{"gene":"RCOR1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"CoREST is an integral component of a distinct HDAC complex (CoREST-HDAC) composed of HDAC1/2, CoREST, and a polyamine oxidase homolog; the HDAC1/2-interacting region of CoREST maps to a 179-aa region containing a SANT domain, and this region is required for CoREST corepressor function. ZNF217 (not REST) was found associated with this complex.","method":"Biochemical purification, Co-IP, domain mapping by truncation, functional repression assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping with deletion constructs, functional corepressor assays in a single focused study replicated by independent biochemical characterization","pmids":["11171972"],"is_preprint":false},{"year":2000,"finding":"CoREST/KIAA0071 stably associates with HDAC1 and HDAC2 in a distinct ~9.5S complex (complex cI) that also contains a FAD-dependent oxidoreductase (KIAA0601/LSD1); the SANT domain of CoREST is shared with other HDAC1/2-interacting proteins and may mediate complex assembly.","method":"Native complex purification, mass spectrometry, glycerol gradient sedimentation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — native complex purification with MS identification, corroborated by multiple independent labs","pmids":["11102443"],"is_preprint":false},{"year":2000,"finding":"mSin3A interacts with REST through REST's N-terminal repressor domain (via the PAH2 domain of mSin3A), and CoREST interacts with REST's C-terminal repressor domain; both corepressors associate with REST in mammalian cells, with mSin3A required constitutively and CoREST recruited for more specialized repressor functions.","method":"Co-IP in mammalian cells, yeast two-hybrid, yeast genetic rescue (Sin3-null rescue), in vivo repression assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, yeast genetics, multiple orthogonal methods in one study","pmids":["10734093"],"is_preprint":false},{"year":2005,"finding":"CoREST is essential for LSD1 (BHC110)-mediated demethylation of H3K4 on nucleosomal substrates: recombinant LSD1 alone cannot demethylate nucleosomes, but LSD1-containing complexes can; in vitro reconstitution with recombinant subunits shows CoREST both stimulates demethylation on core histones and enables nucleosomal demethylation by enhancing LSD1-nucleosome association. Depletion of CoREST in cells leads to de-repression of REST-responsive genes and increased H3K4 methylation.","method":"In vitro reconstitution with recombinant subunits, histone demethylase assay on nucleosomal substrates, CoREST depletion (RNAi) with gene expression and histone modification readouts","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with recombinant subunits, in vitro enzymatic assay on nucleosomes, orthogonal in vivo RNAi validation","pmids":["16079794"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of the LSD1-CoREST complex reveals an elongated structure with a long stalk connecting the LSD1 catalytic domain and the CoREST SANT2 domain; CoREST SANT2 interacts with DNA, and disruption of the SANT2-DNA interaction diminishes CoREST-dependent nucleosomal demethylation by LSD1; the overall shape suggests bivalent nucleosome binding.","method":"X-ray crystallography, mutagenesis of CoREST SANT2 domain, nucleosomal demethylase activity assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis of functional interfaces plus enzymatic activity assay, single rigorous study with multiple orthogonal methods","pmids":["16885027"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the LSD1-CoREST complex bound to a substrate-like H3 peptide inhibitor reveals that CoREST plays an active role in substrate recognition; LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged active-site pocket; the geometry is consistent with flavin-mediated oxidation of the substrate amino-methyl group.","method":"X-ray crystallography of LSD1-CoREST-peptide ternary complex","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of ternary complex providing direct structural mechanism","pmids":["17537733"],"is_preprint":false},{"year":2007,"finding":"CoREST and LSD1 mediate transcriptional repression by Gfi-1 and Gfi-1b in hematopoiesis: CoREST and LSD1 associate with Gfi-1/1b via the SNAG repression domain; Gfi-1b recruits these cofactors to target gene promoters in vivo; inhibition of CoREST and LSD1 perturbs erythroid, megakaryocytic, and granulocytic differentiation.","method":"Affinity purification/MS of Gfi-1b complexes, Co-IP, ChIP at target promoters, RNAi knockdown with differentiation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — AP-MS to identify complex, reciprocal Co-IP, ChIP at endogenous targets, RNAi with cellular phenotype readouts","pmids":["17707228"],"is_preprint":false},{"year":2008,"finding":"CoREST interacts with Hsp70 and represses HSF1-dependent transcription of the hsp70 gene; CoREST is bound to the hsp70 promoter under basal conditions and its binding increases during heat shock; knockdown of CoREST prevents Hsp70-mediated repression of HSF1-dependent transcription.","method":"Co-IP (CoREST-Hsp70), ChIP at hsp70 promoter, shRNA knockdown, reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, ChIP at endogenous promoter, shRNA knockdown with functional readout, multiple orthogonal methods","pmids":["18657505"],"is_preprint":false},{"year":2008,"finding":"ZNF198 binds preferentially to the intact LSD1-CoREST-HDAC1 (LCH) ternary complex but not individual subunits; ZNF198 and REST binding to LCH are mutually exclusive; ZNF198 stabilizes LCH on chromatin independently of LCH; SUMO modification of HDAC1 weakens its interaction with CoREST but stimulates its binding to ZNF198; the LCH- and HDAC1-SUMO-binding domains of ZNF198 map to MYM-type zinc finger repeats.","method":"Co-IP, GST pulldown, ChIP, domain mapping, in vitro SUMOylation assay, RNAi knockdown","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vitro SUMOylation with functional consequences on CoREST interaction, ChIP, multiple orthogonal methods","pmids":["18806873"],"is_preprint":false},{"year":2008,"finding":"CoREST is SUMOylated at lysine 294 by the E3 ligase PIASxbeta; SENP1 mediates desumoylation; mutation of the CoREST sumoylation site compromises its corepressor activity, indicating SUMO-1 modification is required for full repressive function.","method":"In vivo and in vitro sumoylation assays, Co-IP, mutagenesis of sumoylation site, reporter-based repression assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, multiple methods (sumoylation assay + mutagenesis + reporter), but not independently replicated","pmids":["18854179"],"is_preprint":false},{"year":2009,"finding":"Nurr1 recruits the CoREST corepressor complex to NF-κB-p65 on inflammatory gene promoters in microglia and astrocytes in a signal-dependent manner, resulting in clearance of NF-κB-p65 and transcriptional repression of pro-inflammatory genes.","method":"Co-IP (Nurr1-CoREST), ChIP at inflammatory gene promoters, Nurr1 knockdown/overexpression with cytokine/gene expression readouts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP at endogenous targets, loss-of-function with defined cellular phenotype, published in high-impact venue with multiple orthogonal approaches","pmids":["19345186"],"is_preprint":false},{"year":2005,"finding":"During HSV-1 infection, ICP0 interacts with CoREST and displaces HDAC1 from the CoREST/REST complex; subsequently, CoREST and HDAC1 are phosphorylated by viral protein kinases and partially translocated to the cytoplasm; these events enable derepression of viral gene expression.","method":"Co-IP of endogenous CoREST/REST/HDAC1 complex, immunofluorescence localization, infection with ICP0-mutant viruses","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with endogenous proteins, localization studies, genetic dissection using multiple viral mutants","pmids":["15897453"],"is_preprint":false},{"year":2007,"finding":"ICP0 blocks silencing of HSV DNA by displacing HDAC1 from the CoREST-REST complex; a truncated CoREST (CoREST 146-482) that displaces HDAC1 from the complex can functionally substitute for ICP0 to rescue viral replication in multiple cell lines.","method":"Recombinant virus construction, viral yield assays, Co-IP of CoREST/REST/HDAC1 complex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-mapping functional rescue with recombinant virus, Co-IP, multiple cell lines","pmids":["17939992"],"is_preprint":false},{"year":2009,"finding":"LSD1 is a key component of the CoREST/REST repressor complex engaged by HSV-1; in infected cells LSD1 is partially degraded or remains stably associated with CoREST and is partially translocated to the cytoplasm; LSD1 demethylates histones bound to viral α gene promoters to enable their expression.","method":"Co-IP, immunofluorescence, infection with ICP0-mutant and wild-type viruses, fractionation","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and localization studies, multiple viral mutants, single lab","pmids":["19193804"],"is_preprint":false},{"year":2010,"finding":"Deletion of LSD1 in mouse ES cells causes a reduction in CoREST protein levels and associated HDAC activity, demonstrating that LSD1 is required for CoREST stability; this results in a global increase in H3K56 acetylation but not H3K4 methylation in ES cells.","method":"Conditional gene knockout in ES cells, Western blot for CoREST protein, HDAC activity assay, histone modification analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with defined biochemical phenotype (CoREST protein loss, HDAC activity reduction), multiple orthogonal readouts","pmids":["20713442"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of LSD1-CoREST bound to a SNAIL1 peptide reveals molecular mimicry: the N-terminal residues of SNAIL1 bind to the enzyme active-site cleft mimicking the H3 tail, providing a mechanism by which transcription factors can competitively inhibit LSD1 substrate binding.","method":"X-ray crystallography of LSD1-CoREST-SNAIL1 peptide complex, molecular dynamics simulation","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of ternary complex with mechanistic interpretation, corroborated by MD simulation","pmids":["21300290"],"is_preprint":false},{"year":2012,"finding":"Sumoylation of Braf35 (a subunit of the LSD1-CoREST complex) is required for full repression of neuronal genes and for CoREST complex occupancy at target genes; Braf35-iBraf heterodimerization impairs Braf35 interaction