{"gene":"LCOR","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2003,"finding":"LCoR is recruited to agonist-bound nuclear receptors (including estrogen receptor alpha) through a single LXXLL motif; its binding to ERα depends in part on residues in the coactivator binding pocket distinct from those bound by TIF-2.","method":"In vitro binding assays, site-directed mutagenesis of coactivator binding pocket residues","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro binding assays with mutagenesis plus in vivo co-immunoprecipitation, replicated across multiple receptor contexts in a single rigorous study","pmids":["12535528"],"is_preprint":false},{"year":2003,"finding":"LCoR represses agonist-activated nuclear receptor signaling via HDAC-dependent mechanisms; repression is abolished by the HDAC inhibitor trichostatin A in a receptor-dependent fashion, and LCoR binds directly to specific HDACs both in vitro and in vivo.","method":"HDAC inhibitor (TSA) treatment assays, in vitro binding, co-immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (inhibitor pharmacology, in vitro direct binding, in vivo Co-IP) in a single rigorous study","pmids":["12535528"],"is_preprint":false},{"year":2003,"finding":"LCoR represses transcription via an HDAC-independent mechanism by recruiting CtBP corepressors through two consensus CtBP-binding motifs, and LCoR colocalizes with CtBPs in the nucleus.","method":"Co-immunoprecipitation, confocal colocalization, mutational analysis of CtBP-binding motifs","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated in vitro and in vivo with motif mutagenesis, nuclear colocalization confirmed by imaging","pmids":["12535528"],"is_preprint":false},{"year":2009,"finding":"LCoR interacts directly with HDAC6 in vitro via its central domain, and HDAC6 is partially nuclear in ERα-expressing MCF7 cells where it colocalizes with LCoR and augments LCoR-mediated corepression of estrogen-inducible reporter genes; this interaction requires a central domain of LCoR, and LCoR mutants lacking this domain show attenuated repression.","method":"In vitro GST pull-down, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), re-ChIP, confocal colocalization, siRNA knockdown, reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vitro binding, ChIP, re-ChIP, domain mutagenesis, knockdown) in a single study","pmids":["19744931"],"is_preprint":false},{"year":2009,"finding":"Despite being co-recruited to ERα target gene promoters, LCoR and HDAC6 failed to co-immunoprecipitate, indicating they are part of distinct complexes on these genes.","method":"Co-immunoprecipitation, re-ChIP","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP negative result confirmed by re-ChIP, single lab","pmids":["19744931"],"is_preprint":false},{"year":2009,"finding":"siRNA-mediated knockdown of LCoR or HDAC6 unexpectedly reduced expression of some endogenous estrogen target genes, suggesting that LCoR and HDAC6 can also function to enhance expression of certain target genes.","method":"siRNA knockdown, RT-qPCR of endogenous target gene expression in MCF7 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean siRNA knockdown with specific gene expression readout, single lab, single method","pmids":["19744931"],"is_preprint":false},{"year":2012,"finding":"LCoR interacts with the transcription factor KLF6 via its C-terminal domain (identified by yeast two-hybrid); LCoR and KLF6 co-occupy the CDKN1A and CDH1 promoters in cancer cells and LCoR contributes to KLF6-mediated transcriptional repression via HDAC- and CtBP1-dependent mechanisms.","method":"Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter assay with HDAC inhibitor TSA, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — yeast two-hybrid interaction confirmed by Co-IP and ChIP occupancy, functional repression validated by siRNA and inhibitor, multiple orthogonal methods","pmids":["22277651"],"is_preprint":false},{"year":2012,"finding":"LCoR repression of CDKN1A is mediated through its N-terminal domain (CtBP recruitment) and central domain (HDAC recruitment), as revealed by domain-deletion analysis.","method":"Mutational/deletion analysis of LCoR domains, reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional