{"gene":"NCOR2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"SMRT/NCOR2 directly interacts with mSin3A, which in turn interacts with HDAC1, forming a multisubunit repressor complex that mediates transcriptional repression by nuclear receptors (thyroid hormone and retinoic acid receptors).","method":"Co-immunoprecipitation, protein interaction assays, functional reporter assays with HDAC inhibitors","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP establishing multi-component complex, replicated across labs, foundational paper with multiple orthogonal methods","pmids":["9150137"],"is_preprint":false},{"year":2000,"finding":"SMRT and N-CoR exist in large (~1.5–2 MDa) protein complexes in HeLa nuclear extracts containing HDAC3 and TBL1 (a WD-40 repeat protein); these complexes bind unliganded thyroid hormone receptors in vitro, and antibodies against HDAC3 or SMRT/N-CoR partially relieve TR/RXR-mediated repression in Xenopus oocytes.","method":"Conventional and immunoaffinity chromatography, co-immunoprecipitation, in vitro binding assay, antibody microinjection in Xenopus oocytes","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — immunoaffinity purification with functional validation in two independent systems (HeLa and Xenopus), multiple orthogonal methods","pmids":["10944117"],"is_preprint":false},{"year":2000,"finding":"SMRT forms a core complex with HDAC3 and TBL1; TBL1 interacts with histone H3 and is bridged to HDAC3 through SMRT, and TBL1 can potentiate transcriptional repression by thyroid hormone receptor in vivo.","method":"Immunoaffinity purification of HeLa nuclear extract SMRT complex, co-immunoprecipitation, histone interaction assays, transcriptional reporter assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical purification plus functional assays, independently replicated by concurrent paper (PMID 10944117)","pmids":["10809664"],"is_preprint":false},{"year":2001,"finding":"SMRT functions as an activating cofactor for HDAC3 via a deacetylase activating domain (DAD) that includes one of its two SANT motifs. Recombinant HDAC3 alone is enzymatically inactive; SMRT DAD is necessary and sufficient to reconstitute HDAC3 deacetylase activity using purified components. Mutations in the DAD that abolish HDAC3 interaction also eliminate HDAC activity and the major repression function of SMRT.","method":"In vitro reconstitution with purified components, HDAC activity assays, mutagenesis of DAD domain, stable complex isolation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components plus mutagenesis, single lab but multiple rigorous orthogonal methods","pmids":["11509652"],"is_preprint":false},{"year":1997,"finding":"SMRT contains two distinct receptor interaction domains that independently bind nuclear receptors, and two separate transcriptional repression domains. Both repression domains interact weakly with mSin3A, and SMRT overexpression represses transcription from natural promoters.","method":"Deletion analysis, mammalian two-hybrid, Far-Western, co-immunoprecipitation, transcriptional reporter assays","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Far-Western, two-hybrid, reporter assays), independently replicated","pmids":["9415406"],"is_preprint":false},{"year":1996,"finding":"SMRT is a ubiquitous nuclear protein that interacts with unliganded nuclear receptor heterodimers in mammalian cells; expression of the receptor-interacting domain of SMRT acts as an antirepressor, and splicing variants modulate thyroid hormone and retinoic acid signaling.","method":"Mammalian cell transfection, co-immunoprecipitation, transcriptional reporter assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assays and co-IP in a single lab, foundational but limited methods relative to later papers","pmids":["8755515"],"is_preprint":false},{"year":1998,"finding":"SMRT interacts with the BCL-6 POZ/BTB domain, and this interaction is necessary for BCL-6-mediated transcriptional repression; POZ domains from other repressors (PLZF, ZID, GAGA) also interact with SMRT/N-CoR in vitro; BCL-6 and N-CoR co-localize to punctate nuclear regions.","method":"Yeast two-hybrid, mammalian two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence co-localization, transcriptional reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Y2H, mammalian 2H, pulldown, co-localization, functional assay) in a single lab","pmids":["9824158"],"is_preprint":false},{"year":2003,"finding":"Crystal structure (2.2 Å) of the BCL6 BTB homodimer bound to a 17-residue SMRT fragment: two SMRT peptides bind symmetrically to the BCL6 BTB homodimer, revealing the structural basis of SMRT recruitment for transcriptional repression.","method":"X-ray crystallography, biochemical binding assays, in vivo functional assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.2 Å plus biochemical validation, single lab but highest-quality structural evidence","pmids":["14690607"],"is_preprint":false},{"year":2000,"finding":"SMRT function is inhibited by a MAPK kinase kinase cascade downstream of EGF receptor: SMRT is phosphorylated by MEKK-1 and MEK-1, which inhibits its ability to tether to transcription factor partners and causes redistribution from nucleus to a perinuclear/cytoplasmic compartment.","method":"Kinase assays, transfection with constitutively active kinase constructs, subcellular fractionation, co-immunoprecipitation, transcriptional reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — kinase assays plus functional readouts plus localization, multiple orthogonal methods in a single lab","pmids":["10938135"],"is_preprint":false},{"year":2004,"finding":"IKKα phosphorylates SMRT on chromatin, triggering nuclear export of SMRT and loss of chromatin-associated HDAC3, which is prerequisite for NF-κB-dependent transcription of cIAP-2 and IL-8; a nonphosphorylatable SMRT mutant blocks NF-κB recruitment and sensitizes cells to apoptosis.","method":"Chromatin immunoprecipitation (ChIP), nonphosphorylatable SMRT mutant expression, nuclear export assays, transcriptional reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, mutant SMRT functional assays, and export assays provide multiple orthogonal methods in a single lab","pmids":["15494311"],"is_preprint":false},{"year":2006,"finding":"IKKα phosphorylates both SMRT(S2410) and RelA/p65(S536) on chromatin; phospho-SMRT remains bound to NF-κB heterodimer but loses HDAC3 association, enabling p300-mediated acetylation of RelA/p65 at K310; nonphosphorylatable SMRT or RelA mutants maintain active SMRT-HDAC3 repression.","method":"ChIP, re-ChIP, nonphosphorylatable mutant expression, transcriptional reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP/re-ChIP plus phospho-mutant functional assays, multiple orthogonal methods, same lab as PMID 15494311 providing partial replication","pmids":["16382138"],"is_preprint":false},{"year":2001,"finding":"SMRTe (full-length SMRT) inhibits MEF2C transcriptional activation by translocating HDAC4 from the cytoplasm to discrete nuclear domains and recruiting HDAC5 into these domains; SMRTe synergizes with HDAC4 and HDAC5 to inhibit MEF2C-dependent muscle differentiation gene expression.","method":"Indirect immunofluorescence, co-immunoprecipitation, nuclear fractionation, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging plus co-IP plus functional assay, single lab","pmids":["11304536"],"is_preprint":false},{"year":2001,"finding":"SMRT binds to the N-terminal coiled-coil domain of STAT5A and STAT5B, strongly represses STAT5-dependent transcription; a hyperactivating mutation in the STAT5 coiled-coil domain that renders it constitutively active abolishes SMRT interaction; SMRT overexpression suppresses IL-3-induced STAT5 target gene expression.","method":"Yeast two-hybrid, co-immunoprecipitation, transcriptional reporter assays, overexpression in cell lines","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus functional assays, single lab","pmids":["11726519"],"is_preprint":false},{"year":2002,"finding":"SMRT directly interacts with the androgen receptor (AR) ligand-binding domain; the SMRT C-terminal ID2 region mediates interaction; SMRT overexpression inhibits DHT-dependent AR transactivation by inhibiting AR N/C interaction and competing with p160 coactivators; a mutation in the SMRT ID2 corepressor motif abolishes interaction.","method":"GST pulldown, mammalian two-hybrid, transcriptional reporter assays, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple interaction assays plus functional reporter assays, single lab","pmids":["12441355"],"is_preprint":false},{"year":2004,"finding":"SMRT and N-CoR are regulated by distinct kinase signaling pathways: MEKK1 activation leads to SMRT phosphorylation, dissociation from transcription factor partners in vivo and in vitro, and nuclear-to-cytoplasmic redistribution; N-CoR is refractory to all these MAPK cascade effects.","method":"Co-immunoprecipitation, in vitro binding assays, subcellular fractionation, kinase assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo interaction assays plus localization, single lab","pmids":["15491994"],"is_preprint":false},{"year":2001,"finding":"SMRT is phosphorylated in vivo and in vitro at a CK2 motif centered on serine 1492 within the nuclear receptor interaction domain; CK2-mediated phosphorylation stabilizes SMRT interaction with nuclear hormone receptors.","method":"In vitro phosphorylation assays, mutagenesis, co-immunoprecipitation","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro kinase assay with mutagenesis, single lab, single publication","pmids":["11451368"],"is_preprint":false},{"year":2004,"finding":"SMRT binds to the C/EBPβ TAD domain and Nrf2 Neh4/5 domain; glucocorticoid-activated GR recruits SMRT to the GSTA2 promoter to repress C/EBPβ- and Nrf2-mediated GSTA2 induction; siRNA knockdown of SMRT abolishes repression.","method":"Co-immunoprecipitation, ChIP, GST pulldown, siRNA knockdown, transcriptional reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, pulldown, and siRNA with multiple orthogonal methods in single lab","pmids":["15870285"],"is_preprint":false},{"year":2008,"finding":"TBL1 and TBLR1 phosphorylation at the promoter level (e.g., by PKCδ for TBLR1) triggers ubiquitylation and degradation of NCoR/SMRT, enabling corepressor dismissal as a prerequisite for gene activation across multiple signaling pathways (Notch, NF-κB, nuclear receptor ligands).","method":"ChIP, co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, kinase assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus ubiquitylation assays plus siRNA, multiple orthogonal methods in single lab","pmids":["18374649"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of the tetrameric oligomerization domain of TBL1 reveals how it interacts with both SMRT and GPS2; NMR structure of the GPS2-SMRT interface defines assembly mechanism and stoichiometry of the core repression complex. Mutagenesis and functional assays validate the structural model.","method":"X-ray crystallography, NMR spectroscopy, computational docking, mutagenesis, functional assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure and NMR with mutagenesis and functional validation, multiple rigorous orthogonal methods","pmids":["21240272"],"is_preprint":false},{"year":2005,"finding":"SMRT interacts with PXR through PXR's ligand-binding domain and SMRT's nuclear receptor-interacting domain 2; the PXR-SMRT interaction is disrupted by PXR ligands (Rif, CTZ), causing exchange of SMRT for the p160 coactivator RAC3; deletion of AF-2 helix enhances SMRT binding; SMRT overexpression inhibits PXR transactivation of CYP3A4 and siRNA depletion enhances it.","method":"GST pulldown, yeast two-hybrid, mammalian two-hybrid, co-localization, siRNA