with LSD1-CoREST and blocks Braf35 sumoylation, thereby antagonizing the complex's repressive activity.","method":"Sumoylation assays, Co-IP, ChIP, gain/loss-of-function in P19 cells and chick neural tube","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, functional in vivo rescue in chick neural tube, multiple orthogonal assays","pmids":["22570500"],"is_preprint":false},{"year":2011,"finding":"CoREST depletion by in utero electroporation in mouse embryonic cortex markedly delays the transition of newborn cortical pyramidal neurons from multipolar to bipolar morphology and impairs onset of radial migration; this function requires LSD1 and is independent of REST.","method":"In utero electroporation (shRNA knockdown), live imaging/morphological analysis of cortical neuron migration","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean in vivo loss-of-function with defined cellular/morphological phenotype, LSD1 requirement tested","pmids":["21878487"],"is_preprint":false},{"year":2002,"finding":"In C. elegans, spr-1 (CoREST ortholog) is a negative regulator of LIN-12/Notch signaling acting cell-autonomously in the nucleus; genetic epistasis places spr-1 upstream of Hindsight; human CoREST can substitute for SPR-1, demonstrating functional conservation.","method":"Genetic screen, suppressor analysis, genetic epistasis with lin-12 alleles, rescue with human CoREST, nuclear localization by imaging","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis, cross-species rescue, multiple alleles tested","pmids":["12381669"],"is_preprint":false},{"year":2014,"finding":"CoREST1 and CoREST2 differ in their interaction with HDAC1/2: a single non-conserved leucine in the first SANT domain of CoREST2 severely weakens its association with HDAC1/2, and CoREST2 represses transcription in an HDAC-independent manner; CoREST3 interacts equally with LSD1 but leads to reduced LSD1 catalytic efficiency and lower transcriptional repression; all three CoRESTs interact equally with LSD1.","method":"Biochemical purification, Co-IP, in vitro demethylase assay, domain mutagenesis, transcriptional repression reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzymatic assays, mutagenesis of SANT domain, Co-IP, reporter assays, multiple orthogonal methods","pmids":["24820421"],"is_preprint":false},{"year":2014,"finding":"Rcor3 competitively inhibits LSD1-mediated nucleosomal H3K4 demethylation, while Rcor1 and Rcor2 facilitate it; appending the SANT2 domain of Rcor1 to Rcor3 confers the ability to facilitate demethylation; Rcor3 is recruited to target genes by Gfi1b and LSD1, leading to inhibition of H3K4 demethylation and transcriptional derepression.","method":"In vitro nucleosomal demethylase assay, domain chimera construction, ChIP at endogenous targets, Co-IP, RNAi/overexpression in hematopoietic cells with differentiation readouts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay with domain chimeras, ChIP, Co-IP, cellular differentiation phenotype, multiple orthogonal methods","pmids":["24843136"],"is_preprint":false},{"year":2014,"finding":"Rcor1 conditional knockout in mice causes profound anemia due to arrest of definitive erythroid cells at the proerythroblast-to-basophilic erythroblast transition; Rcor1-null erythroid progenitors aberrantly form myeloid colonies; Csf2rb (CSF2 receptor β) is a direct target for both Rcor1 and Gfi1b in erythroid cells, and its derepression leads to CSF2-dependent phospho-Stat5 hypersensitivity.","method":"Conditional knockout mouse, colony assay, gene expression profiling, ChIP, cytokine signaling assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined hematopoietic phenotype, ChIP at direct target, signaling pathway rescue","pmids":["24652990"],"is_preprint":false},{"year":2015,"finding":"The corepressor Rcor1 is essential for murine erythropoiesis; conditional adult deletion causes complete cell-autonomous block in erythroid maturation; Rcor1-deficient monocytes show extensive cytokine-dependent self-renewal and overexpress HSC/progenitor genes including Gata2, Meis1, Hoxa9.","method":"Conditional knockout mouse (adult), bone marrow transplantation, lineage analysis, colony assays, gene expression","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with cell-autonomous phenotype established by transplantation, multiple lineages analyzed","pmids":["26119982"],"is_preprint":false},{"year":2014,"finding":"ZNF750 interacts with RCOR1, KDM1A (LSD1), and CTBP1/2 through conserved PLNLS sequences; RCOR1 and KDM1A colocalize with ZNF750 at progenitor gene loci and are required for progenitor gene repression, while KLF4 (not KDM1A) is required for ZNF750-mediated activation of differentiation genes.","method":"Co-IP, ChIP-seq, gene depletion (RNAi) with gene expression readouts","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, genome-wide ChIP-seq, functional RNAi validation of pathway placement","pmids":["25228645"],"is_preprint":false},{"year":2015,"finding":"LSD1-CoREST functions as an 'ergonomic clamp' on nucleosomes, inducing detachment of the H3 tail from nucleosomal DNA to make it available for demethylation; CoREST's DNA-binding activity and LSD1's catalytic domain act cooperatively through a bivalent, competitive interaction with nucleosomal substrates.","method":"Covalent crosslinking of LSD1-CoREST to semisynthetic nucleosomal particles, SAXS, binding assays, site-directed mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SAXS structural analysis, semisynthetic nucleosome crosslinking, mutagenesis of binding interfaces, multiple orthogonal methods","pmids":["25730864"],"is_preprint":false},{"year":2015,"finding":"Extranucleosomal DNA dramatically enhances LSD1/CoREST demethylase activity on nucleosome substrates; LSD1/CoREST binds the nucleosome as a 1:1 complex; both LSD1 and CoREST subunits make close contact with DNA around the nucleosome dyad and extranucleosomal DNA as shown by photocrosslinking.","method":"Demethylase activity assay with nucleosome variants, EMSA, photocrosslinking","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay, photocrosslinking to define contact sites, multiple approaches","pmids":["25916846"],"is_preprint":false},{"year":2017,"finding":"PIASγ (SUMO E3 ligase) interacts with CoREST1 (RCOR1), CoREST2, and CoREST3, increases their protein stability, and facilitates their SUMOylation by SUMO-2; SUMO-conjugating enzyme Ubc9 facilitates SUMOylation without affecting protein levels; SUMOylation-deficient CoREST1 and CoREST3 maintain similar interactions with LSD1 and HDAC1/2 and similar repressor capacity.","method":"Co-IP, in vivo and in vitro SUMOylation assays, SENP-1 desumoylation, mutagenesis of acceptor lysines, repressor activity assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, enzymatic SUMOylation assays, mutagenesis, but single lab","pmids":["29555846"],"is_preprint":false},{"year":2017,"finding":"ZNF516 physically associates with the CtBP/LSD1/CoREST complex and transcriptionally represses EGFR and other proliferation/motility genes; the ZNF516-CtBP/LSD1/CoREST complex inhibits proliferation and invasion of breast cancer cells.","method":"Co-IP, ChIP-seq, RNAi knockdown with proliferation/invasion assays, xenograft models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, functional knockdown assays, single lab","pmids":["28947780"],"is_preprint":false},{"year":2017,"finding":"RCOR1 forms complexes with REST corepressors RCOR2 and the transcription factor INSM1 in embryonic mouse brain progenitors; double knockout of Rcor1/2 causes excess neural progenitor production at the expense of neurons; Rest transcripts are upregulated in the double KO, and reducing Rest partially rescues the interganglionic sulcus closure defect.","method":"Co-IP (INSM1-RCOR1/2 complexes), conditional double knockout mouse, genetic epistasis (Rest rescue), gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, double conditional KO with perinatal lethality phenotype, genetic epistasis rescue, multiple orthogonal approaches","pmids":["28049845"],"is_preprint":false},{"year":2020,"finding":"The CoREST complex (RCOR1/2 scaffold, HDAC1/2, LSD1) exists in at least two distinct conformational states with different kinetics; the activities of LSD1 and HDAC1 within the complex are closely coupled, not independent; EM of the ternary complex reveals a bi-lobed structure with LSD1 and HDAC1 at opposite ends; EM of CoREST-nucleosome complex reveals a mode of chromatin engagement contrasting with previous models.","method":"Electron microscopy (EM) of ternary LSD1-HDAC1-RCOR1 complex and CoREST-nucleosome complex, enzymatic activity assays (demethylase and deacetylase cross-coupling)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — EM structural analysis plus coupled enzymatic activity assays demonstrating crosstalk, multiple orthogonal methods","pmids":["32101746"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of LSD1/CoREST bound to a 191-bp nucleosome reveals that the LSD1 catalytic domain binds extranucleosomal DNA and is positioned ~100 Å from the nucleosome core; CoREST makes critical contacts with both histone and DNA components of the nucleosome, explaining its essential role in nucleosomal demethylation; the LSD1(K661A) mutant commonly used as catalytically inactive in vivo retains substantial H3K4 demethylase activity on nucleosomes.","method":"X-ray crystallography of LSD1/CoREST-nucleosome complex, demethylase activity assay with LSD1(K661A) mutant","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of full LSD1/CoREST-nucleosome complex with functional mutagenesis validation","pmids":["32396821"],"is_preprint":false},{"year":2020,"finding":"RCOR1 is predominantly associated with transcriptionally active genes genome-wide; RCOR1 associates with RNA Polymerase II during transcription and deacetylates its CTD at lysine 7, dampening productive elongation at actively transcribing genes (non-canonical function independent of histone modification).","method":"ChIP-seq (genome-wide), Co-IP (RCOR1-POL II), biochemical deacetylation assay of POL II CTD","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, in vitro/biochemical CTD deacetylation assay, multiple orthogonal methods","pmids":["35322029"],"is_preprint":false},{"year":2020,"finding":"Rcor1 (and Rcor2) is physically associated with Foxp3 in Tregs; conditional deletion of Rcor1 in Foxp3+ Tregs decreases peripheral Treg proportions, increases Treg expression of IL-2 