reporter readout, single lab","pmids":["22277651"],"is_preprint":false},{"year":2017,"finding":"miR-199a directly represses LCOR expression by targeting its mRNA, thereby suppressing LCOR-primed interferon response pathways and promoting stem cell properties in mammary stem cells and breast cancer stem cells.","method":"miRNA overexpression/inhibition, luciferase reporter assay for direct miR-199a targeting of LCOR 3'-UTR, rescue experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct 3'-UTR reporter validation of miR-199a→LCOR targeting, rescue experiments linking LCOR loss to IFN response attenuation, multiple cell and in vivo models","pmids":["28530657"],"is_preprint":false},{"year":2017,"finding":"LCOR primes interferon (IFN) responses in mammary epithelial and breast cancer cells; its loss (via miR-199a-mediated repression) protects stem-like cells from IFN-induced differentiation and senescence.","method":"LCOR knockdown/overexpression, IFN stimulation assays, gene expression profiling, in vivo tumor initiation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with specific IFN-pathway phenotype, validated in multiple model systems including in vivo","pmids":["28530657"],"is_preprint":false},{"year":2017,"finding":"LCoR interacts with RIP140 (receptor-interacting protein 140) via the helix-turn-helix (HTH) domain of LCoR and the N- and C-terminal regions of RIP140; this interaction is required for LCoR-mediated inhibition of gene expression and reduction of breast cancer cell proliferation.","method":"In vitro interaction assay, co-immunoprecipitation, proximity ligation assay, confocal microscopy, mutagenesis of HTH domain, siRNA knockdown of RIP140","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (in vitro binding, reciprocal Co-IP, PLA, confocal) plus functional rescue by siRNA, single lab but rigorous","pmids":["28414308"],"is_preprint":false},{"year":2017,"finding":"The helix-turn-helix (HTH) domain of LCoR is required for transcriptional repression and inhibition of estrogen-induced target gene expression, as shown by mutagenesis analysis.","method":"Mutagenesis of HTH domain, reporter gene assays, endogenous gene expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — domain mutagenesis with functional readout, single lab","pmids":["28414308"],"is_preprint":false},{"year":2017,"finding":"LCoR interacts with and represses the transcription factor C/EBPβ through its C-terminal HTH domain, suppressing C/EBPβ transcriptional activity on C/EBPα and PPARγ2 promoters by recruiting CtBPs and modulating histone modifications, thereby inhibiting early adipogenesis.","method":"Affinity purification/mass spectrometry, co-immunoprecipitation, reporter assay, ChIP, overexpression and knockdown in 3T3-L1 adipocytes, rescue with C/EBPα or PPARγ2","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — interaction identified by unbiased AP-MS, confirmed by Co-IP and ChIP, domain mutagenesis, functional rescue experiment, multiple orthogonal methods","pmids":["28972158"],"is_preprint":false},{"year":2018,"finding":"LCOR and LCORL gene loci encode vertebrate-specific PRC2.1-associated proteins PALI1 and PALI2, respectively. PALI1 (encoded by LCOR) promotes PRC2 methyltransferase activity (H3K27 mono-, di-, and tri-methylation) in vitro and in vivo, and is essential for mouse development; PALI1 defines a PRC2.1 subtype mutually exclusive with and antagonistic to the PRC2.2 (AEBP2/JARID2) subtype.","method":"Biochemical reconstitution of PRC2 complexes, in vitro methyltransferase assay, genetic knockout (Pali1-null mice), ChIP-seq, co-immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with methyltransferase activity assay, confirmed by ChIP-seq and genetic knockout with developmental phenotype, multiple orthogonal methods","pmids":["29628311"],"is_preprint":false},{"year":2018,"finding":"LCoR acts as a coactivator (not corepressor) for PPARγ-RXRα heterodimers at the Muc1 promoter; LCoR interacts with PPARγ and RXRα via adjacent non-canonical protein motifs in a synergistic fashion, and this coactivator function is inhibited by the RXRα AF2 domain when bound by rexinoid ligand.","method":"Reporter