knockdown, transcriptional reporter assays","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple interaction assays plus functional reporter and siRNA, single lab","pmids":["16219912"],"is_preprint":false},{"year":2008,"finding":"Cdk2 phosphorylates SMRT at multiple sites required for interaction with the peptidyl-prolyl isomerase Pin1; Pin1 interaction decreases SMRT protein stability and reduces SMRT-dependent transcriptional repression; Her2/Neu/ErbB2 receptor activation leads to SMRT destabilization via this Cdk2-Pin1 cascade.","method":"Co-immunoprecipitation, in vitro binding assays, mutagenesis, protein stability assays, transcriptional reporter assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and mutagenesis plus stability assays, single lab, multiple methods","pmids":["18838553"],"is_preprint":false},{"year":2008,"finding":"SMRT repression of nuclear receptors via its receptor interaction domain (RID) controls the adipogenic set point; SMRT(mRID) knock-in mice disrupting NHR interaction develop widespread metabolic defects including increased adiposity (70%), reduced respiration, and altered insulin sensitivity; MEFs from SMRT(mRID) mice display dramatically increased adipogenic capacity.","method":"Knock-in mouse model (RID mutation), metabolic phenotyping, MEF differentiation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in model with defined molecular disruption and multiple metabolic phenotypes","pmids":["19066220"],"is_preprint":false},{"year":2010,"finding":"SMRT expression and its occupancy on PPAR target gene promoters increase with age; selective disabling of SMRT's RID1 (SMRT(mRID1)) shifts repression to RID2-associated receptors (notably PPARs), causing premature aging-related metabolic diseases with reduced mitochondrial function; SMRT(mRID1) cells show increased susceptibility to oxidative damage rescued by PPAR activation or antioxidant treatment.","method":"Knock-in mouse model, ChIP, metabolic and mitochondrial function assays, antioxidant rescue experiments","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knock-in model with ChIP and multiple phenotypic rescue approaches","pmids":["21109196"],"is_preprint":false},{"year":2012,"finding":"SMRT is required for full agonist-dependent ERα transcriptional activation; SMRT is recruited (along with ERα and SRC-3) to estrogen-responsive promoters in MCF-7 cells; SMRT depletion (but not HDAC1 or HDAC3 depletion) reduces estradiol-stimulated ERα activity and attenuates estrogen-dependent MCF-7 cell proliferation in a cell-type-specific manner.","method":"ChIP, siRNA knockdown, transcriptional reporter assays, cell proliferation assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus siRNA with multiple functional readouts, single lab","pmids":["17591692"],"is_preprint":false},{"year":2004,"finding":"In frog development, unliganded thyroid hormone receptor recruits N-CoR/SMRT-TBLR1 complexes to chromatinized TR target promoters in vivo, accompanied by histone deacetylation and gene repression; T3 treatment dissociates these complexes and activates gene expression during metamorphosis.","method":"Frog oocyte chromatin injection, ChIP assays during spontaneous and T3-induced metamorphosis, dominant-negative constructs","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo ChIP in developmental system with functional knockdown, multiple orthogonal approaches in single lab","pmids":["15060155"],"is_preprint":false},{"year":2016,"finding":"NCOR1 and NCOR2 redundantly mediate RA-dependent repression of Fgf8 during somitogenesis; Ncor1;Ncor2 double mutants generated by CRISPR/Cas9 exhibit increased Fgf8 expression and FGF signaling; embryo ChIP reveals NCOR1/2 (but not coactivators) are recruited to the Fgf8 RARE in RA-dependent manner, whereas coactivators (not NCOR1/2) are recruited to an activated RARE near Rarb.","method":"CRISPR/Cas9 double knockout, embryo ChIP, CRISPR deletion of Fgf8 RARE, phenotypic analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR-based genetic knockout with in vivo ChIP, multiple orthogonal approaches","pmids":["27506116"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, ncor2 is required for hematopoietic stem cell emergence in the AGM region; ncor2 knockdown upregulates fos transcription by increasing histone acetylation at the fos promoter, enhancing Vegfd signaling, which promotes Notch-dependent arterial endothelial fate and suppresses hemogenic endothelial specification.","method":"Zebrafish morpholino knockdown, ChIP (histone acetylation), epistasis experiments with Vegfd and Notch pathway inhibitors/activators","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus pathway epistasis in zebrafish model, single lab","pmids":["25006126"],"is_preprint":false},{"year":2019,"finding":"NCOR1 and NCOR2 loss specifically in GABAergic neurons reduces GABRA2 expression in lateral hypothalamus GABAergic neurons, causing neuron hyperexcitability and impaired hippocampal LTP through a monosynaptic LH-GABAergic to CA3-GABAergic projection; optogenetic activation of this projection causes memory deficits, and targeted manipulation of LH or CA3 neuron activity reverses memory deficits.","method":"Cell-type-specific conditional knockout, optogenetics, electrophysiology (LTP), Western blot, behavioral assays","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout combined with optogenetics, electrophysiology, and rescue experiments, multiple orthogonal approaches","pmids":["30664766"],"is_preprint":false},{"year":2012,"finding":"Wnt5a-induced CaMKII directly phosphorylates SMRT at Ser-1407, triggering translocation of SMRT from nucleus to cytoplasm and proteasomal degradation; this destabilizes SMRT and derepresses Notch1 signaling by enhancing Notch1-IC/RBP-Jk association and suppressing RBP-Jk/SMRT association.","method":"Kinase assay, phospho-site mutagenesis, co-immunoprecipitation, subcellular fractionation, proteasome inhibitor experiments, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase assay with phospho-site mutagenesis plus co-IP and functional assays, single lab","pmids":["22888005"],"is_preprint":false},{"year":2010,"finding":"SMRT forms a protein homodimer; Erk2 phosphorylation disrupts SMRT self-dimerization in vitro and in vivo, resulting in a reorganized corepressor complex with reduced sedimentation coefficient, partial release of HDAC3, TBL-1, and TBLR-1, and inhibition of transcriptional repression.","method":"Co-immunoprecipitation, sedimentation analysis (sucrose gradient), in vitro binding and kinase assays, transcriptional reporter assays","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods plus functional assays, single lab","pmids":["20965228"],"is_preprint":false},{"year":2016,"finding":"All components of the NCoR/SMRT corepressor complex (HDAC3, GPS2, NCoR, SMRT, TBL1, TBLR1) interact with HPV E8^E2C protein in an E8-domain-dependent manner; this interaction is required for E8^E2C-mediated inhibition of both viral transcription and HPV origin replication; a dominant-negative NCoR fragment activates transcription and replication only from wild-type but not NCoR/SMRT-binding-deficient E8^E2C genomes.","method":"Proteomics (co-precipitation/mass spectrometry), co-immunoprecipitation, co-localization, siRNA knockdown, viral replication assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic identification plus co-IP plus siRNA knockdown plus functional genetic rescue, multiple orthogonal methods","pmids":["27064408"],"is_preprint":false},{"year":2014,"finding":"NCoR1 is the principal mediator of thyroid hormone sensitivity in liver in vivo, while SMRT plays little independent role in TH signaling; however, combined deletion of both SMRT and NCoR1 in liver greatly accentuates hepatic lipid synthesis, indicating cooperative control of hepatic lipid content through regulation of multiple nuclear receptors including TR.","method":"Liver-specific conditional knockout mice (SMRT-only, NCoR1-only, double KO), global SMRT KO, metabolic and gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional knockout mouse models with defined molecular disruptions and metabolic phenotyping","pmids":["25421714"],"is_preprint":false},{"year":2021,"finding":"GPS2 and SMRT co-occupy candidate enhancers with coactivators CBP and MED1 but antagonistically repress eRNA transcription-coupled H3K27 acetylation; corepressor depletion or inflammatory signaling triggers enhancer activation via a similar mechanism; depletion of SMRT/GPS2 causes derepression of inflammatory genes (Ccl2) in macrophages.","method":"ChIP-seq, CRISPR genome editing, transcriptional interference, 4C-seq, cistrome analysis, siRNA knockdown, in vivo macrophage-selective eRNA depletion in ob/ob mice","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq plus CRISPR editing plus 4C-seq plus in vivo validation, multiple rigorous orthogonal methods","pmids":["33503407"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of two SMRT repression domain 3 (SRD3c) GSI-containing peptides in complex with HDAC4 show that these peptides form β-hairpin structures blocking the catalytic entry site of HDAC4 at class IIa HDAC-specific residues; SMRT binding does not activate the cryptic deacetylase activity of HDAC4, and mutagenesis confirms critical residues (including Arg1369) for optimal binding to HDAC4 and HDAC5.","method":"X-ray crystallography, mutagenesis, binding/interaction assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with structure-guided mutagenesis validating interaction, single lab but high-quality structural evidence","pmids":["30321390"],"is_preprint":false},{"year":2022,"finding":"NCOR2 inhibits antitumor treatment by regulating HDAC3 to repress IRF-1-dependent gene expression and interferon signaling; reducing NCOR2 or impairing its interaction with HDAC3 (via adeno-associated viral NCOR2-HDAC3 competitor) enhances chemotherapy responsiveness and restores antitumor immunity by permitting transcription of IRF-1-regulated proapoptosis and inflammatory genes.","method":"Functional proteomic screening of patient-derived organoids, knockdown, AAV competitor construct, in vivo tumor models, gene expression assays","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived organoids plus in vivo models plus mechanistic intervention, multiple orthogonal approaches","pmids":["35618935"],"is_preprint":false},{"year":2008,"finding":"VDR-bound SMRT represses CYP24A1; vitamin D3 activates CYP24A1 by dissociating SMRT from VDR at the promoter; PXR 'locks' SMRT onto the CYP24A1 promoter by preventing ligand-dependent dissociation of SMRT from VDR, thereby attenuating vitamin D3 activation; this mechanism was confirmed in Pxr+/+ vs Pxr-/- mice.","method":"ChIP, co-immunoprecipitation, transcriptional reporter assays, Pxr knockout mouse model","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus in vivo mouse model with defined genetic disruption, single lab","pmids":["18981260"],"is_preprint":false},{"year":2020,"finding":"In type 2 diabetic hearts, loss of NCOR2 repression leads to PPARα-mediated upregulation of MCUb (mitochondrial calcium uniporter inhibitory subunit), limiting mitochondrial Ca2+ uptake and impairing glucose oxidation; identified using Cas9-based gene promoter pulldown coupled with mass spectrometry and confirmed by ChIP.","method":"dCas9-based promoter pulldown with mass spectrometry, ChIP assays, gene therapy with dominant-negative MCUb transgene, metabolic and cardiac function assays","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel dCas9 pulldown method plus ChIP plus in vivo rescue, single lab","pmids":["33303689"],"is_preprint":false},{"year":2022,"finding":"NCOR1/2 deletion in B cells limits B cell differentiation via impaired V(D)J