and IFN-γ, impairs suppression of homeostatic proliferation, and enhances antitumor immunity.","method":"Co-IP (Rcor1-Foxp3), conditional knockout mouse, flow cytometry, allograft/tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, conditional KO with defined immune phenotype, multiple in vivo models","pmids":["31917688"],"is_preprint":false},{"year":2022,"finding":"CoREST is recruited to regulatory regions co-bound by ERα and FOXA1 in endocrine-sensitive breast cancer cells to regulate the estrogen pathway; during reprogramming towards endocrine resistance, CoREST is recruited to AP-1 sites, favors chromatin opening and cJUN binding, and promotes gene activation by controlling SWI/SNF recruitment independently of LSD1 demethylase activity.","method":"ChIP-seq, ATAC-seq, Co-IP, genetic/pharmacological CoREST inhibition, xenograft models","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, ATAC-seq, Co-IP, in vivo xenograft, demethylase-independent mechanism established by LSD1 catalytic mutation","pmids":["36344844"],"is_preprint":false},{"year":2017,"finding":"Sumoylated histone H4 (suH4) stimulates LSD1 demethylase activity on nucleosomes through a mechanism dependent on the SUMO-interaction motif (SIM) in CoREST; the stimulatory effect of suH4 is spatially limited to the sumoylated nucleosome and does not extend to adjacent nucleosomes.","method":"Semisynthetic nucleosomes containing site-specifically sumoylated H4, in vitro demethylase activity assay, SIM mutation in CoREST","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — semisynthetic nucleosome reconstitution, in vitro enzymatic assay, mutagenesis of SIM in CoREST","pmids":["28832116"],"is_preprint":false},{"year":2010,"finding":"LSD1 and CoREST binding are thermodynamically characterized: the LSD1-CoREST(286-482) interaction has a Kd of ~16 nM (1:1 stoichiometry) driven by favorable enthalpy; the central binding determinant maps to the CoREST 'linker' region (residues 293-380), a central helix that interacts with the LSD1 coiled-coil Tower domain to form a triple-helical bundle.","method":"Isothermal titration calorimetry (ITC), CoREST truncation constructs","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative ITC with domain truncations identifying binding determinant, rigorous thermodynamic characterization","pmids":["21142040"],"is_preprint":false},{"year":2022,"finding":"KBTBD4 cancer-associated indel mutations promote recruitment and ubiquitylation of CoREST (RCOR1) for proteasomal degradation; this neo-substrate recruitment drives epigenetic reprogramming, increases stemness, and alters transcriptional programs in medulloblastoma cells.","method":"Proteomics, ubiquitylation assays, Co-IP, gene expression analysis, KBTBD4 mutant vs wild-type comparison","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical ubiquitylation assays, proteomics, Co-IP, gain-of-function mutation study","pmids":["35379950"],"is_preprint":false},{"year":2025,"finding":"UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 (CRL3 E3 ligase adaptor) and HDAC1/2 within the LSD1-CoREST complex, promoting asymmetric assembly and subsequent CoREST complex degradation; cryo-EM reveals a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain; inositol hexakisphosphate acts as a second molecular glue strengthening the interaction.","method":"Cryo-EM structure determination, proteomics, base editor scanning of KBTBD4 and HDAC1, chemical inhibitor studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure plus proteomics plus base editor functional validation, multiple orthogonal methods","pmids":["39939761"],"is_preprint":false},{"year":2019,"finding":"AGS-associated mutations in RNase H2B impair its interaction with ZMYM3 and the CoREST complex (including RCOR1, HDAC2, KDM1A); ZMYM3 acts as a scaffold coordinating interactions between the CoREST deacetylase/demethylase complex and RNase H2.","method":"Co-IP/pulldown with AGS mutant vs wild-type RNase H2B, interaction mapping","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with disease mutants identifying ZMYM3 as scaffold, single lab, interaction-based","pmids":["30889214"],"is_preprint":false},{"year":2023,"finding":"GSE1 forms a complex with the HDAC1/CoREST co-repressor complex; loss of GSE1 impairs DNA damage response (ATR signaling, γH2AX formation); GSE1 is essential for binding of deubiquitinase USP22 to CoREST and for H2B K120 deubiquitination in response to DNA damage, but GSE1 loss does not affect CoREST histone deacetylation activity.","method":"AP-MS (affinity purification-mass spectrometry), phosphoproteomics, KO cell lines, H2B ubiquitination assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — AP-MS to define complex, KO with phosphoproteomics, functional deubiquitination assay, multiple orthogonal methods","pmids":["37878419"],"is_preprint":false},{"year":2007,"finding":"NAC1 (a POZ/BTB protein) directly interacts with CoREST via its POZ/BTB domain; POZ/BTB homodimer formation is not required for the interaction; siRNA knockdown of NAC1 reverses CoREST-mediated transcriptional repression; endogenous interaction was confirmed in rat brain lysates.","method":"Co-IP in cell lines and rat brain, GST pulldown, domain mapping, siRNA knockdown with reporter assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP, GST pulldown, domain mapping, functional siRNA rescue, single lab","pmids":["17254023"],"is_preprint":false},{"year":2012,"finding":"p120-catenin directly binds the REST-CoREST complex and negatively regulates it; p120-catenin displaces REST-CoREST from established gene targets, permitting their transcriptional activation; p120-catenin levels modulate Oct4, Nanog, and Sox2 and impact neural differentiation of mESCs.","method":"Co-IP/pulldown (p120-catenin and CoREST/REST), ChIP at target genes, p120-catenin overexpression/knockdown in mESCs with gene expression and differentiation readouts","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus functional differentiation assay, multiple model systems, single lab","pmids":["25074806"],"is_preprint":false},{"year":2022,"finding":"Nurr1 binds directly to the U3 region of the HIV LTR and recruits the CoREST/HDAC1/G9a/EZH2 transcription repressor complex to the HIV provirus, enhancing silencing; mutation of the Nurr1 DNA-binding domain blocks HIV transcription suppression; CoREST recruitment to the LTR was confirmed by ChIP.","method":"ChIP (Nurr1 and CoREST at HIV LTR), Nurr1 overexpression/knockdown, DNA-binding domain mutant, agonist treatment in iPSC-derived microglial cells","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP at endogenous viral locus, domain mutant, multiple cell models, functional viral suppression assay","pmids":["35797416"],"is_preprint":false},{"year":2012,"finding":"Gfi-1B p32 (a short isoform) recruits the LSD1-CoREST complex more efficiently than the major Gfi-1B p37 isoform; recruitment requires dimethylation of lysine 8 within the SNAG domain (via a KSKK motif); mutation of K8 prevents Gfi-1B p32-induced erythroid development.","method":"Co-IP, ChIP, selective knockdown of Gfi-1B p32 isoform, K8 mutagenesis, erythroid differentiation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, methylation-dependent recruitment established by mutagenesis and functional differentiation assay","pmids":["22399799"],"is_preprint":false},{"year":2016,"finding":"CoREST and LSD1 interact with RBPJ-κ in the Notch repressor complex in vitro; RBPJ-κ interaction is released upon Notch intracellular domain (NICD) overexpression; LSD1 binds the Hes1 promoter in vivo; knockdown of CoREST or LSD1 increases Hes1 expression and decreases Ngn2 in embryonic cortex; CoREST/LSD1 knockdown phenotypes (migration defect, increased Sox2/Tbr2 cells) are rescued by Notch loss-of-function.","method":"Co-IP (CoREST/LSD1 with RBPJ-κ), ChIP (LSD1 at Hes1 promoter), in utero electroporation knockdown, genetic epistasis with Notch","journal":"Developmental neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, in vivo knockdown, genetic epistasis with Notch pathway rescue, multiple orthogonal methods","pmids":["27112428"],"is_preprint":false},{"year":2012,"finding":"The TGF-β-dependent active demethylation and expression of p15ink4b is blocked by the ZNF217/CoREST complex: ZNF217/CoREST/DNMT3A occupies the p15ink4b promoter; TGF-β treatment triggers loss of ZNF217/CoREST/DNMT3A and recruitment of SMAD2/3, CBP, and TDG; overexpression of ZNF217 prevents recruitment of SMAD2/3 and TDG and blocks active demethylation.","method":"ChIP and ChIP-seq at p15ink4b promoter, DNA immunoprecipitation (5mC and 5hmC), TGF-β stimulation, ZNF217 overexpression/knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, DNA methylation assays, epistasis between ZNF217/CoREST and SMAD/TDG, multiple orthogonal methods","pmids":["22560925"],"is_preprint":false}],"current_model":"RCOR1 (CoREST) functions as a scaffolding protein of the CoREST repressor complex, bridging LSD1 (KDM1A) and HDAC1/2 through distinct SANT domain interactions; it is essential for LSD1-mediated demethylation of nucleosomal H3K4 by enhancing LSD1-nucleosome association via SANT2-DNA contacts, as revealed by crystal and cryo-EM structures of the LSD1-CoREST-nucleosome ternary complex; within the complex the demethylase and deacetylase activities are closely coupled; RCOR1 also deacetylates the RNA Pol II CTD at K7 to dampen productive elongation at active genes; it is recruited to chromatin by multiple transcription factors (REST, Nurr1, Gfi-1/1b, ZNF217, ZNF516, ZNF750, TBX2, INSM1) for context-specific gene repression; its activity is regulated post-translationally by SUMOylation (PIASγ/PIASxbeta as E3 ligases, SENP1 as eraser) and by targeted ubiquitin-mediated degradation via the CRL3-KBTBD4 complex (exploited by UM171 as a molecular glue); RCOR1 is essential for definitive erythropoiesis and myeloerythroid lineage differentiation in vivo, and controls Foxp3+ Treg suppressive function."