assays, co-immunoprecipitation, Lcor-null mouse placenta analysis (Muc1 expression), mutagenesis of AF2 domain","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, reporter assays, and in vivo genetic (null mouse) validation, single lab","pmids":["29463649"],"is_preprint":false},{"year":2018,"finding":"KLF6 is a component of Muc1 regulation in cooperation with PPARγ, RXRα, and LCoR in placental cells.","method":"Reporter assays, co-immunoprecipitation in placental context","journal":"Molecular and cellular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, reporter assay and Co-IP without extensive mechanistic follow-up for this specific interaction in placenta","pmids":["29463649"],"is_preprint":false},{"year":2022,"finding":"LCOR functions as a master transcriptional activator of antigen processing/presentation machinery (APM) genes by binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner; loss of LCOR in cancer stem cells reduces APM expression and drives immune escape.","method":"Genetic modification of LCOR expression (overexpression/knockdown), ChIP at ISRE elements, gene expression profiling, in vivo tumor immunotherapy models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct ISRE binding, genetic loss-of-function with APM phenotype, in vivo validation with immunotherapy models, multiple orthogonal methods","pmids":["35301507"],"is_preprint":false},{"year":2025,"finding":"LCOR interacts with RUNX1 transcriptional suppressor and relieves RUNX1-mediated repression of PLCL1, leading to increased PLCL1 expression that inhibits lipid accumulation and tumor progression in clear cell renal cell carcinoma.","method":"Co-immunoprecipitation (LCOR-RUNX1 interaction), ChIP-qPCR, reporter assays, overexpression/knockdown in vitro and in vivo tumor models","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for protein interaction, ChIP and reporter assays for functional mechanism, in vivo tumor model, single lab","pmids":["40083699"],"is_preprint":false}],"current_model":"LCOR (Ligand-dependent Corepressor) is a multifunctional transcriptional coregulator that: (1) is recruited to agonist-bound nuclear receptors (e.g., ERα) via an LXXLL motif and represses their activity by directly binding HDACs (including HDAC3 and HDAC6) and recruiting CtBP corepressors through consensus binding motifs; (2) also acts as a non-receptor transcription factor corepressor by interacting with KLF6 and C/EBPβ via its C-terminal HTH domain to repress target genes including CDKN1A and adipogenic regulators; (3) interacts with RIP140 (requiring HTH domain) to co-regulate gene expression and cell proliferation; (4) acts as a context-dependent coactivator of PPARγ-RXRα at certain promoters via non-canonical motifs; (5) encodes the PRC2.1-associated protein PALI1, which promotes PRC2 H3K27 methyltransferase activity and defines a PRC2 subtype antagonistic to AEBP2/JARID2-containing PRC2.2; (6) acts as an IFN-independent transcriptional activator of antigen processing/presentation machinery (APM) genes by binding ISREs, with its expression regulated by miR-199a; and (7) relieves RUNX1-mediated repression of PLCL1 to restrain lipid accumulation in renal cancer."},"narrative":{"mechanistic_narrative":"LCOR is a multifunctional transcriptional coregulator that controls gene expression through context-dependent corepression, coactivation, and chromatin modification [PMID:12535528, PMID:29628311]. In its founding role, LCoR is recruited to agonist-bound nuclear receptors including estrogen receptor alpha through a single LXXLL motif and represses receptor signaling by two parallel routes: an HDAC-dependent mechanism involving direct binding to histone deacetylases (including HDAC6 via its central domain) and an HDAC-independent mechanism through recruitment of CtBP corepressors at consensus CtBP-binding motifs [PMID:12535528, PMID:19744931]. Beyond nuclear receptors, LCoR uses its C-terminal helix-turn-helix (HTH) domain to engage sequence-specific transcription factors — KLF6 at the CDKN1A and CDH1 promoters, C/EBPβ to suppress adipogenic genes, and RIP140 to restrain breast cancer cell proliferation — combining N-terminal CtBP recruitment and central-domain HDAC recruitment to effect