recombination, attenuates pre-BCR signaling, enhances STAT5-dependent transcription, causes derepression of EZH2-repressed gene modules including p53 pathway, and leads to aberrant Rag1/Rag2 expression with increased structural variants bearing cryptic recombination signal sequences.","method":"B cell-specific conditional knockout, whole-genome sequencing, ChIP-seq/ATAC-seq, gene expression analysis, flow cytometry","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with whole-genome sequencing, chromatin profiling, and multiple cellular phenotype readouts","pmids":["36316474"],"is_preprint":false},{"year":1999,"finding":"The TEL/ETV6 leukemia-associated transcription repressor's central region (maintained in t(12;21)) recruits a repression complex containing SMRT and mSin3A to mediate transcriptional repression, while its HLH domain represses via a SMRT/Sin3A-independent mechanism.","method":"Co-immunoprecipitation, transcriptional reporter assays, deletion analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus functional reporter assays, single lab but interaction confirmed by two methods","pmids":["10544023"],"is_preprint":false},{"year":2005,"finding":"AhR activation by TCDD causes physical interaction between AhR and SMRT (corepressor of RARα), sequestering SMRT into nuclear bodies and activating RARα signaling in a ligand-independent manner; AhR and SMRT co-localize in nuclear bodies during this sequestration.","method":"Co-immunoprecipitation, immunocytochemistry, transcriptional reporter assays, TSA inhibitor experiments","journal":"Biochimie","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP and co-localization in single lab, limited mechanistic depth","pmids":["16480812"],"is_preprint":false},{"year":2008,"finding":"VDR specifically interacts with SMRT interaction domain 1 (ID1) rather than ID2; specific residues within and outside the extended helix motif of SMRT-ID1 are required for VDR binding; SMRT mutants defective in VDR interaction fail to repress endogenous VDR target genes (osteocalcin, CYP24A1) in vivo.","method":"One- plus two-hybrid genetic selection, siRNA knockdown, ChIP, mutagenesis, transcriptional reporter assays","journal":"Molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic selection for missense mutations plus ChIP plus siRNA, multiple methods in single lab","pmids":["19098224"],"is_preprint":false},{"year":2009,"finding":"Alternative splicing of SMRT generates isoforms with 1, 2, or 3 CoRNR box motifs; all six isoforms are expressed in human cell lines; the full complement of CoRNR boxes rather than individual box identity determines interaction affinity with nuclear receptors; 1-box isoform discriminates between DNA response elements, 2-box isoforms prefer TR complexes, and 3-box isoforms show differential receptor binding.","method":"RT-PCR (isoform detection), in vitro binding affinity measurements with nuclear receptor-DNA complexes","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic binding affinity measurements across isoforms and receptor complexes, single lab","pmids":["18752469"],"is_preprint":false},{"year":2021,"finding":"Combined global postnatal deletion of NCOR1 and SMRT in adult mice is lethal within ten days; double knockout mice rapidly develop hypoglycemia, hypothermia, and hepatosteatosis with alterations in lipogenesis and beta-oxidation; this phenotype is distinct from HDAC3 knockout mice, implying NCOR1/SMRT together regulate a critical pathway required for adult survival that is separate from HDAC3.","method":"Tamoxifen-inducible conditional double knockout mouse model (UBC-Cre-ERT2), metabolic phenotyping, hepatic gene expression analysis","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible conditional double knockout with defined timing, comparison to HDAC3 KO separates mechanisms, multiple metabolic phenotypes","pmids":["34390859"],"is_preprint":false},{"year":2020,"finding":"HDAC3 protein stability in epidermal cells depends on NCoR and SMRT functioning redundantly; however, point mutations in the NCoR and SMRT deacetylase-activating domains (DAD), which abolish HDAC3's enzymatic function, still permit normal epidermal stratification, indicating HDAC3's roles in this context are largely independent of its histone deacetylase activity.","method":"Conditional knockout of NCoR/SMRT in epidermis, DAD point-mutation knock-in mice, ChIP-seq, phenotypic analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo genetic models (KO and DAD point-mutant knock-in) with ChIP-seq validation","pmids":["32467224"],"is_preprint":false}],"current_model":"NCOR2/SMRT is a transcriptional corepressor that assembles a large (~1.5–2 MDa) multi-subunit complex containing HDAC3 (which it activates through its SANT-domain-containing deacetylase activating domain, DAD), GPS2, TBL1, and TBLR1; it is recruited to gene promoters via direct interaction with unliganded nuclear hormone receptors (through CoRNR-box receptor interaction domains), POZ/BTB domain transcription factors (BCL6), and other transcription factors (STAT5, AR, ERα, VDR, PXR, C/EBPβ, Nrf2), mediating chromatin compaction and transcriptional silencing; its repressive activity is relieved by multiple kinase signaling cascades (MAPK/MEKK1, IKKα, CaMKII, Cdk2/Pin1) that phosphorylate SMRT to trigger its nuclear export or proteasomal degradation, enabling corepressor-to-coactivator exchange; and in vivo, NCOR2 plays essential roles in metabolism (adipogenesis set point, mitochondrial oxidative metabolism, hepatic lipid homeostasis in cooperation with NCOR1), neural GABAergic signaling and memory, hematopoiesis (HSC emergence and B cell differentiation/genomic integrity), and embryonic development (RA-dependent Fgf8 repression during somitogenesis)."},"narrative":{"mechanistic_narrative":"NCOR2 (SMRT) is a transcriptional corepressor that nucleates a large multi-subunit complex to enforce chromatin-based gene silencing across nuclear receptor and developmental signaling programs [PMID:10944117, PMID:10809664]. It assembles a core repression module with HDAC3, TBL1/TBLR1, and GPS2, whose architecture and stoichiometry have been defined structurally [PMID:10809664, PMID:21240272]; within this complex NCOR2 is not a passive scaffold but an obligate activator of HDAC3, supplying a SANT-containing deacetylase-activating domain (DAD) that is necessary and sufficient to reconstitute HDAC3 enzymatic activity from purified components [PMID:11509652]. NCOR2 is recruited to chromatin through tandem CoRNR-box receptor interaction domains that engage unliganded nuclear receptors (TR, RAR, AR, VDR, PXR, ERα) [PMID:8755515, PMID:12441355, PMID:19098224], and through dedicated repression domains that bind the BCL6 BTB/POZ homodimer—a contact resolved at 2.2 Å—and other transcription factors including STAT5 and C/EBPβ/Nrf2 [PMID:14690607, PMID:11726519, PMID:15870285]. The number of CoRNR-box motifs, set by alternative splicing, tunes receptor-complex selectivity [PMID:18752469]. Its repressive output is reversibly disabled by phosphorylation: MAPK/MEKK1, IKKα, CaMKII, and Cdk2/Pin1 cascades phosphorylate NCOR2 to drive nuclear export, dimer disassembly, or degradation, and TBL1/TBLR1-coupled ubiquitylation dismisses the complex to permit corepressor-to-coactivator exchange [PMID:10938135, PMID:15494311, PMID:18374649, PMID:22888005]. In vivo, NCOR2 acting through its receptor interaction domains sets the adipogenic and mitochondrial-oxidative set point and, redundantly with NCOR1, controls hepatic lipid homeostasis, RA-dependent Fgf8 repression in somitogenesis, GABAergic neuronal excitability and memory, and B-cell differentiation and genomic integrity [PMID:19066220, PMID:27506116, PMID:30664766, PMID:25421714, PMID:36316474, PMID:34390859]. NCOR2 is also co-opted in disease, repressing IRF-1-dependent interferon and proapoptotic genes via HDAC3 to limit antitumor immunity [PMID:35618935].","teleology":[{"year":1996,"claim":"Established NCOR2/SMRT as a ubiquitous nuclear factor that binds unliganded nuclear receptors and represses their target genes, defining its founding role as a hormone-receptor corepressor.","evidence":"Co-IP and reporter assays in transfected mammalian cells, plus antirepressor activity of the receptor-interacting domain","pmids":["8755515"],"confidence":"Medium","gaps":["Did not define the repression machinery downstream of receptor binding","Mechanism of silencing unknown"]},{"year":1997,"claim":"Connected NCOR2's repressive output to histone deacetylation by showing it bridges receptors to an mSin3A/HDAC1 complex, providing the first enzymatic mechanism for corepression.","evidence":"Reciprocal co-IP and reporter assays with HDAC inhibitors (TR/RAR systems); parallel deletion mapping of two receptor-interaction and two repression domains","pmids":["9150137","9415406"],"confidence":"High","gaps":["HDAC1/Sin3 later shown to be a minor partner relative to HDAC3","Stoichiometry and complex composition not resolved"]},{"year":1998,"claim":"Extended corepressor recruitment beyond nuclear receptors to BTB/POZ transcription factors by showing BCL6-mediated repression requires direct SMRT interaction.","evidence":"Y2H, mammalian two-hybrid, GST pulldown, co-localization, and reporter assays","pmids":["9824158"],"confidence":"High","gaps":["Structural basis of the SMRT-BTB contact not yet defined","In vivo BCL6 target gene consequences not tested"]},{"year":2000,"claim":"Identified the physiological core complex as a ~1.5–2 MDa assembly of SMRT/N-CoR with HDAC3 and TBL1, and showed TBL1 bridges to histone H3 and potentiates repression, reframing the central enzymatic partner from HDAC1 to HDAC3.","evidence":"Immunoaffinity purification of HeLa nuclear complexes, in vitro receptor binding, antibody microinjection in Xenopus, histone-interaction and reporter assays","pmids":["10944117","10809664"],"confidence":"High","gaps":["How SMRT confers HDAC3 activity not yet explained","Subunit stoichiometry unresolved"]},{"year":2001,"claim":"Defined NCOR2 as an obligate allosteric activator of HDAC3 via its SANT-containing DAD, explaining why HDAC3 is catalytically inert without the corepressor.","evidence":"In vitro reconstitution with purified components, HDAC assays, and DAD mutagenesis","pmids":["11509652"],"confidence":"High","gaps":["In vivo requirement of DAD-driven activity for specific genes not yet tested","Structural mechanism of activation not solved here"]},{"year":2001,"claim":"Showed NCOR2 also regulates class IIa HDACs and non-receptor factors, translocating HDAC4 to nuclear domains to silence MEF2C, and repressing STAT5, broadening its target factor repertoire.","evidence":"Immunofluorescence, nuclear fractionation, co-IP, Y2H, and reporter assays (MEF2C/HDAC4-5; STAT5)","pmids":["11304536","11726519"],"confidence":"Medium","gaps":["Single-lab functional assays","In vivo significance for muscle/cytokine programs not established"]},{"year":2003,"claim":"Provided the atomic basis of corepressor recruitment by solving the BCL6 BTB homodimer bound to two symmetric SMRT peptides.","evidence":"2.2 Å X-ray crystallography with biochemical and in vivo functional validation","pmids":["14690607"],"confidence":"High","gaps":["Structure limited to a short SMRT fragment","Does not address full-complex assembly"]},{"year":2004,"claim":"Established phosphorylation as the master switch turning off NCOR2 repression, with MEKK1/MAPK and IKKα cascades driving nuclear export and chromatin loss of SMRT-HDAC3 to license NF-κB and other activation; NCOR1 is refractory, defining functional divergence of the paralogs.","evidence":"Kinase assays, ChIP, nonphosphorylatable mutants, nuclear export and fractionation, reporter assays; CK2 site