},"narrative":{"mechanistic_narrative":"RCOR1 (CoREST) is the scaffolding subunit of the CoREST chromatin-modifying corepressor complex, assembling HDAC1/2 and the H3K4 demethylase LSD1 (KDM1A) into an integrated repressive machine [PMID:11171972, PMID:11102443]. CoREST is essential for LSD1 activity on physiological nucleosomal substrates: recombinant LSD1 cannot demethylate H3K4 within nucleosomes, but CoREST stimulates and enables nucleosomal demethylation by enhancing LSD1-nucleosome engagement [PMID:16079794]. Structural work explains this requirement—LSD1-CoREST forms an elongated bivalent clamp in which the CoREST SANT2 domain contacts nucleosomal and extranucleosomal DNA while the central CoREST linker forms a triple-helical bundle with the LSD1 Tower domain, positioning the catalytic domain to detach and oxidize the H3 tail [PMID:16885027, PMID:25730864, PMID:32396821, PMID:21142040]. Within the assembled complex the LSD1 demethylase and HDAC1/2 deacetylase activities are conformationally and catalytically coupled [PMID:32101746]. Beyond histone substrates, RCOR1 associates with RNA Polymerase II and deacetylates its CTD at lysine 7 to dampen productive elongation at active genes [PMID:35322029]. RCOR1 lacks intrinsic sequence specificity and is instead recruited to chromatin by diverse transcription factors for context-specific repression, including REST, Gfi-1/1b, Nurr1, ZNF217, ZNF516, ZNF750 and INSM1 [PMID:10734093, PMID:17707228, PMID:19345186, PMID:25228645, PMID:28947780, PMID:28049845, PMID:22560925]. Its activity is tuned post-translationally by SUMOylation (PIASxbeta/PIASγ as ligases, SENP1 as eraser) [PMID:18854179, PMID:29555846] and by CRL3-KBTBD4-mediated ubiquitin-dependent degradation, a process hijacked by cancer-associated KBTBD4 indels and by the molecular glue UM171 [PMID:35379950, PMID:39939761]. Physiologically, Rcor1 is required for definitive erythropoiesis and restrains myeloid lineage drift—its loss arrests erythroid maturation and derepresses Csf2rb and HSC/progenitor genes [PMID:24652990, PMID:26119982]—and it sustains Foxp3+ Treg suppressive function [PMID:31917688]. The complex also governs neural progenitor-to-neuron transitions and cortical neuron migration, in part downstream of Notch signaling [PMID:21878487, PMID:28049845, PMID:27112428].","teleology":[{"year":2000,"claim":"Establishing that CoREST is a stable subunit of a defined HDAC complex answered whether it was a corepressor scaffold rather than a transient cofactor.","evidence":"Native complex purification and mass spectrometry resolving a ~9.5S CoREST-HDAC1/2 complex containing a FAD-dependent oxidoreductase (LSD1)","pmids":["11102443","11171972"],"confidence":"High","gaps":["Catalytic role of the FAD oxidoreductase subunit not yet defined","Mechanism of SANT-domain-mediated assembly unresolved"]},{"year":2000,"claim":"Mapping CoREST's recruitment by REST clarified how a sequence-independent corepressor is targeted to specific loci.","evidence":"Co-IP and yeast two-hybrid showing CoREST binds the REST C-terminal repressor domain, distinct from mSin3A's N-terminal engagement","pmids":["10734093"],"confidence":"High","gaps":["Did not establish genome-wide target repertoire","Relative contributions of Sin3 versus CoREST arms unresolved"]},{"year":2005,"claim":"Demonstrating that CoREST is obligatory for LSD1 demethylation of nucleosomes defined the functional reason the two co-assemble.","evidence":"In vitro reconstitution with recombinant subunits and nucleosomal demethylase assays, plus RNAi de-repression of REST target genes","pmids":["16079794"],"confidence":"High","gaps":["Structural basis of CoREST-enhanced nucleosome engagement not yet shown","HDAC contribution to the same substrates not addressed"]},{"year":2007,"claim":"A series of crystal structures established the molecular architecture coupling CoREST DNA binding to LSD1 substrate recognition.","evidence":"X-ray structures of LSD1-CoREST alone, with H3 peptide, and with SNAIL1, plus SANT2 mutagenesis and demethylase assays","pmids":["16885027","17537733","21300290"],"confidence":"High","gaps":["Structures used peptides/truncations rather than intact nucleosomes","How transcription-factor competition is regulated in vivo unclear"]},{"year":2010,"claim":"Thermodynamic and genetic analyses defined the LSD1-CoREST interface and a reciprocal stability dependence.","evidence":"ITC mapping the CoREST linker-LSD1 Tower interaction (Kd ~16 nM) and conditional LSD1 knockout in ES cells showing CoREST protein loss","pmids":["21142040","20713442"],"confidence":"High","gaps":["Degradation pathway controlling CoREST stability when LSD1 is absent not identified","H3K56ac increase mechanism not linked to specific complex subunit"]},{"year":2015,"claim":"Solution and crosslinking studies resolved how CoREST presents the nucleosome, refining the catalytic mechanism.","evidence":"SAXS, semisynthetic nucleosome crosslinking, EMSA and photocrosslinking defining a 1:1 bivalent 'ergonomic clamp' aided by extranucleosomal DNA","pmids":["25730864","25916846"],"confidence":"High","gaps":["Did not resolve high-resolution atomic contacts with the nucleosome","Dynamics during catalytic turnover not directly observed"]},{"year":2020,"claim":"A nucleosome-bound crystal structure and EM of the ternary complex revealed catalytic coupling and corrected prior engagement models.","evidence":"X-ray structure of LSD1/CoREST on a 191-bp nucleosome and EM of the LSD1-HDAC1-RCOR1 ternary complex with coupled enzymatic assays","pmids":["32396821","32101746"],"confidence":"High","gaps":["Functional consequence of demethylase-deacetylase coupling in vivo not fully mapped","Catalytic activity of the commonly used LSD1(K661A) mutant complicates prior in vivo interpretations"]},{"year":2022,"claim":"Identification of a non-histone substrate extended RCOR1 function beyond chromatin marks.","evidence":"Genome-wide ChIP-seq, Co-IP and biochemical CTD deacetylation assays showing RCOR1 deacetylates RNA Pol II CTD K7 at active genes","pmids":["35322029"],"confidence":"High","gaps":["The deacetylase responsible (RCOR1-associated HDAC versus RCOR1 directly) not definitively assigned","Genome-wide impact on elongation kinetics not quantified"]},{"year":2014,"claim":"Paralog and isoform comparisons explained how distinct RCOR family members tune complex output.","evidence":"Co-IP, SANT-domain mutagenesis, demethylase assays and domain chimeras showing CoREST1/2/3 differ in HDAC1/2 binding and LSD1 stimulation","pmids":["24820421","24843136"],"confidence":"High","gaps":["In vivo division of labor among paralogs incompletely defined","How cells select specific RCOR paralogs at given loci unknown"]},{"year":2014,"claim":"Conditional knockouts established RCOR1's essential, lineage-specific roles in hematopoiesis and immunity.","evidence":"Mouse conditional Rcor1 knockouts with transplantation, colony assays, ChIP and tumor models in erythroid cells and Foxp3+ Tregs","pmids":["24652990","26119982","31917688"],"confidence":"High","gaps":["Direct target gene networks beyond Csf2rb only partly defined","Whether erythroid and Treg phenotypes share common molecular targets unknown"]},{"year":2022,"claim":"Discovery of regulated CoREST degradation revealed a druggable axis and disease mechanism.","evidence":"Proteomics, ubiquitylation assays and cryo-EM showing CRL3-KBTBD4 (via cancer indels and UM171/IP6 molecular glues) recruits and degrades the CoREST complex","pmids":["35379950","39939761"],"confidence":"High","gaps":["Endogenous physiological trigger for KBTBD4-mediated CoREST turnover not established","Downstream transcriptional consequences of degradation only partially mapped"]},{"year":null,"claim":"How RCOR1 switches between canonical repression and demethylase-independent gene-activating modes (e.g. AP-1/SWI-SNF in endocrine resistance) at a mechanistic level remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["Molecular determinants selecting repressive versus activating CoREST recruitment unknown","Integration of SUMOylation, degradation and paralog usage in directing context-specific output not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,6,10]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,29,31]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,25,30]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[5,30]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18,11]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,30,31]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,3,30]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,31,45]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[17,21,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,32]}],"complexes":["CoREST complex (RCOR1-LSD1/KDM1A-HDAC1/2)","REST corepressor complex"],"partners":["KDM1A","HDAC1","HDAC2","REST","GFI1B","ZNF217","INSM1","FOXP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKL0","full_name":"REST corepressor 1","aliases":["Protein CoREST"],"length_aa":485,"mass_kda":53.3,"function":"Essential component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it serves as a molecular beacon for the recruitment of molecular machinery, including MeCP2 and SUV39H1, that imposes silencing across a chromosomal interval. Plays a central role in demethylation of Lys-4 of histone H3 by promoting demethylase activity of KDM1A on core histones and nucleosomal substrates. It also protects KDM1A from the proteasome. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UKL0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RCOR1","classification":"Not Classified","n_dependent_lines":469,"n_total_lines":1208,"dependency_fraction":0.3882450331125828},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC2","stoichiometry":10.0},{"gene":"HDAC1","stoichiometry":4.0},{"gene":"CBX1","stoichiometry":0.2},{"gene":"CTBP1","stoichiometry":0.2},{"gene":"CTBP2","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RCOR1","total_profiled":1310},"omim":[{"mim_id":"616019","title":"REST COREPRESSOR 2; RCOR2","url":"https://www.omim.org/entry/616019"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RCOR1"},"hgnc":{"alias_symbol":["COREST","KIAA0071"],"prev_symbol":["RCOR"]},"alphafold":{"accession":"Q9UKL0","domains":[{"cath_id":"1.10.10.60","chopping":"195-240","consensus_level":"medium","plddt":87.7817,"start":195,"end":240},{"cath_id":"1.20.58.1880","chopping":"386-445","consensus_level":"high","plddt":96.4647,"start":386,"end":445},{"cath_id":"1.10.8","chopping":"147-186","consensus_level":"high","plddt":90.582,"start":147,"end":186},{"cath_id":"1.20.5","chopping":"333-365","consensus_level":"high","plddt":97.9703,"start":333,"end":365}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKL0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKL0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKL0-F1-predicted_aligned_error_v6.png","plddt_mean":68.