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic specificity versus complex-dependent activity not separated for each substrate\", \"In vitro reconstitution of deacetylation reactions not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single low-activity catalytic domain achieves the broad non-histone substrate selectivity observed, and which substrates require complex-assembled versus intrinsic HDAC7 activity.\",\n      \"evidence\": \"No reconstituted enzyme-substrate study in the corpus reconciles intrinsic catalytic weakness with the documented deacetylation events\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of HDAC7 bound to a non-histone substrate\", \"Substrate-recognition determinants undefined\", \"Quantitative contribution of HDAC3-complex activity to each reported substrate unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 19, 20, 18, 40, 41, 42, 47]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 3, 13, 23, 9, 39]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [30, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 4, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 4, 14, 25, 27]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 13, 23, 36]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [31, 32, 30, 35, 36]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [29, 30, 20, 21]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [38, 37, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [31, 33]}\n    ],\n    \"complexes\": [\"SMRT/N-CoR-HDAC3 corepressor complex\"],\n    \"partners\": [\"MEF2C\", \"HDAC3\", \"PKD1\", \"MYPT1\", \"CTNNB1\", \"STAT3\", \"TRAF6\", \"IKBKB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}