mapping","pmids":["10938135","15494311","15491994","11451368"],"confidence":"High","gaps":["Full repertoire of relevant kinases not enumerated","Quantitative dynamics of export vs degradation not resolved"]},{"year":2004,"claim":"Demonstrated in vivo developmental corepression by showing unliganded TR recruits N-CoR/SMRT-TBLR1 to chromatinized targets, with T3-induced dismissal driving metamorphic gene activation.","evidence":"Frog oocyte chromatin injection and ChIP across metamorphosis with dominant-negative constructs","pmids":["15060155"],"confidence":"High","gaps":["Direct genetic loss-of-function not performed in this system","Mammalian developmental relevance addressed later"]},{"year":2006,"claim":"Refined the IKKα switch by showing SMRT remains NF-κB-bound after phosphorylation but selectively loses HDAC3, enabling p300 acetylation of RelA, distinguishing complex remodeling from wholesale dismissal.","evidence":"ChIP/re-ChIP and phospho-mutant functional assays","pmids":["16382138"],"confidence":"High","gaps":["Single-lab system","Generality across NF-κB targets not fully mapped"]},{"year":2008,"claim":"Connected NCOR2's molecular receptor interactions to organismal physiology by showing its RID-mediated repression sets the adipogenic threshold, with RID-mutant mice developing adiposity and insulin defects.","evidence":"SMRT(mRID) knock-in mice, metabolic phenotyping, MEF differentiation assays","pmids":["19066220"],"confidence":"High","gaps":["Which receptor(s) dominate the adipogenic phenotype not isolated here","Tissue-specific contributions unresolved"]},{"year":2008,"claim":"Established corepressor dismissal as an active, ubiquitin-coupled step by showing TBL1/TBLR1 phosphorylation triggers NCoR/SMRT ubiquitylation and degradation as a prerequisite for activation; Cdk2/Pin1 separately destabilizes SMRT downstream of ErbB2.","evidence":"ChIP, ubiquitylation assays, siRNA, kinase assays; co-IP, stability and reporter assays for Cdk2-Pin1","pmids":["18374649","18838553"],"confidence":"High","gaps":["E3 ligase identity in some pathways not defined","Cdk2-Pin1 axis single-lab"]},{"year":2010,"claim":"Linked NCOR2 to mitochondrial oxidative metabolism and aging by showing RID1-selective disabling redirects repression to PPARs, causing premature metabolic disease rescuable by PPAR activation or antioxidants; also showed Erk2 disrupts SMRT homodimerization to remodel the complex.","evidence":"SMRT(mRID1) knock-in mice with ChIP and rescue; sucrose-gradient sedimentation and kinase assays for dimerization","pmids":["21109196","20965228"],"confidence":"Medium","gaps":["Dimerization study single-lab in vitro","Direct causal PPAR target genes for aging phenotype not fully enumerated"]},{"year":2011,"claim":"Resolved the assembly mechanism of the core repression module by determining the TBL1 tetrameric oligomerization domain bound to SMRT and the GPS2-SMRT interface.","evidence":"X-ray crystallography, NMR, docking, mutagenesis, functional assays","pmids":["21240272"],"confidence":"High","gaps":["Full-complex structure including HDAC3 not solved","Dynamics of phospho-triggered disassembly not captured"]},{"year":2012,"claim":"Expanded the kinase-off-switch to Wnt5a/CaMKII-driven SMRT degradation that derepresses Notch1, and established that NCOR2 can also be required for full agonist-dependent ERα activation, revealing a context-dependent coactivator-like role.","evidence":"CaMKII kinase/phospho-mutant, co-IP, fractionation, proteasome assays; ChIP and siRNA for ERα in MCF-7","pmids":["22888005","17591692"],"confidence":"Medium","gaps":["Mechanism of ERα coactivation by a corepressor not fully explained","Both single-lab"]},{"year":2014,"claim":"Demonstrated developmental and hematopoietic roles in vivo, with zebrafish ncor2 required for HSC emergence via fos/Vegfd/Notch control, and mouse genetics showing NCoR1 dominates hepatic TH sensitivity while NCoR1/SMRT cooperatively restrain hepatic lipid synthesis.","evidence":"Zebrafish morpholino knockdown with ChIP and pathway epistasis; liver-specific single and double conditional knockout mice","pmids":["25006126","25421714"],"confidence":"Medium","gaps":["Zebrafish knockdown is morpholino-based","Receptor targets mediating hepatic lipid phenotype only partially defined"]},{"year":2016,"claim":"Established direct, redundant developmental corepression in mammals by showing NCOR1/2 are recruited to the Fgf8 RARE to enforce RA-dependent repression during somitogenesis; also revealed viral hijacking of the complex by HPV E8^E2C.","evidence":"CRISPR/Cas9 double knockout with embryo ChIP and RARE deletion; proteomics, co-IP, siRNA and viral replication assays","pmids":["27506116","27064408"],"confidence":"High","gaps":["Individual contribution of NCOR2 vs NCOR1 not separated in Fgf8 study","Viral mechanism is single-system"]},{"year":2018,"claim":"Provided structural insight into how SMRT engages class IIa HDACs, showing SRD3c GSI peptides form β-hairpins blocking the HDAC4 catalytic entry without activating its cryptic deacetylase activity—contrasting with HDAC3 activation.","evidence":"X-ray crystallography with structure-guided mutagenesis","pmids":["30321390"],"confidence":"High","gaps":["Functional consequence of class IIa binding in cells not addressed here","Single-lab"]},{"year":2019,"claim":"Defined a neural circuit function by showing NCoR1/2 loss in GABAergic neurons reduces GABRA2, driving hyperexcitability and impaired LTP through an LH-to-CA3 GABAergic projection controlling memory.","evidence":"Cell-type-specific conditional knockout, optogenetics, electrophysiology, behavior, and rescue manipulations","pmids":["30664766"],"confidence":"High","gaps":["Direct transcriptional regulation of GABRA2 by NCOR2 vs NCOR1 not separated","Generality beyond LH-CA3 circuit unknown"]},{"year":2020,"claim":"Showed HDAC3 activity is dispensable for some in vivo NCOR functions and extended metabolic roles to the heart, where loss of NCOR2 repression elevates PPARα-driven MCUb and impairs cardiac glucose oxidation in diabetes.","evidence":"Epidermal NCoR/SMRT KO and DAD point-mutant knock-in with ChIP-seq; dCas9 promoter pulldown/MS, ChIP, and gene therapy in diabetic hearts","pmids":["32467224","33303689"],"confidence":"Medium","gaps":["Cardiac study single-lab with novel method","Which deacetylase-independent activities matter in epidermis not defined"]},{"year":2021,"claim":"Established that NCOR1/SMRT together are essential for adult survival via a hepatic lipid/metabolic pathway distinct from HDAC3, and showed at enhancers SMRT/GPS2 antagonize eRNA-coupled H3K27 acetylation to restrain inflammatory genes.","evidence":"Inducible global double knockout mice with metabolic phenotyping; ChIP-seq, CRISPR, 4C-seq, and in vivo macrophage eRNA depletion","pmids":["34390859","33503407"],"confidence":"High","gaps":["Identity of the survival-critical pathway not pinpointed","Direct enhancer targets driving lethality unknown"]},{"year":2022,"claim":"Demonstrated NCOR2 functions in immunity and cancer—restraining B-cell differentiation and genomic stability, and repressing IRF-1-dependent interferon/proapoptotic genes via HDAC3 to limit antitumor responses, identifying the NCOR2-HDAC3 interface as a therapeutic target.","evidence":"B-cell conditional knockout with WGS/ChIP-seq/ATAC-seq; patient-derived organoid screening, AAV NCOR2-HDAC3 competitor, and in vivo tumor models","pmids":["36316474","35618935"],"confidence":"High","gaps":["NCOR2 vs NCOR1 specificity in B cells not fully separated","Clinical translatability of the competitor not established"]},{"year":null,"claim":"How phosphorylation, ubiquitylation, dimerization, and splicing collectively program promoter-specific corepressor dismissal versus retention, and how NCOR2-specific (vs NCOR1-redundant) functions are partitioned across tissues, remain unresolved.","evidence":"No single study in the corpus integrates these regulatory layers with paralog-specific genetics genome-wide","pmids":[],"confidence":"Low","gaps":["No unified model linking SMRT post-translational state to gene-selective output","Paralog division of labor incompletely defined","Full-complex structure including HDAC3 unsolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,5,6,24,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,33]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,18]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,6,8]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[9,10,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,11,28]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,4,32]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,3,32,43]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8,9,17,28]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[21,22,31,36,42]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[24,25,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[32,34,37]}],"complexes":["NCoR/SMRT corepressor complex (HDAC3-TBL1-TBLR1-GPS2)","mSin3A/HDAC1 complex"],"partners":["HDAC3","TBL1","TBLR1","GPS2","BCL6","HDAC4","STAT5","NCOR1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y618","full_name":"Nuclear receptor corepressor 2","aliases":["CTG repeat protein 26","SMAP270","Silencing mediator of retinoic acid and thyroid hormone receptor","SMRT","T3 receptor-associating factor","TRAC","Thyroid-, retinoic-acid-receptor-associated corepressor"],"length_aa":2514,"mass_kda":273.7,"function":"Transcriptional corepressor that mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription (PubMed:10077563, PubMed:10097068, PubMed:18212045, PubMed:20812024, PubMed:22230954, PubMed:23911289). Acts by recruiting chromatin modifiers, such as histone deacetylases HDAC1, HDAC2 and HDAC3 (PubMed:22230954). Required to activate the histone deacetylase activity of HDAC3 (PubMed:22230954). Involved in the regulation BCL6-dependent of the germinal center (GC) reactions, mainly through the control of the GC B-cells proliferation and survival (PubMed:18212045, PubMed:23911289). Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024) Isoform 1 and isoform 4 have different affinities for different nuclear receptors Isoform 1 and isoform 4 have different affinities for different nuclear receptors","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y618/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NCOR2","classification":"Not Classified","n_dependent_lines":45,"n_total_lines":1208,"dependency_fraction":0.037251655629139076},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC3","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/NCOR2","total_profiled":1310},"omim":[{"mim_id":"619039","title":"REPLICATION INITIATOR 1; REPIN1","url":"https://www.omim.org/entry/619039"},{"mim_id":"616595","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 2; ZBTB2","url":"https://www.omim.org/entry/616595"},{"mim_id":"616590","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 5; ZBTB5","url":"https://www.omim.org/entry/616590"},{"mim_id":"614301","title":"ATAXIN 1-LIKE; ATXN1L","url":"https://www.omim.org/entry/614301"},{"mim_id":"613484","title":"SPEN FAMILY TRANSCRIPTIONAL REPRESSOR; SPEN","url":"https://www.omim.org/entry/613484"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NCOR2"},"hgnc":{"alias_symbol":["SMRT","SMRTE","TRAC-1","CTG26","TNRC14"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y618","domains":[{"cath_id":"1.10.10.60","chopping":"420-490","consensus_level":"medium","plddt":84.2327,"start":420,"end":490},{"cath_id":"1.10.10.60","chopping":"614-679","consensus_level":"medium","plddt":88.8691,"start":614,"end":679}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y618","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y618-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y618-F1-predicted_aligned_error_v6.png","plddt_mean":40.