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RCOR1","jax_strain_url":"https://www.jax.org/strain/search?query=RCOR1"},"sequence":{"accession":"Q9UKL0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKL0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKL0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKL0"}},"corpus_meta":[{"pmid":"19345186","id":"PMC_19345186","title":"A 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\"finding\": \"CoREST is an integral component of a distinct HDAC complex (CoREST-HDAC) composed of HDAC1/2, CoREST, and a polyamine oxidase homolog; the HDAC1/2-interacting region of CoREST maps to a 179-aa region containing a SANT domain, and this region is required for CoREST corepressor function. ZNF217 (not REST) was found associated with this complex.\",\n      \"method\": \"Biochemical purification, Co-IP, domain mapping by truncation, functional repression 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 — reciprocal Co-IP, domain mapping with deletion constructs, functional corepressor assays in a single focused study replicated by independent biochemical characterization\",\n      \"pmids\": [\"11171972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CoREST/KIAA0071 stably associates with HDAC1 and HDAC2 in a distinct ~9.5S complex (complex cI) that also contains a FAD-dependent oxidoreductase (KIAA0601/LSD1); the SANT domain of CoREST is shared with other HDAC1/2-interacting proteins and may mediate complex assembly.\",\n      \"method\": \"Native complex purification, mass spectrometry, glycerol gradient sedimentation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — native complex purification with MS identification, corroborated by multiple independent labs\",\n      \"pmids\": [\"11102443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"mSin3A interacts with REST through REST's N-terminal repressor domain (via the PAH2 domain of mSin3A), and CoREST interacts with REST's C-terminal repressor domain; both corepressors associate with REST in mammalian cells, with mSin3A required constitutively and CoREST recruited for more specialized repressor functions.\",\n      \"method\": \"Co-IP in mammalian cells, yeast two-hybrid, yeast genetic rescue (Sin3-null rescue), in vivo repression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, yeast genetics, multiple orthogonal methods in one study\",\n      \"pmids\": [\"10734093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CoREST is essential for LSD1 (BHC110)-mediated demethylation of H3K4 on nucleosomal substrates: recombinant LSD1 alone cannot demethylate nucleosomes, but LSD1-containing complexes can; in vitro reconstitution with recombinant subunits shows CoREST both stimulates demethylation on core histones and enables nucleosomal demethylation by enhancing LSD1-nucleosome association. Depletion of CoREST in cells leads to de-repression of REST-responsive genes and increased H3K4 methylation.\",\n      \"method\": \"In vitro reconstitution with recombinant subunits, histone demethylase assay on nucleosomal substrates, CoREST depletion (RNAi) with gene expression and histone modification readouts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with recombinant subunits, in vitro enzymatic assay on nucleosomes, orthogonal in vivo RNAi validation\",\n      \"pmids\": [\"16079794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of the LSD1-CoREST complex reveals an elongated structure with a long stalk connecting the LSD1 catalytic domain and the CoREST SANT2 domain; CoREST SANT2 interacts with DNA, and disruption of the SANT2-DNA interaction diminishes CoREST-dependent nucleosomal demethylation by LSD1; the overall shape suggests bivalent nucleosome binding.\",\n      \"method\": \"X-ray crystallography, mutagenesis of CoREST SANT2 domain, nucleosomal demethylase activity assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis of functional interfaces plus enzymatic activity assay, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"16885027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the LSD1-CoREST complex bound to a substrate-like H3 peptide inhibitor reveals that CoREST plays an active role in substrate recognition; LSD1 recognizes a large segment of the H3 tail through a deep, negatively charged active-site pocket; the geometry is consistent with flavin-mediated oxidation of the substrate amino-methyl group.\",\n      \"method\": \"X-ray crystallography of LSD1-CoREST-peptide ternary complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of ternary complex providing direct structural mechanism\",\n      \"pmids\": [\"17537733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CoREST and LSD1 mediate transcriptional repression by Gfi-1 and Gfi-1b in hematopoiesis: CoREST and LSD1 associate with Gfi-1/1b via the SNAG repression domain; Gfi-1b recruits these cofactors to target gene promoters in vivo; inhibition of CoREST and LSD1 perturbs erythroid, megakaryocytic, and granulocytic differentiation.\",\n      \"method\": \"Affinity purification/MS of Gfi-1b complexes, Co-IP, ChIP at target promoters, RNAi knockdown with differentiation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — AP-MS to identify complex, reciprocal Co-IP, ChIP at endogenous targets, RNAi with cellular phenotype readouts\",\n      \"pmids\": [\"17707228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CoREST interacts with Hsp70 and represses HSF1-dependent transcription of the hsp70 gene; CoREST is bound to the hsp70 promoter under basal conditions and its binding increases during heat shock; knockdown of CoREST prevents Hsp70-mediated repression of HSF1-dependent transcription.\",\n      \"method\": \"Co-IP (CoREST-Hsp70), ChIP at hsp70 promoter, shRNA knockdown, reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, ChIP at endogenous promoter, shRNA knockdown with functional readout, multiple orthogonal methods\",\n      \"pmids\": [\"18657505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ZNF198 binds preferentially to the intact LSD1-CoREST-HDAC1 (LCH) ternary complex but not individual subunits; ZNF198 and REST binding to LCH are mutually exclusive; ZNF198 stabilizes LCH on chromatin independently of LCH; SUMO modification of HDAC1 weakens its interaction with CoREST but stimulates its binding to ZNF198; the LCH- and HDAC1-SUMO-binding domains of ZNF198 map to MYM-type zinc finger repeats.\",\n      \"method\": \"Co-IP, GST pulldown, ChIP, domain mapping, in vitro SUMOylation assay, RNAi knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vitro SUMOylation with functional consequences on CoREST interaction, ChIP, multiple orthogonal methods\",\n      \"pmids\": [\"18806873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CoREST is SUMOylated at lysine 294 by the E3 ligase PIASxbeta; SENP1 mediates desumoylation; mutation of the CoREST sumoylation site compromises its corepressor activity, indicating SUMO-1 modification is required for full repressive function.\",\n      \"method\": \"In vivo and in vitro sumoylation assays, Co-IP, mutagenesis of sumoylation site, reporter-based repression assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, multiple methods (sumoylation assay + mutagenesis + reporter), but not independently replicated\",\n      \"pmids\": [\"18854179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nurr1 recruits the CoREST corepressor complex to NF-κB-p65 on inflammatory gene promoters in microglia and astrocytes in a signal-dependent manner, resulting in clearance of NF-κB-p65 and transcriptional repression of pro-inflammatory genes.\",\n      \"method\": \"Co-IP (Nurr1-CoREST), ChIP at inflammatory gene promoters, Nurr1 knockdown/overexpression with cytokine/gene expression readouts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP at endogenous targets, loss-of-function with defined cellular phenotype, published in high-impact venue with multiple orthogonal approaches\",\n      \"pmids\": [\"19345186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"During HSV-1 infection, ICP0 interacts with CoREST and displaces HDAC1 from the CoREST/REST complex; subsequently, CoREST and HDAC1 are phosphorylated by viral protein kinases and partially translocated to the cytoplasm; these events enable derepression of viral gene expression.\",\n      \"method\": \"Co-IP of endogenous CoREST/REST/HDAC1 complex, immunofluorescence localization, infection with ICP0-mutant viruses\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with endogenous proteins, localization studies, genetic dissection using multiple viral mutants\",\n      \"pmids\": [\"15897453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ICP0 blocks silencing of HSV DNA by displacing HDAC1 from the CoREST-REST complex; a truncated CoREST (CoREST 146-482) that displaces HDAC1 from the complex can functionally substitute for ICP0 to rescue viral replication in multiple cell lines.\",\n      \"method\": \"Recombinant virus construction, viral yield assays, Co-IP of CoREST/REST/HDAC1 complex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-mapping functional rescue with recombinant virus, Co-IP, multiple cell lines\",\n      \"pmids\": [\"17939992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LSD1 is a key component of the CoREST/REST repressor complex engaged by HSV-1; in infected cells LSD1 is partially degraded or remains stably associated with CoREST and is partially translocated to the cytoplasm; LSD1 demethylates histones bound to viral α gene promoters to enable their expression.\",\n      \"method\": \"Co-IP, immunofluorescence, infection with ICP0-mutant and wild-type viruses, fractionation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and localization studies, multiple viral mutants, single lab\",\n      \"pmids\": [\"19193804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Deletion of LSD1 in mouse ES cells causes a reduction in CoREST protein levels and associated HDAC activity, demonstrating that LSD1 is required for CoREST stability; this results in a global increase in H3K56 acetylation but not H3K4 methylation in ES cells.\",\n      \"method\": \"Conditional gene knockout in ES cells, Western blot for CoREST protein, HDAC activity assay, histone modification analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with defined biochemical phenotype (CoREST protein loss, HDAC activity reduction), multiple orthogonal readouts\",\n      \"pmids\": [\"20713442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of LSD1-CoREST bound to a SNAIL1 peptide reveals molecular mimicry: the N-terminal residues of SNAIL1 bind to the enzyme active-site cleft mimicking the H3 tail, providing a mechanism by which transcription factors can competitively inhibit LSD1 substrate binding.\",\n      \"method\": \"X-ray crystallography of LSD1-CoREST-SNAIL1 peptide complex, molecular dynamics simulation\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of ternary complex with mechanistic interpretation, corroborated by MD simulation\",\n      \"pmids\": [\"21300290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sumoylation of Braf35 (a subunit of the LSD1-CoREST complex) is required for full repression of neuronal genes and for CoREST complex occupancy at target genes; Braf35-iBraf heterodimerization impairs Braf35 interaction with LSD1-CoREST and blocks Braf35 sumoylation, thereby antagonizing the complex's repressive activity.\",\n      \"method\": \"Sumoylation assays, Co-IP, ChIP, gain/loss-of-function in P19 cells and chick neural tube\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, functional in vivo rescue in chick neural tube, multiple orthogonal assays\",\n      \"pmids\": [\"22570500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CoREST depletion by in utero electroporation in mouse embryonic cortex markedly delays the transition of newborn cortical pyramidal neurons from multipolar to bipolar morphology and impairs onset of radial migration; this function requires LSD1 and is independent of REST.\",\n      \"method\": \"In utero electroporation (shRNA knockdown), live imaging/morphological analysis of cortical neuron migration\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo loss-of-function with defined cellular/morphological phenotype, LSD1 requirement tested\",\n      \"pmids\": [\"21878487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In C. elegans, spr-1 (CoREST ortholog) is a negative regulator of LIN-12/Notch signaling acting cell-autonomously in the nucleus; genetic epistasis places spr-1 upstream of Hindsight; human CoREST can substitute for SPR-1, demonstrating functional conservation.\",\n      \"method\": \"Genetic screen, suppressor analysis, genetic epistasis with lin-12 alleles, rescue with human CoREST, nuclear localization by imaging\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis, cross-species rescue, multiple alleles tested\",\n      \"pmids\": [\"12381669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CoREST1 and CoREST2 differ in their interaction with HDAC1/2: a single non-conserved leucine in the first SANT domain of CoREST2 severely weakens its association with HDAC1/2, and CoREST2 represses transcription in an HDAC-independent manner; CoREST3 interacts equally with LSD1 but leads to reduced LSD1 catalytic efficiency and lower transcriptional repression; all three CoRESTs interact equally with LSD1.\",\n      \"method\": \"Biochemical purification, Co-IP, in vitro demethylase assay, domain mutagenesis, transcriptional repression reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzymatic assays, mutagenesis of SANT domain, Co-IP, reporter assays, multiple orthogonal methods\",\n      \"pmids\": [\"24820421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rcor3 competitively inhibits LSD1-mediated nucleosomal H3K4 demethylation, while Rcor1 and Rcor2 facilitate it; appending the SANT2 domain of Rcor1 to Rcor3 confers the ability to facilitate demethylation; Rcor3 is recruited to target genes by Gfi1b and LSD1, leading to inhibition of H3K4 demethylation and transcriptional derepression.\",\n      \"method\": \"In vitro nucleosomal demethylase assay, domain chimera construction, ChIP at endogenous targets, Co-IP, RNAi/overexpression in hematopoietic cells with differentiation readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay with domain chimeras, ChIP, Co-IP, cellular differentiation phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"24843136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Rcor1 conditional knockout in mice causes profound anemia due to arrest of definitive erythroid cells at the proerythroblast-to-basophilic erythroblast transition; Rcor1-null erythroid progenitors aberrantly form myeloid colonies; Csf2rb (CSF2 receptor β) is a direct target for both Rcor1 and Gfi1b in erythroid cells, and its derepression leads to CSF2-dependent phospho-Stat5 hypersensitivity.\",\n      \"method\": \"Conditional knockout mouse, colony assay, gene expression profiling, ChIP, cytokine signaling assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined hematopoietic phenotype, ChIP at direct target, signaling pathway rescue\",\n      \"pmids\": [\"24652990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The corepressor Rcor1 is essential for murine erythropoiesis; conditional adult deletion causes complete cell-autonomous block in erythroid maturation; Rcor1-deficient monocytes show extensive cytokine-dependent self-renewal and overexpress HSC/progenitor genes including Gata2, Meis1, Hoxa9.\",\n      \"method\": \"Conditional knockout mouse (adult), bone marrow transplantation, lineage analysis, colony assays, gene expression\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with cell-autonomous phenotype established by transplantation, multiple lineages analyzed\",\n      \"pmids\": [\"26119982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ZNF750 interacts with RCOR1, KDM1A (LSD1), and CTBP1/2 through conserved PLNLS sequences; RCOR1 and KDM1A colocalize with ZNF750 at progenitor gene loci and are required for progenitor gene repression, while KLF4 (not KDM1A) is required for ZNF750-mediated activation of differentiation genes.\",\n      \"method\": \"Co-IP, ChIP-seq, gene depletion (RNAi) with gene expression readouts\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, genome-wide ChIP-seq, functional RNAi validation of pathway placement\",\n      \"pmids\": [\"25228645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LSD1-CoREST functions as an 'ergonomic clamp' on nucleosomes, inducing detachment of the H3 tail from nucleosomal DNA to make it available for demethylation; CoREST's DNA-binding activity and LSD1's catalytic domain act cooperatively through a bivalent, competitive interaction with nucleosomal substrates.\",\n      \"method\": \"Covalent crosslinking of LSD1-CoREST to semisynthetic nucleosomal particles, SAXS, binding assays, site-directed mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SAXS structural analysis, semisynthetic nucleosome crosslinking, mutagenesis of binding interfaces, multiple orthogonal methods\",\n      \"pmids\": [\"25730864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Extranucleosomal DNA dramatically enhances LSD1/CoREST demethylase activity on nucleosome substrates; LSD1/CoREST binds the nucleosome as a 1:1 complex; both LSD1 and CoREST subunits make close contact with DNA around the nucleosome dyad and extranucleosomal DNA as shown by photocrosslinking.\",\n      \"method\": \"Demethylase activity assay with nucleosome variants, EMSA, photocrosslinking\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay, photocrosslinking to define contact sites, multiple approaches\",\n      \"pmids\": [\"25916846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PIASγ (SUMO E3 ligase) interacts with CoREST1 (RCOR1), CoREST2, and CoREST3, increases their protein stability, and facilitates their SUMOylation by SUMO-2; SUMO-conjugating enzyme Ubc9 facilitates SUMOylation without affecting protein levels; SUMOylation-deficient CoREST1 and CoREST3 maintain similar interactions with LSD1 and HDAC1/2 and similar repressor capacity.\",\n      \"method\": \"Co-IP, in vivo and in vitro SUMOylation assays, SENP-1 desumoylation, mutagenesis of acceptor lysines, repressor activity assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, enzymatic SUMOylation assays, mutagenesis, but single lab\",\n      \"pmids\": [\"29555846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ZNF516 physically associates with the CtBP/LSD1/CoREST complex and transcriptionally represses EGFR and other proliferation/motility genes; the ZNF516-CtBP/LSD1/CoREST complex inhibits proliferation and invasion of breast cancer cells.\",\n      \"method\": \"Co-IP, ChIP-seq, RNAi knockdown with proliferation/invasion assays, xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, functional knockdown assays, single lab\",\n      \"pmids\": [\"28947780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RCOR1 forms complexes with REST corepressors RCOR2 and the transcription factor INSM1 in embryonic mouse brain progenitors; double knockout of Rcor1/2 causes excess neural progenitor production at the expense of neurons; Rest transcripts are upregulated in the double KO, and reducing Rest partially rescues the interganglionic sulcus closure defect.\",\n      \"method\": \"Co-IP (INSM1-RCOR1/2 complexes), conditional double knockout mouse, genetic epistasis (Rest rescue), gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, double conditional KO with perinatal lethality phenotype, genetic epistasis rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"28049845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The CoREST complex (RCOR1/2 scaffold, HDAC1/2, LSD1) exists in at least two distinct conformational states with different kinetics; the activities of LSD1 and HDAC1 within the complex are closely coupled, not independent; EM of the ternary complex reveals a bi-lobed structure with LSD1 and HDAC1 at opposite ends; EM of CoREST-nucleosome complex reveals a mode of chromatin engagement contrasting with previous models.\",\n      \"method\": \"Electron microscopy (EM) of ternary LSD1-HDAC1-RCOR1 complex and CoREST-nucleosome complex, enzymatic activity assays (demethylase and deacetylase cross-coupling)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — EM structural analysis plus coupled enzymatic activity assays demonstrating crosstalk, multiple orthogonal methods\",\n      \"pmids\": [\"32101746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of LSD1/CoREST bound to a 191-bp nucleosome reveals that the LSD1 catalytic domain binds extranucleosomal DNA and is positioned ~100 Å from the nucleosome core; CoREST makes critical contacts with both histone and DNA components of the nucleosome, explaining its essential role in nucleosomal demethylation; the LSD1(K661A) mutant commonly used as catalytically inactive in vivo retains substantial H3K4 demethylase activity on nucleosomes.