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NCOR2","jax_strain_url":"https://www.jax.org/strain/search?query=NCOR2"},"sequence":{"accession":"Q9Y618","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y618.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y618/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y618"}},"corpus_meta":[{"pmid":"9150137","id":"PMC_9150137","title":"Nuclear 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\"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"SMRT/NCOR2 directly interacts with mSin3A, which in turn interacts with HDAC1, forming a multisubunit repressor complex that mediates transcriptional repression by nuclear receptors (thyroid hormone and retinoic acid receptors).\",\n      \"method\": \"Co-immunoprecipitation, protein interaction assays, functional reporter assays with HDAC inhibitors\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP establishing multi-component complex, replicated across labs, foundational paper with multiple orthogonal methods\",\n      \"pmids\": [\"9150137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SMRT and N-CoR exist in large (~1.5–2 MDa) protein complexes in HeLa nuclear extracts containing HDAC3 and TBL1 (a WD-40 repeat protein); these complexes bind unliganded thyroid hormone receptors in vitro, and antibodies against HDAC3 or SMRT/N-CoR partially relieve TR/RXR-mediated repression in Xenopus oocytes.\",\n      \"method\": \"Conventional and immunoaffinity chromatography, co-immunoprecipitation, in vitro binding assay, antibody microinjection in Xenopus oocytes\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — immunoaffinity purification with functional validation in two independent systems (HeLa and Xenopus), multiple orthogonal methods\",\n      \"pmids\": [\"10944117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SMRT forms a core complex with HDAC3 and TBL1; TBL1 interacts with histone H3 and is bridged to HDAC3 through SMRT, and TBL1 can potentiate transcriptional repression by thyroid hormone receptor in vivo.\",\n      \"method\": \"Immunoaffinity purification of HeLa nuclear extract SMRT complex, co-immunoprecipitation, histone interaction assays, transcriptional reporter assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical purification plus functional assays, independently replicated by concurrent paper (PMID 10944117)\",\n      \"pmids\": [\"10809664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SMRT functions as an activating cofactor for HDAC3 via a deacetylase activating domain (DAD) that includes one of its two SANT motifs. Recombinant HDAC3 alone is enzymatically inactive; SMRT DAD is necessary and sufficient to reconstitute HDAC3 deacetylase activity using purified components. Mutations in the DAD that abolish HDAC3 interaction also eliminate HDAC activity and the major repression function of SMRT.\",\n      \"method\": \"In vitro reconstitution with purified components, HDAC activity assays, mutagenesis of DAD domain, stable complex isolation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components plus mutagenesis, single lab but multiple rigorous orthogonal methods\",\n      \"pmids\": [\"11509652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SMRT contains two distinct receptor interaction domains that independently bind nuclear receptors, and two separate transcriptional repression domains. Both repression domains interact weakly with mSin3A, and SMRT overexpression represses transcription from natural promoters.\",\n      \"method\": \"Deletion analysis, mammalian two-hybrid, Far-Western, co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Far-Western, two-hybrid, reporter assays), independently replicated\",\n      \"pmids\": [\"9415406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SMRT is a ubiquitous nuclear protein that interacts with unliganded nuclear receptor heterodimers in mammalian cells; expression of the receptor-interacting domain of SMRT acts as an antirepressor, and splicing variants modulate thyroid hormone and retinoic acid signaling.\",\n      \"method\": \"Mammalian cell transfection, co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assays and co-IP in a single lab, foundational but limited methods relative to later papers\",\n      \"pmids\": [\"8755515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SMRT interacts with the BCL-6 POZ/BTB domain, and this interaction is necessary for BCL-6-mediated transcriptional repression; POZ domains from other repressors (PLZF, ZID, GAGA) also interact with SMRT/N-CoR in vitro; BCL-6 and N-CoR co-localize to punctate nuclear regions.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, GST pulldown, co-immunoprecipitation, immunofluorescence co-localization, transcriptional reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Y2H, mammalian 2H, pulldown, co-localization, functional assay) in a single lab\",\n      \"pmids\": [\"9824158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure (2.2 Å) of the BCL6 BTB homodimer bound to a 17-residue SMRT fragment: two SMRT peptides bind symmetrically to the BCL6 BTB homodimer, revealing the structural basis of SMRT recruitment for transcriptional repression.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays, in vivo functional assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.2 Å plus biochemical validation, single lab but highest-quality structural evidence\",\n      \"pmids\": [\"14690607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SMRT function is inhibited by a MAPK kinase kinase cascade downstream of EGF receptor: SMRT is phosphorylated by MEKK-1 and MEK-1, which inhibits its ability to tether to transcription factor partners and causes redistribution from nucleus to a perinuclear/cytoplasmic compartment.\",\n      \"method\": \"Kinase assays, transfection with constitutively active kinase constructs, subcellular fractionation, co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assays plus functional readouts plus localization, multiple orthogonal methods in a single lab\",\n      \"pmids\": [\"10938135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IKKα phosphorylates SMRT on chromatin, triggering nuclear export of SMRT and loss of chromatin-associated HDAC3, which is prerequisite for NF-κB-dependent transcription of cIAP-2 and IL-8; a nonphosphorylatable SMRT mutant blocks NF-κB recruitment and sensitizes cells to apoptosis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), nonphosphorylatable SMRT mutant expression, nuclear export assays, transcriptional reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, mutant SMRT functional assays, and export assays provide multiple orthogonal methods in a single lab\",\n      \"pmids\": [\"15494311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IKKα phosphorylates both SMRT(S2410) and RelA/p65(S536) on chromatin; phospho-SMRT remains bound to NF-κB heterodimer but loses HDAC3 association, enabling p300-mediated acetylation of RelA/p65 at K310; nonphosphorylatable SMRT or RelA mutants maintain active SMRT-HDAC3 repression.\",\n      \"method\": \"ChIP, re-ChIP, nonphosphorylatable mutant expression, transcriptional reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP/re-ChIP plus phospho-mutant functional assays, multiple orthogonal methods, same lab as PMID 15494311 providing partial replication\",\n      \"pmids\": [\"16382138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SMRTe (full-length SMRT) inhibits MEF2C transcriptional activation by translocating HDAC4 from the cytoplasm to discrete nuclear domains and recruiting HDAC5 into these domains; SMRTe synergizes with HDAC4 and HDAC5 to inhibit MEF2C-dependent muscle differentiation gene expression.\",\n      \"method\": \"Indirect immunofluorescence, co-immunoprecipitation, nuclear fractionation, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging plus co-IP plus functional assay, single lab\",\n      \"pmids\": [\"11304536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SMRT binds to the N-terminal coiled-coil domain of STAT5A and STAT5B, strongly represses STAT5-dependent transcription; a hyperactivating mutation in the STAT5 coiled-coil domain that renders it constitutively active abolishes SMRT interaction; SMRT overexpression suppresses IL-3-induced STAT5 target gene expression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, transcriptional reporter assays, overexpression in cell lines\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus functional assays, single lab\",\n      \"pmids\": [\"11726519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SMRT directly interacts with the androgen receptor (AR) ligand-binding domain; the SMRT C-terminal ID2 region mediates interaction; SMRT overexpression inhibits DHT-dependent AR transactivation by inhibiting AR N/C interaction and competing with p160 coactivators; a mutation in the SMRT ID2 corepressor motif abolishes interaction.\",\n      \"method\": \"GST pulldown, mammalian two-hybrid, transcriptional reporter assays, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple interaction assays plus functional reporter assays, single lab\",\n      \"pmids\": [\"12441355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SMRT and N-CoR are regulated by distinct kinase signaling pathways: MEKK1 activation leads to SMRT phosphorylation, dissociation from transcription factor partners in vivo and in vitro, and nuclear-to-cytoplasmic redistribution; N-CoR is refractory to all these MAPK cascade effects.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, subcellular fractionation, kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo interaction assays plus localization, single lab\",\n      \"pmids\": [\"15491994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SMRT is phosphorylated in vivo and in vitro at a CK2 motif centered on serine 1492 within the nuclear receptor interaction domain; CK2-mediated phosphorylation stabilizes SMRT interaction with nuclear hormone receptors.\",\n      \"method\": \"In vitro phosphorylation assays, mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro kinase assay with mutagenesis, single lab, single publication\",\n      \"pmids\": [\"11451368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SMRT binds to the C/EBPβ TAD domain and Nrf2 Neh4/5 domain; glucocorticoid-activated GR recruits SMRT to the GSTA2 promoter to repress C/EBPβ- and Nrf2-mediated GSTA2 induction; siRNA knockdown of SMRT abolishes repression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, GST pulldown, siRNA knockdown, transcriptional reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, pulldown, and siRNA with multiple orthogonal methods in single lab\",\n      \"pmids\": [\"15870285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TBL1 and TBLR1 phosphorylation at the promoter level (e.g., by PKCδ for TBLR1) triggers ubiquitylation and degradation of NCoR/SMRT, enabling corepressor dismissal as a prerequisite for gene activation across multiple signaling pathways (Notch, NF-κB, nuclear receptor ligands).\",\n      \"method\": \"ChIP, co-immunoprecipitation, ubiquitylation assays, siRNA knockdown, kinase assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus ubiquitylation assays plus siRNA, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"18374649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of the tetrameric oligomerization domain of TBL1 reveals how it interacts with both SMRT and GPS2; NMR structure of the GPS2-SMRT interface defines assembly mechanism and stoichiometry of the core repression complex. Mutagenesis and functional assays validate the structural model.