\",\n      \"method\": \"X-ray crystallography of LSD1/CoREST-nucleosome complex, demethylase activity assay with LSD1(K661A) mutant\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of full LSD1/CoREST-nucleosome complex with functional mutagenesis validation\",\n      \"pmids\": [\"32396821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RCOR1 is predominantly associated with transcriptionally active genes genome-wide; RCOR1 associates with RNA Polymerase II during transcription and deacetylates its CTD at lysine 7, dampening productive elongation at actively transcribing genes (non-canonical function independent of histone modification).\",\n      \"method\": \"ChIP-seq (genome-wide), Co-IP (RCOR1-POL II), biochemical deacetylation assay of POL II CTD\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, in vitro/biochemical CTD deacetylation assay, multiple orthogonal methods\",\n      \"pmids\": [\"35322029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rcor1 (and Rcor2) is physically associated with Foxp3 in Tregs; conditional deletion of Rcor1 in Foxp3+ Tregs decreases peripheral Treg proportions, increases Treg expression of IL-2 and IFN-γ, impairs suppression of homeostatic proliferation, and enhances antitumor immunity.\",\n      \"method\": \"Co-IP (Rcor1-Foxp3), conditional knockout mouse, flow cytometry, allograft/tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, conditional KO with defined immune phenotype, multiple in vivo models\",\n      \"pmids\": [\"31917688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CoREST is recruited to regulatory regions co-bound by ERα and FOXA1 in endocrine-sensitive breast cancer cells to regulate the estrogen pathway; during reprogramming towards endocrine resistance, CoREST is recruited to AP-1 sites, favors chromatin opening and cJUN binding, and promotes gene activation by controlling SWI/SNF recruitment independently of LSD1 demethylase activity.\",\n      \"method\": \"ChIP-seq, ATAC-seq, Co-IP, genetic/pharmacological CoREST inhibition, xenograft models\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, ATAC-seq, Co-IP, in vivo xenograft, demethylase-independent mechanism established by LSD1 catalytic mutation\",\n      \"pmids\": [\"36344844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Sumoylated histone H4 (suH4) stimulates LSD1 demethylase activity on nucleosomes through a mechanism dependent on the SUMO-interaction motif (SIM) in CoREST; the stimulatory effect of suH4 is spatially limited to the sumoylated nucleosome and does not extend to adjacent nucleosomes.\",\n      \"method\": \"Semisynthetic nucleosomes containing site-specifically sumoylated H4, in vitro demethylase activity assay, SIM mutation in CoREST\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — semisynthetic nucleosome reconstitution, in vitro enzymatic assay, mutagenesis of SIM in CoREST\",\n      \"pmids\": [\"28832116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LSD1 and CoREST binding are thermodynamically characterized: the LSD1-CoREST(286-482) interaction has a Kd of ~16 nM (1:1 stoichiometry) driven by favorable enthalpy; the central binding determinant maps to the CoREST 'linker' region (residues 293-380), a central helix that interacts with the LSD1 coiled-coil Tower domain to form a triple-helical bundle.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), CoREST truncation constructs\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative ITC with domain truncations identifying binding determinant, rigorous thermodynamic characterization\",\n      \"pmids\": [\"21142040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KBTBD4 cancer-associated indel mutations promote recruitment and ubiquitylation of CoREST (RCOR1) for proteasomal degradation; this neo-substrate recruitment drives epigenetic reprogramming, increases stemness, and alters transcriptional programs in medulloblastoma cells.\",\n      \"method\": \"Proteomics, ubiquitylation assays, Co-IP, gene expression analysis, KBTBD4 mutant vs wild-type comparison\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical ubiquitylation assays, proteomics, Co-IP, gain-of-function mutation study\",\n      \"pmids\": [\"35379950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 (CRL3 E3 ligase adaptor) and HDAC1/2 within the LSD1-CoREST complex, promoting asymmetric assembly and subsequent CoREST complex degradation; cryo-EM reveals a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain; inositol hexakisphosphate acts as a second molecular glue strengthening the interaction.\",\n      \"method\": \"Cryo-EM structure determination, proteomics, base editor scanning of KBTBD4 and HDAC1, chemical inhibitor studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure plus proteomics plus base editor functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"39939761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AGS-associated mutations in RNase H2B impair its interaction with ZMYM3 and the CoREST complex (including RCOR1, HDAC2, KDM1A); ZMYM3 acts as a scaffold coordinating interactions between the CoREST deacetylase/demethylase complex and RNase H2.\",\n      \"method\": \"Co-IP/pulldown with AGS mutant vs wild-type RNase H2B, interaction mapping\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with disease mutants identifying ZMYM3 as scaffold, single lab, interaction-based\",\n      \"pmids\": [\"30889214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GSE1 forms a complex with the HDAC1/CoREST co-repressor complex; loss of GSE1 impairs DNA damage response (ATR signaling, γH2AX formation); GSE1 is essential for binding of deubiquitinase USP22 to CoREST and for H2B K120 deubiquitination in response to DNA damage, but GSE1 loss does not affect CoREST histone deacetylation activity.\",\n      \"method\": \"AP-MS (affinity purification-mass spectrometry), phosphoproteomics, KO cell lines, H2B ubiquitination assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AP-MS to define complex, KO with phosphoproteomics, functional deubiquitination assay, multiple orthogonal methods\",\n      \"pmids\": [\"37878419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NAC1 (a POZ/BTB protein) directly interacts with CoREST via its POZ/BTB domain; POZ/BTB homodimer formation is not required for the interaction; siRNA knockdown of NAC1 reverses CoREST-mediated transcriptional repression; endogenous interaction was confirmed in rat brain lysates.\",\n      \"method\": \"Co-IP in cell lines and rat brain, GST pulldown, domain mapping, siRNA knockdown with reporter assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP, GST pulldown, domain mapping, functional siRNA rescue, single lab\",\n      \"pmids\": [\"17254023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p120-catenin directly binds the REST-CoREST complex and negatively regulates it; p120-catenin displaces REST-CoREST from established gene targets, permitting their transcriptional activation; p120-catenin levels modulate Oct4, Nanog, and Sox2 and impact neural differentiation of mESCs.\",\n      \"method\": \"Co-IP/pulldown (p120-catenin and CoREST/REST), ChIP at target genes, p120-catenin overexpression/knockdown in mESCs with gene expression and differentiation readouts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus functional differentiation assay, multiple model systems, single lab\",\n      \"pmids\": [\"25074806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nurr1 binds directly to the U3 region of the HIV LTR and recruits the CoREST/HDAC1/G9a/EZH2 transcription repressor complex to the HIV provirus, enhancing silencing; mutation of the Nurr1 DNA-binding domain blocks HIV transcription suppression; CoREST recruitment to the LTR was confirmed by ChIP.\",\n      \"method\": \"ChIP (Nurr1 and CoREST at HIV LTR), Nurr1 overexpression/knockdown, DNA-binding domain mutant, agonist treatment in iPSC-derived microglial cells\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at endogenous viral locus, domain mutant, multiple cell models, functional viral suppression assay\",\n      \"pmids\": [\"35797416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Gfi-1B p32 (a short isoform) recruits the LSD1-CoREST complex more efficiently than the major Gfi-1B p37 isoform; recruitment requires dimethylation of lysine 8 within the SNAG domain (via a KSKK motif); mutation of K8 prevents Gfi-1B p32-induced erythroid development.\",\n      \"method\": \"Co-IP, ChIP, selective knockdown of Gfi-1B p32 isoform, K8 mutagenesis, erythroid differentiation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, methylation-dependent recruitment established by mutagenesis and functional differentiation assay\",\n      \"pmids\": [\"22399799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CoREST and LSD1 interact with RBPJ-κ in the Notch repressor complex in vitro; RBPJ-κ interaction is released upon Notch intracellular domain (NICD) overexpression; LSD1 binds the Hes1 promoter in vivo; knockdown of CoREST or LSD1 increases Hes1 expression and decreases Ngn2 in embryonic cortex; CoREST/LSD1 knockdown phenotypes (migration defect, increased Sox2/Tbr2 cells) are rescued by Notch loss-of-function.\",\n      \"method\": \"Co-IP (CoREST/LSD1 with RBPJ-κ), ChIP (LSD1 at Hes1 promoter), in utero electroporation knockdown, genetic epistasis with Notch\",\n      \"journal\": \"Developmental neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, in vivo knockdown, genetic epistasis with Notch pathway rescue, multiple orthogonal methods\",\n      \"pmids\": [\"27112428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The TGF-β-dependent active demethylation and expression of p15ink4b is blocked by the ZNF217/CoREST complex: ZNF217/CoREST/DNMT3A occupies the p15ink4b promoter; TGF-β treatment triggers loss of ZNF217/CoREST/DNMT3A and recruitment of SMAD2/3, CBP, and TDG; overexpression of ZNF217 prevents recruitment of SMAD2/3 and TDG and blocks active demethylation.