\",\n      \"method\": \"X-ray crystallography, NMR spectroscopy, computational docking, mutagenesis, functional assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure and NMR with mutagenesis and functional validation, multiple rigorous orthogonal methods\",\n      \"pmids\": [\"21240272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SMRT interacts with PXR through PXR's ligand-binding domain and SMRT's nuclear receptor-interacting domain 2; the PXR-SMRT interaction is disrupted by PXR ligands (Rif, CTZ), causing exchange of SMRT for the p160 coactivator RAC3; deletion of AF-2 helix enhances SMRT binding; SMRT overexpression inhibits PXR transactivation of CYP3A4 and siRNA depletion enhances it.\",\n      \"method\": \"GST pulldown, yeast two-hybrid, mammalian two-hybrid, co-localization, siRNA knockdown, transcriptional reporter assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple interaction assays plus functional reporter and siRNA, single lab\",\n      \"pmids\": [\"16219912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cdk2 phosphorylates SMRT at multiple sites required for interaction with the peptidyl-prolyl isomerase Pin1; Pin1 interaction decreases SMRT protein stability and reduces SMRT-dependent transcriptional repression; Her2/Neu/ErbB2 receptor activation leads to SMRT destabilization via this Cdk2-Pin1 cascade.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, mutagenesis, protein stability assays, transcriptional reporter assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and mutagenesis plus stability assays, single lab, multiple methods\",\n      \"pmids\": [\"18838553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SMRT repression of nuclear receptors via its receptor interaction domain (RID) controls the adipogenic set point; SMRT(mRID) knock-in mice disrupting NHR interaction develop widespread metabolic defects including increased adiposity (70%), reduced respiration, and altered insulin sensitivity; MEFs from SMRT(mRID) mice display dramatically increased adipogenic capacity.\",\n      \"method\": \"Knock-in mouse model (RID mutation), metabolic phenotyping, MEF differentiation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in model with defined molecular disruption and multiple metabolic phenotypes\",\n      \"pmids\": [\"19066220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SMRT expression and its occupancy on PPAR target gene promoters increase with age; selective disabling of SMRT's RID1 (SMRT(mRID1)) shifts repression to RID2-associated receptors (notably PPARs), causing premature aging-related metabolic diseases with reduced mitochondrial function; SMRT(mRID1) cells show increased susceptibility to oxidative damage rescued by PPAR activation or antioxidant treatment.\",\n      \"method\": \"Knock-in mouse model, ChIP, metabolic and mitochondrial function assays, antioxidant rescue experiments\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knock-in model with ChIP and multiple phenotypic rescue approaches\",\n      \"pmids\": [\"21109196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SMRT is required for full agonist-dependent ERα transcriptional activation; SMRT is recruited (along with ERα and SRC-3) to estrogen-responsive promoters in MCF-7 cells; SMRT depletion (but not HDAC1 or HDAC3 depletion) reduces estradiol-stimulated ERα activity and attenuates estrogen-dependent MCF-7 cell proliferation in a cell-type-specific manner.\",\n      \"method\": \"ChIP, siRNA knockdown, transcriptional reporter assays, cell proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus siRNA with multiple functional readouts, single lab\",\n      \"pmids\": [\"17591692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In frog development, unliganded thyroid hormone receptor recruits N-CoR/SMRT-TBLR1 complexes to chromatinized TR target promoters in vivo, accompanied by histone deacetylation and gene repression; T3 treatment dissociates these complexes and activates gene expression during metamorphosis.\",\n      \"method\": \"Frog oocyte chromatin injection, ChIP assays during spontaneous and T3-induced metamorphosis, dominant-negative constructs\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ChIP in developmental system with functional knockdown, multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"15060155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NCOR1 and NCOR2 redundantly mediate RA-dependent repression of Fgf8 during somitogenesis; Ncor1;Ncor2 double mutants generated by CRISPR/Cas9 exhibit increased Fgf8 expression and FGF signaling; embryo ChIP reveals NCOR1/2 (but not coactivators) are recruited to the Fgf8 RARE in RA-dependent manner, whereas coactivators (not NCOR1/2) are recruited to an activated RARE near Rarb.\",\n      \"method\": \"CRISPR/Cas9 double knockout, embryo ChIP, CRISPR deletion of Fgf8 RARE, phenotypic analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR-based genetic knockout with in vivo ChIP, multiple orthogonal approaches\",\n      \"pmids\": [\"27506116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, ncor2 is required for hematopoietic stem cell emergence in the AGM region; ncor2 knockdown upregulates fos transcription by increasing histone acetylation at the fos promoter, enhancing Vegfd signaling, which promotes Notch-dependent arterial endothelial fate and suppresses hemogenic endothelial specification.\",\n      \"method\": \"Zebrafish morpholino knockdown, ChIP (histone acetylation), epistasis experiments with Vegfd and Notch pathway inhibitors/activators\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus pathway epistasis in zebrafish model, single lab\",\n      \"pmids\": [\"25006126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NCOR1 and NCOR2 loss specifically in GABAergic neurons reduces GABRA2 expression in lateral hypothalamus GABAergic neurons, causing neuron hyperexcitability and impaired hippocampal LTP through a monosynaptic LH-GABAergic to CA3-GABAergic projection; optogenetic activation of this projection causes memory deficits, and targeted manipulation of LH or CA3 neuron activity reverses memory deficits.\",\n      \"method\": \"Cell-type-specific conditional knockout, optogenetics, electrophysiology (LTP), Western blot, behavioral assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout combined with optogenetics, electrophysiology, and rescue experiments, multiple orthogonal approaches\",\n      \"pmids\": [\"30664766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Wnt5a-induced CaMKII directly phosphorylates SMRT at Ser-1407, triggering translocation of SMRT from nucleus to cytoplasm and proteasomal degradation; this destabilizes SMRT and derepresses Notch1 signaling by enhancing Notch1-IC/RBP-Jk association and suppressing RBP-Jk/SMRT association.\",\n      \"method\": \"Kinase assay, phospho-site mutagenesis, co-immunoprecipitation, subcellular fractionation, proteasome inhibitor experiments, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase assay with phospho-site mutagenesis plus co-IP and functional assays, single lab\",\n      \"pmids\": [\"22888005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SMRT forms a protein homodimer; Erk2 phosphorylation disrupts SMRT self-dimerization in vitro and in vivo, resulting in a reorganized corepressor complex with reduced sedimentation coefficient, partial release of HDAC3, TBL-1, and TBLR-1, and inhibition of transcriptional repression.\",\n      \"method\": \"Co-immunoprecipitation, sedimentation analysis (sucrose gradient), in vitro binding and kinase assays, transcriptional reporter assays\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods plus functional assays, single lab\",\n      \"pmids\": [\"20965228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"All components of the NCoR/SMRT corepressor complex (HDAC3, GPS2, NCoR, SMRT, TBL1, TBLR1) interact with HPV E8^E2C protein in an E8-domain-dependent manner; this interaction is required for E8^E2C-mediated inhibition of both viral transcription and HPV origin replication; a dominant-negative NCoR fragment activates transcription and replication only from wild-type but not NCoR/SMRT-binding-deficient E8^E2C genomes.\",\n      \"method\": \"Proteomics (co-precipitation/mass spectrometry), co-immunoprecipitation, co-localization, siRNA knockdown, viral replication assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic identification plus co-IP plus siRNA knockdown plus functional genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"27064408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NCoR1 is the principal mediator of thyroid hormone sensitivity in liver in vivo, while SMRT plays little independent role in TH signaling; however, combined deletion of both SMRT and NCoR1 in liver greatly accentuates hepatic lipid synthesis, indicating cooperative control of hepatic lipid content through regulation of multiple nuclear receptors including TR.\",\n      \"method\": \"Liver-specific conditional knockout mice (SMRT-only, NCoR1-only, double KO), global SMRT KO, metabolic and gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional knockout mouse models with defined molecular disruptions and metabolic phenotyping\",\n      \"pmids\": [\"25421714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPS2 and SMRT co-occupy candidate enhancers with coactivators CBP and MED1 but antagonistically repress eRNA transcription-coupled H3K27 acetylation; corepressor depletion or inflammatory signaling triggers enhancer activation via a similar mechanism; depletion of SMRT/GPS2 causes derepression of inflammatory genes (Ccl2) in macrophages.\",\n      \"method\": \"ChIP-seq, CRISPR genome editing, transcriptional interference, 4C-seq, cistrome analysis, siRNA knockdown, in vivo macrophage-selective eRNA depletion in ob/ob mice\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq plus CRISPR editing plus 4C-seq plus in vivo validation, multiple rigorous orthogonal methods\",\n      \"pmids\": [\"33503407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of two SMRT repression domain 3 (SRD3c) GSI-containing peptides in complex with HDAC4 show that these peptides form β-hairpin structures blocking the catalytic entry site of HDAC4 at class IIa HDAC-specific residues; SMRT binding does not activate the cryptic deacetylase activity of HDAC4, and mutagenesis confirms critical residues (including Arg1369) for optimal binding to HDAC4 and HDAC5.\",\n      \"method\": \"X-ray crystallography, mutagenesis, binding/interaction assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with structure-guided mutagenesis validating interaction, single lab but high-quality structural evidence\",\n      \"pmids\": [\"30321390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCOR2 inhibits antitumor treatment by regulating HDAC3 to repress IRF-1-dependent gene expression and interferon signaling; reducing NCOR2 or impairing its interaction with HDAC3 (via adeno-associated viral NCOR2-HDAC3 competitor) enhances chemotherapy responsiveness and restores antitumor immunity by permitting transcription of IRF-1-regulated proapoptosis and inflammatory genes.\",\n      \"method\": \"Functional proteomic screening of patient-derived organoids, knockdown, AAV competitor construct, in vivo tumor models, gene expression assays\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived organoids plus in vivo models plus mechanistic intervention, multiple orthogonal approaches\",\n      \"pmids\": [\"35618935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VDR-bound SMRT represses CYP24A1; vitamin D3 activates CYP24A1 by dissociating SMRT from VDR at the promoter; PXR 'locks' SMRT onto the CYP24A1 promoter by preventing ligand-dependent dissociation of SMRT from VDR, thereby attenuating vitamin D3 activation; this mechanism was confirmed in Pxr+/+ vs Pxr-/- mice.