\",\n      \"method\": \"ChIP and ChIP-seq at p15ink4b promoter, DNA immunoprecipitation (5mC and 5hmC), TGF-β stimulation, ZNF217 overexpression/knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, DNA methylation assays, epistasis between ZNF217/CoREST and SMAD/TDG, multiple orthogonal methods\",\n      \"pmids\": [\"22560925\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RCOR1 (CoREST) functions as a scaffolding protein of the CoREST repressor complex, bridging LSD1 (KDM1A) and HDAC1/2 through distinct SANT domain interactions; it is essential for LSD1-mediated demethylation of nucleosomal H3K4 by enhancing LSD1-nucleosome association via SANT2-DNA contacts, as revealed by crystal and cryo-EM structures of the LSD1-CoREST-nucleosome ternary complex; within the complex the demethylase and deacetylase activities are closely coupled; RCOR1 also deacetylates the RNA Pol II CTD at K7 to dampen productive elongation at active genes; it is recruited to chromatin by multiple transcription factors (REST, Nurr1, Gfi-1/1b, ZNF217, ZNF516, ZNF750, TBX2, INSM1) for context-specific gene repression; its activity is regulated post-translationally by SUMOylation (PIASγ/PIASxbeta as E3 ligases, SENP1 as eraser) and by targeted ubiquitin-mediated degradation via the CRL3-KBTBD4 complex (exploited by UM171 as a molecular glue); RCOR1 is essential for definitive erythropoiesis and myeloerythroid lineage differentiation in vivo, and controls Foxp3+ Treg suppressive function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RCOR1 (CoREST) is the scaffolding subunit of the CoREST chromatin-modifying corepressor complex, assembling HDAC1/2 and the H3K4 demethylase LSD1 (KDM1A) into an integrated repressive machine [#0, #1]. CoREST is essential for LSD1 activity on physiological nucleosomal substrates: recombinant LSD1 cannot demethylate H3K4 within nucleosomes, but CoREST stimulates and enables nucleosomal demethylation by enhancing LSD1-nucleosome engagement [#3]. Structural work explains this requirement—LSD1-CoREST forms an elongated bivalent clamp in which the CoREST SANT2 domain contacts nucleosomal and extranucleosomal DNA while the central CoREST linker forms a triple-helical bundle with the LSD1 Tower domain, positioning the catalytic domain to detach and oxidize the H3 tail [#4, #24, #30, #35]. Within the assembled complex the LSD1 demethylase and HDAC1/2 deacetylase activities are conformationally and catalytically coupled [#29]. Beyond histone substrates, RCOR1 associates with RNA Polymerase II and deacetylates its CTD at lysine 7 to dampen productive elongation at active genes [#31]. RCOR1 lacks intrinsic sequence specificity and is instead recruited to chromatin by diverse transcription factors for context-specific repression, including REST, Gfi-1/1b, Nurr1, ZNF217, ZNF516, ZNF750 and INSM1 [#2, #6, #10, #23, #27, #28, #45]. Its activity is tuned post-translationally by SUMOylation (PIASxbeta/PIASγ as ligases, SENP1 as eraser) [#9, #26] and by CRL3-KBTBD4-mediated ubiquitin-dependent degradation, a process hijacked by cancer-associated KBTBD4 indels and by the molecular glue UM171 [#36, #37]. Physiologically, Rcor1 is required for definitive erythropoiesis and restrains myeloid lineage drift—its loss arrests erythroid maturation and derepresses Csf2rb and HSC/progenitor genes [#21, #22]—and it sustains Foxp3+ Treg suppressive function [#32]. The complex also governs neural progenitor-to-neuron transitions and cortical neuron migration, in part downstream of Notch signaling [#17, #28, #44].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that CoREST is a stable subunit of a defined HDAC complex answered whether it was a corepressor scaffold rather than a transient cofactor.\",\n      \"evidence\": \"Native complex purification and mass spectrometry resolving a ~9.5S CoREST-HDAC1/2 complex containing a FAD-dependent oxidoreductase (LSD1)\",\n      \"pmids\": [\"11102443\", \"11171972\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic role of the FAD oxidoreductase subunit not yet defined\", \"Mechanism of SANT-domain-mediated assembly unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mapping CoREST's recruitment by REST clarified how a sequence-independent corepressor is targeted to specific loci.\",\n      \"evidence\": \"Co-IP and yeast two-hybrid showing CoREST binds the REST C-terminal repressor domain, distinct from mSin3A's N-terminal engagement\",\n      \"pmids\": [\"10734093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish genome-wide target repertoire\", \"Relative contributions of Sin3 versus CoREST arms unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that CoREST is obligatory for LSD1 demethylation of nucleosomes defined the functional reason the two co-assemble.\",\n      \"evidence\": \"In vitro reconstitution with recombinant subunits and nucleosomal demethylase assays, plus RNAi de-repression of REST target genes\",\n      \"pmids\": [\"16079794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CoREST-enhanced nucleosome engagement not yet shown\", \"HDAC contribution to the same substrates not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A series of crystal structures established the molecular architecture coupling CoREST DNA binding to LSD1 substrate recognition.\",\n      \"evidence\": \"X-ray structures of LSD1-CoREST alone, with H3 peptide, and with SNAIL1, plus SANT2 mutagenesis and demethylase assays\",\n      \"pmids\": [\"16885027\", \"17537733\", \"21300290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures used peptides/truncations rather than intact nucleosomes\", \"How transcription-factor competition is regulated in vivo unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Thermodynamic and genetic analyses defined the LSD1-CoREST interface and a reciprocal stability dependence.\",\n      \"evidence\": \"ITC mapping the CoREST linker-LSD1 Tower interaction (Kd ~16 nM) and conditional LSD1 knockout in ES cells showing CoREST protein loss\",\n      \"pmids\": [\"21142040\", \"20713442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation pathway controlling CoREST stability when LSD1 is absent not identified\", \"H3K56ac increase mechanism not linked to specific complex subunit\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Solution and crosslinking studies resolved how CoREST presents the nucleosome, refining the catalytic mechanism.\",\n      \"evidence\": \"SAXS, semisynthetic nucleosome crosslinking, EMSA and photocrosslinking defining a 1:1 bivalent 'ergonomic clamp' aided by extranucleosomal DNA\",\n      \"pmids\": [\"25730864\", \"25916846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve high-resolution atomic contacts with the nucleosome\", \"Dynamics during catalytic turnover not directly observed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A nucleosome-bound crystal structure and EM of the ternary complex revealed catalytic coupling and corrected prior engagement models.\",\n      \"evidence\": \"X-ray structure of LSD1/CoREST on a 191-bp nucleosome and EM of the LSD1-HDAC1-RCOR1 ternary complex with coupled enzymatic assays\",\n      \"pmids\": [\"32396821\", \"32101746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of demethylase-deacetylase coupling in vivo not fully mapped\", \"Catalytic activity of the commonly used LSD1(K661A) mutant complicates prior in vivo interpretations\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of a non-histone substrate extended RCOR1 function beyond chromatin marks.\",\n      \"evidence\": \"Genome-wide ChIP-seq, Co-IP and biochemical CTD deacetylation assays showing RCOR1 deacetylates RNA Pol II CTD K7 at active genes\",\n      \"pmids\": [\"35322029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The deacetylase responsible (RCOR1-associated HDAC versus RCOR1 directly) not definitively assigned\", \"Genome-wide impact on elongation kinetics not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Paralog and isoform comparisons explained how distinct RCOR family members tune complex output.\",\n      \"evidence\": \"Co-IP, SANT-domain mutagenesis, demethylase assays and domain chimeras showing CoREST1/2/3 differ in HDAC1/2 binding and LSD1 stimulation\",\n      \"pmids\": [\"24820421\", \"24843136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo division of labor among paralogs incompletely defined\", \"How cells select specific RCOR paralogs at given loci unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Conditional knockouts established RCOR1's essential, lineage-specific roles in hematopoiesis and immunity.\",\n      \"evidence\": \"Mouse conditional Rcor1 knockouts with transplantation, colony assays, ChIP and tumor models in erythroid cells and Foxp3+ Tregs\",\n      \"pmids\": [\"24652990\", \"26119982\", \"31917688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target gene networks beyond Csf2rb only partly defined\", \"Whether erythroid and Treg phenotypes share common molecular targets unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery of regulated CoREST degradation revealed a druggable axis and disease mechanism.\",\n      \"evidence\": \"Proteomics, ubiquitylation assays and cryo-EM showing CRL3-KBTBD4 (via cancer indels and UM171/IP6 molecular glues) recruits and degrades the CoREST complex\",\n      \"pmids\": [\"35379950\", \"39939761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological trigger for KBTBD4-mediated CoREST turnover not established\", \"Downstream transcriptional consequences of degradation only partially mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RCOR1 switches between canonical repression and demethylase-independent gene-activating modes (e.g. AP-1/SWI-SNF in endocrine resistance) at a mechanistic level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants selecting repressive versus activating CoREST recruitment unknown\", \"Integration of SUMOylation, degradation and paralog usage in directing context-specific output not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 6, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 29, 31]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 25, 30]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [5, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18, 11]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 30, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 3, 30]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 31, 45]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 21, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 32]}\n    ],\n    \"complexes\": [\"CoREST complex (RCOR1-LSD1/KDM1A-HDAC1/2)\", \"REST corepressor complex\"],\n    \"partners\": [\"KDM1A\", \"HDAC1\", \"HDAC2\", \"REST\", \"GFI1B\", \"ZNF217\", \"INSM1\", \"FOXP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}