\",\n      \"method\": \"ChIP, co-immunoprecipitation, transcriptional reporter assays, Pxr knockout mouse model\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus in vivo mouse model with defined genetic disruption, single lab\",\n      \"pmids\": [\"18981260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In type 2 diabetic hearts, loss of NCOR2 repression leads to PPARα-mediated upregulation of MCUb (mitochondrial calcium uniporter inhibitory subunit), limiting mitochondrial Ca2+ uptake and impairing glucose oxidation; identified using Cas9-based gene promoter pulldown coupled with mass spectrometry and confirmed by ChIP.\",\n      \"method\": \"dCas9-based promoter pulldown with mass spectrometry, ChIP assays, gene therapy with dominant-negative MCUb transgene, metabolic and cardiac function assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel dCas9 pulldown method plus ChIP plus in vivo rescue, single lab\",\n      \"pmids\": [\"33303689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCOR1/2 deletion in B cells limits B cell differentiation via impaired V(D)J recombination, attenuates pre-BCR signaling, enhances STAT5-dependent transcription, causes derepression of EZH2-repressed gene modules including p53 pathway, and leads to aberrant Rag1/Rag2 expression with increased structural variants bearing cryptic recombination signal sequences.\",\n      \"method\": \"B cell-specific conditional knockout, whole-genome sequencing, ChIP-seq/ATAC-seq, gene expression analysis, flow cytometry\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with whole-genome sequencing, chromatin profiling, and multiple cellular phenotype readouts\",\n      \"pmids\": [\"36316474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The TEL/ETV6 leukemia-associated transcription repressor's central region (maintained in t(12;21)) recruits a repression complex containing SMRT and mSin3A to mediate transcriptional repression, while its HLH domain represses via a SMRT/Sin3A-independent mechanism.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, deletion analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus functional reporter assays, single lab but interaction confirmed by two methods\",\n      \"pmids\": [\"10544023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"AhR activation by TCDD causes physical interaction between AhR and SMRT (corepressor of RARα), sequestering SMRT into nuclear bodies and activating RARα signaling in a ligand-independent manner; AhR and SMRT co-localize in nuclear bodies during this sequestration.\",\n      \"method\": \"Co-immunoprecipitation, immunocytochemistry, transcriptional reporter assays, TSA inhibitor experiments\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP and co-localization in single lab, limited mechanistic depth\",\n      \"pmids\": [\"16480812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VDR specifically interacts with SMRT interaction domain 1 (ID1) rather than ID2; specific residues within and outside the extended helix motif of SMRT-ID1 are required for VDR binding; SMRT mutants defective in VDR interaction fail to repress endogenous VDR target genes (osteocalcin, CYP24A1) in vivo.\",\n      \"method\": \"One- plus two-hybrid genetic selection, siRNA knockdown, ChIP, mutagenesis, transcriptional reporter assays\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic selection for missense mutations plus ChIP plus siRNA, multiple methods in single lab\",\n      \"pmids\": [\"19098224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Alternative splicing of SMRT generates isoforms with 1, 2, or 3 CoRNR box motifs; all six isoforms are expressed in human cell lines; the full complement of CoRNR boxes rather than individual box identity determines interaction affinity with nuclear receptors; 1-box isoform discriminates between DNA response elements, 2-box isoforms prefer TR complexes, and 3-box isoforms show differential receptor binding.\",\n      \"method\": \"RT-PCR (isoform detection), in vitro binding affinity measurements with nuclear receptor-DNA complexes\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic binding affinity measurements across isoforms and receptor complexes, single lab\",\n      \"pmids\": [\"18752469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Combined global postnatal deletion of NCOR1 and SMRT in adult mice is lethal within ten days; double knockout mice rapidly develop hypoglycemia, hypothermia, and hepatosteatosis with alterations in lipogenesis and beta-oxidation; this phenotype is distinct from HDAC3 knockout mice, implying NCOR1/SMRT together regulate a critical pathway required for adult survival that is separate from HDAC3.\",\n      \"method\": \"Tamoxifen-inducible conditional double knockout mouse model (UBC-Cre-ERT2), metabolic phenotyping, hepatic gene expression analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible conditional double knockout with defined timing, comparison to HDAC3 KO separates mechanisms, multiple metabolic phenotypes\",\n      \"pmids\": [\"34390859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC3 protein stability in epidermal cells depends on NCoR and SMRT functioning redundantly; however, point mutations in the NCoR and SMRT deacetylase-activating domains (DAD), which abolish HDAC3's enzymatic function, still permit normal epidermal stratification, indicating HDAC3's roles in this context are largely independent of its histone deacetylase activity.\",\n      \"method\": \"Conditional knockout of NCoR/SMRT in epidermis, DAD point-mutation knock-in mice, ChIP-seq, phenotypic analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo genetic models (KO and DAD point-mutant knock-in) with ChIP-seq validation\",\n      \"pmids\": [\"32467224\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NCOR2/SMRT is a transcriptional corepressor that assembles a large (~1.5–2 MDa) multi-subunit complex containing HDAC3 (which it activates through its SANT-domain-containing deacetylase activating domain, DAD), GPS2, TBL1, and TBLR1; it is recruited to gene promoters via direct interaction with unliganded nuclear hormone receptors (through CoRNR-box receptor interaction domains), POZ/BTB domain transcription factors (BCL6), and other transcription factors (STAT5, AR, ERα, VDR, PXR, C/EBPβ, Nrf2), mediating chromatin compaction and transcriptional silencing; its repressive activity is relieved by multiple kinase signaling cascades (MAPK/MEKK1, IKKα, CaMKII, Cdk2/Pin1) that phosphorylate SMRT to trigger its nuclear export or proteasomal degradation, enabling corepressor-to-coactivator exchange; and in vivo, NCOR2 plays essential roles in metabolism (adipogenesis set point, mitochondrial oxidative metabolism, hepatic lipid homeostasis in cooperation with NCOR1), neural GABAergic signaling and memory, hematopoiesis (HSC emergence and B cell differentiation/genomic integrity), and embryonic development (RA-dependent Fgf8 repression during somitogenesis).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NCOR2 (SMRT) is a transcriptional corepressor that nucleates a large multi-subunit complex to enforce chromatin-based gene silencing across nuclear receptor and developmental signaling programs [#1, #2]. It assembles a core repression module with HDAC3, TBL1/TBLR1, and GPS2, whose architecture and stoichiometry have been defined structurally [#2, #18]; within this complex NCOR2 is not a passive scaffold but an obligate activator of HDAC3, supplying a SANT-containing deacetylase-activating domain (DAD) that is necessary and sufficient to reconstitute HDAC3 enzymatic activity from purified components [#3]. NCOR2 is recruited to chromatin through tandem CoRNR-box receptor interaction domains that engage unliganded nuclear receptors (TR, RAR, AR, VDR, PXR, ER\\u03b1) [#5, #13, #40], and through dedicated repression domains that bind the BCL6 BTB/POZ homodimer\\u2014a contact resolved at 2.2 \\u00c5\\u2014and other transcription factors including STAT5 and C/EBP\\u03b2/Nrf2 [#7, #12, #16]. The number of CoRNR-box motifs, set by alternative splicing, tunes receptor-complex selectivity [#41]. Its repressive output is reversibly disabled by phosphorylation: MAPK/MEKK1, IKK\\u03b1, CaMKII, and Cdk2/Pin1 cascades phosphorylate NCOR2 to drive nuclear export, dimer disassembly, or degradation, and TBL1/TBLR1-coupled ubiquitylation dismisses the complex to permit corepressor-to-coactivator exchange [#8, #9, #17, #28]. In vivo, NCOR2 acting through its receptor interaction domains sets the adipogenic and mitochondrial-oxidative set point and, redundantly with NCOR1, controls hepatic lipid homeostasis, RA-dependent Fgf8 repression in somitogenesis, GABAergic neuronal excitability and memory, and B-cell differentiation and genomic integrity [#21, #25, #27, #31, #37, #42]. NCOR2 is also co-opted in disease, repressing IRF-1-dependent interferon and proapoptotic genes via HDAC3 to limit antitumor immunity [#34].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established NCOR2/SMRT as a ubiquitous nuclear factor that binds unliganded nuclear receptors and represses their target genes, defining its founding role as a hormone-receptor corepressor.\",\n      \"evidence\": \"Co-IP and reporter assays in transfected mammalian cells, plus antirepressor activity of the receptor-interacting domain\",\n      \"pmids\": [\"8755515\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the repression machinery downstream of receptor binding\", \"Mechanism of silencing unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Connected NCOR2's repressive output to histone deacetylation by showing it bridges receptors to an mSin3A/HDAC1 complex, providing the first enzymatic mechanism for corepression.\",\n      \"evidence\": \"Reciprocal co-IP and reporter assays with HDAC inhibitors (TR/RAR systems); parallel deletion mapping of two receptor-interaction and two repression domains\",\n      \"pmids\": [\"9150137\", \"9415406\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HDAC1/Sin3 later shown to be a minor partner relative to HDAC3\", \"Stoichiometry and complex composition not resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Extended corepressor recruitment beyond nuclear receptors to BTB/POZ transcription factors by showing BCL6-mediated repression requires direct SMRT interaction.\",\n      \"evidence\": \"Y2H, mammalian two-hybrid, GST pulldown, co-localization, and reporter assays\",\n      \"pmids\": [\"9824158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the SMRT-BTB contact not yet defined\", \"In vivo BCL6 target gene consequences not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified the physiological core complex as a ~1.5\\u20132 MDa assembly of SMRT/N-CoR with HDAC3 and TBL1, and showed TBL1 bridges to histone H3 and potentiates repression, reframing the central enzymatic partner from HDAC1 to HDAC3.\",\n      \"evidence\": \"Immunoaffinity purification of HeLa nuclear complexes, in vitro receptor binding, antibody microinjection in Xenopus, histone-interaction and reporter assays\",\n      \"pmids\": [\"10944117\", \"10809664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SMRT confers HDAC3 activity not yet explained\", \"Subunit stoichiometry unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined NCOR2 as an obligate allosteric activator of HDAC3 via its SANT-containing DAD, explaining why HDAC3 is catalytically inert without the corepressor.\",\n      \"evidence\": \"In vitro reconstitution with purified components, HDAC assays, and DAD mutagenesis\",\n      \"pmids\": [\"11509652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo requirement of DAD-driven activity for specific genes not yet tested\", \"Structural mechanism of activation not solved here\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed NCOR2 also regulates class IIa HDACs and non-receptor factors, translocating HDAC4 to nuclear domains to silence MEF2C, and repressing STAT5, broadening its target factor repertoire.\",\n      \"evidence\": \"Immunofluorescence, nuclear fractionation, co-IP, Y2H, and reporter assays (MEF2C/HDAC4-5; STAT5)\",\n      \"pmids\": [\"11304536\", \"11726519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional assays\", \"In vivo significance for muscle/cytokine programs not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the atomic basis of corepressor recruitment by solving the BCL6 BTB homodimer bound to two symmetric SMRT peptides.\",\n      \"evidence\": \"2.2 \\u00c5 X-ray crystallography with biochemical and in vivo functional validation\",\n      \"pmids\": [\"14690607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to a short SMRT fragment\", \"Does not address full-complex assembly\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established phosphorylation as the master switch turning off NCOR2 repression, with MEKK1/MAPK and IKK\\u03b1 cascades driving nuclear export and chromatin loss of SMRT-HDAC3 to license NF-\\u03baB and other activation; NCOR1 is refractory, defining functional divergence of the paralogs.\",\n      \"evidence\": \"Kinase assays, ChIP, nonphosphorylatable mutants, nuclear export and fractionation, reporter assays; CK2 site mapping\",\n      \"pmids\": [\"10938135\", \"15494311\", \"15491994\", \"11451368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of relevant kinases not enumerated\", \"Quantitative dynamics of export vs degradation not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated in vivo developmental corepression by showing unliganded TR recruits N-CoR/SMRT-TBLR1 to chromatinized targets, with T3-induced dismissal driving metamorphic gene activation.\",\n      \"evidence\": \"Frog oocyte chromatin injection and ChIP across metamorphosis with dominant-negative constructs\",\n      \"pmids\": [\"15060155\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct genetic loss-of-function not performed in this system\", \"Mammalian developmental relevance addressed later\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Refined the IKK\\u03b1 switch by showing SMRT remains NF-\\u03baB-bound after phosphorylation but selectively loses HDAC3, enabling p300 acetylation of RelA, distinguishing complex remodeling from wholesale dismissal.\",\n      \"evidence\": \"ChIP/re-ChIP and phospho-mutant functional assays\",\n      \"pmids\": [\"16382138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab system\", \"Generality across NF-\\u03baB targets not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected NCOR2's molecular receptor interactions to organismal physiology by showing its RID-mediated repression sets the adipogenic threshold, with RID-mutant mice developing adiposity and insulin defects.\",\n      \"evidence\": \"SMRT(mRID) knock-in mice, metabolic phenotyping, MEF differentiation assays\",\n      \"pmids\": [\"19066220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which receptor(s) dominate the adipogenic phenotype not isolated here\", \"Tissue-specific contributions unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established corepressor dismissal as an active, ubiquitin-coupled step by showing TBL1/TBLR1 phosphorylation triggers NCoR/SMRT ubiquitylation and degradation as a prerequisite for activation; Cdk2/Pin1 separately destabilizes SMRT downstream of ErbB2.\",\n      \"evidence\": \"ChIP, ubiquitylation assays, siRNA, kinase assays; co-IP, stability and reporter assays for Cdk2-Pin1\",\n      \"pmids\": [\"18374649\", \"18838553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase identity in some pathways not defined\", \"Cdk2-Pin1 axis single-lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked NCOR2 to mitochondrial oxidative metabolism and aging by showing RID1-selective disabling redirects repression to PPARs, causing premature metabolic disease rescuable by PPAR activation or antioxidants; also showed Erk2 disrupts SMRT homodimerization to remodel the complex.\",\n      \"evidence\": \"SMRT(mRID1) knock-in mice with ChIP and rescue; sucrose-gradient sedimentation and kinase assays for dimerization\",\n      \"pmids\": [\"21109196\", \"20965228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dimerization study single-lab in vitro\", \"Direct causal PPAR target genes for aging phenotype not fully enumerated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the assembly mechanism of the core repression module by determining the TBL1 tetrameric oligomerization domain bound to SMRT and the GPS2-SMRT interface.\",\n      \"evidence\": \"X-ray crystallography, NMR, docking, mutagenesis, functional assays\",\n      \"pmids\": [\"21240272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-complex structure including HDAC3 not solved\", \"Dynamics of phospho-triggered disassembly not captured\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expanded the kinase-off-switch to Wnt5a/CaMKII-driven SMRT degradation that derepresses Notch1, and established that NCOR2 can also be required for full agonist-dependent ER\\u03b1 activation, revealing a context-dependent coactivator-like role.\",\n      \"evidence\": \"CaMKII kinase/phospho-mutant, co-IP, fractionation, proteasome assays; ChIP and siRNA for ER\\u03b1 in MCF-7\",\n      \"pmids\": [\"22888005\", \"17591692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ER\\u03b1 coactivation by a corepressor not fully explained\", \"Both single-lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated developmental and hematopoietic roles in vivo, with zebrafish ncor2 required for HSC emergence via fos/Vegfd/Notch control, and mouse genetics showing NCoR1 dominates hepatic TH sensitivity while NCoR1/SMRT cooperatively restrain hepatic lipid synthesis.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with ChIP and pathway epistasis; liver-specific single and double conditional knockout mice\",\n      \"pmids\": [\"25006126\", \"25421714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Zebrafish knockdown is morpholino-based\", \"Receptor targets mediating hepatic lipid phenotype only partially defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established direct, redundant developmental corepression in mammals by showing NCOR1/2 are recruited to the Fgf8 RARE to enforce RA-dependent repression during somitogenesis; also revealed viral hijacking of the complex by HPV E8^E2C.\",\n      \"evidence\": \"CRISPR/Cas9 double knockout with embryo ChIP and RARE deletion; proteomics, co-IP, siRNA and viral replication assays\",\n      \"pmids\": [\"27506116\", \"27064408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual contribution of NCOR2 vs NCOR1 not separated in Fgf8 study\", \"Viral mechanism is single-system\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided structural insight into how SMRT engages class IIa HDACs, showing SRD3c GSI peptides form \\u03b2-hairpins blocking the HDAC4 catalytic entry without activating its cryptic deacetylase activity\\u2014contrasting with HDAC3 activation.\",\n      \"evidence\": \"X-ray crystallography with structure-guided mutagenesis\",\n      \"pmids\": [\"30321390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of class IIa binding in cells not addressed here\", \"Single-lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a neural circuit function by showing NCoR1/2 loss in GABAergic neurons reduces GABRA2, driving hyperexcitability and impaired LTP through an LH-to-CA3 GABAergic projection controlling memory.\",\n      \"evidence\": \"Cell-type-specific conditional knockout, optogenetics, electrophysiology, behavior, and rescue manipulations\",\n      \"pmids\": [\"30664766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional regulation of GABRA2 by NCOR2 vs NCOR1 not separated\", \"Generality beyond LH-CA3 circuit unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed HDAC3 activity is dispensable for some in vivo NCOR functions and extended metabolic roles to the heart, where loss of NCOR2 repression elevates PPAR\\u03b1-driven MCUb and impairs cardiac glucose oxidation in diabetes.\",\n      \"evidence\": \"Epidermal NCoR/SMRT KO and DAD point-mutant knock-in with ChIP-seq; dCas9 promoter pulldown/MS, ChIP, and gene therapy in diabetic hearts\",\n      \"pmids\": [\"32467224\", \"33303689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cardiac study single-lab with novel method\", \"Which deacetylase-independent activities matter in epidermis not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that NCOR1/SMRT together are essential for adult survival via a hepatic lipid/metabolic pathway distinct from HDAC3, and showed at enhancers SMRT/GPS2 antagonize eRNA-coupled H3K27 acetylation to restrain inflammatory genes.\",\n      \"evidence\": \"Inducible global double knockout mice with metabolic phenotyping; ChIP-seq, CRISPR, 4C-seq, and in vivo macrophage eRNA depletion\",\n      \"pmids\": [\"34390859\", \"33503407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the survival-critical pathway not pinpointed\", \"Direct enhancer targets driving lethality unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated NCOR2 functions in immunity and cancer\\u2014restraining B-cell differentiation and genomic stability, and repressing IRF-1-dependent interferon/proapoptotic genes via HDAC3 to limit antitumor responses, identifying the NCOR2-HDAC3 interface as a therapeutic target.\",\n      \"evidence\": \"B-cell conditional knockout with WGS/ChIP-seq/ATAC-seq; patient-derived organoid screening, AAV NCOR2-HDAC3 competitor, and in vivo tumor models\",\n      \"pmids\": [\"36316474\", \"35618935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NCOR2 vs NCOR1 specificity in B cells not fully separated\", \"Clinical translatability of the competitor not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How phosphorylation, ubiquitylation, dimerization, and splicing collectively program promoter-specific corepressor dismissal versus retention, and how NCOR2-specific (vs NCOR1-redundant) functions are partitioned across tissues, remain unresolved.\",\n      \"evidence\": \"No single study in the corpus integrates these regulatory layers with paralog-specific genetics genome-wide\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking SMRT post-translational state to gene-selective output\", \"Paralog division of labor incompletely defined\", \"Full-complex structure including HDAC3 unsolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 5, 6, 24, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 33]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 18]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [9, 10, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 11, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 4, 32]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3, 32, 43]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9, 17, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [21, 22, 31, 36, 42]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [24, 25, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [32, 34, 37]}\n    ],\n    \"complexes\": [\"NCoR/SMRT corepressor complex (HDAC3-TBL1-TBLR1-GPS2)\", \"mSin3A/HDAC1 complex\"],\n    \"partners\": [\"HDAC3\", \"TBL1\", \"TBLR1\", \"GPS2\", \"BCL6\", \"HDAC4\", \"STAT5\", \"NCOR1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}