repression [PMID:22277651, PMID:28414308, PMID:28972158]. The LCOR locus also encodes PALI1, a PRC2.1-associated subunit that stimulates PRC2 H3K27 methyltransferase activity and defines a PRC2 subtype antagonistic to AEBP2/JARID2-containing PRC2.2, and Pali1-null mice are embryonic-lethal [PMID:29628311]. In an opposing transcriptional capacity, LCOR acts as an interferon-independent activator that binds ISRE elements to drive antigen processing/presentation machinery gene expression; this activity is silenced by miR-199a, whose targeting of the LCOR 3'-UTR licenses immune escape and stem-like properties in breast cancer [PMID:28530657, PMID:35301507]. LCoR can also operate as a coactivator of PPARγ-RXRα heterodimers at the Muc1 promoter [PMID:29463649].","teleology":[{"year":2003,"claim":"Established LCoR as a ligand-dependent corepressor by showing how it docks onto activated nuclear receptors and the dual machinery it uses to silence them, defining its founding mechanism.","evidence":"In vitro binding, coactivator-pocket mutagenesis, HDAC-inhibitor (TSA) pharmacology, Co-IP, and confocal colocalization with CtBPs","pmids":["12535528"],"confidence":"High","gaps":["Which specific HDACs were engaged was not fully resolved","Genome-wide receptor targets not mapped"]},{"year":2009,"claim":"Resolved the central-domain HDAC6 interaction and revealed that LCoR-HDAC6 co-recruitment can both repress and, unexpectedly, enhance some endogenous estrogen target genes, indicating context-dependent output.","evidence":"GST pull-down, Co-IP, ChIP/re-ChIP, siRNA knockdown and RT-qPCR in MCF7 cells","pmids":["19744931"],"confidence":"High","gaps":["LCoR and HDAC6 did not co-IP on target genes, leaving the complex composition unclear","Basis for gene-specific activation versus repression unexplained"]},{"year":2012,"claim":"Extended LCoR function beyond nuclear receptors by identifying KLF6 as a direct partner, showing LCoR acts as a corepressor for sequence-specific transcription factors at cell-cycle and adhesion genes.","evidence":"Yeast two-hybrid, Co-IP, ChIP at CDKN1A/CDH1, TSA reporter assays, domain-deletion analysis, siRNA","pmids":["22277651"],"confidence":"High","gaps":["In vivo relevance of KLF6-LCoR repression not tested","Whether HTH domain directly contacts KLF6 not mapped at residue level"]},{"year":2017,"claim":"Mapped the HTH domain as the interaction surface for RIP140 and C/EBPβ, linking LCoR to control of breast cancer proliferation and adipogenesis, and showed miR-199a represses LCOR to attenuate IFN priming and promote stemness.","evidence":"AP-MS, reciprocal Co-IP, PLA, HTH mutagenesis, ChIP, 3'-UTR luciferase reporter, knockdown/overexpression and in vivo tumor-initiation models","pmids":["28414308","28972158","28530657"],"confidence":"High","gaps":["Direct structural basis of HTH-partner binding not solved","Mechanism by which LCOR primes IFN responses not detailed at this stage"]},{"year":2018,"claim":"Revealed two new dimensions: the LCOR-encoded PALI1 is a PRC2.1 subunit that stimulates H3K27 methylation and is required for development, and LCoR can act as a coactivator of PPARγ-RXRα, broadening its mechanistic repertoire beyond repression.","evidence":"Biochemical reconstitution and in vitro methyltransferase assays, ChIP-seq, Pali1-null mice; Co-IP, reporter assays, and Lcor-null placenta analysis for PPARγ-RXRα coactivation","pmids":["29628311","29463649"],"confidence":"High","gaps":["Relationship between PALI1/PRC2 function and the corepressor LCoR isoform not integrated","Determinants switching LCoR between corepressor and coactivator modes unknown"]},{"year":2022,"claim":"Defined LCOR as an IFN-independent transcriptional activator that binds ISRE elements to drive antigen processing/presentation machinery, mechanistically explaining how its miR-199a-mediated loss enables tumor immune escape.","evidence":"ChIP at ISRE elements, genetic gain/loss of function, expression profiling, in vivo immunotherapy tumor models","pmids":["35301507"],"confidence":"High","gaps":["Cofactors enabling ISRE-bound activation versus repression not identified","How the same protein selects activator versus corepressor targets unresolved"]},{"year":2025,"claim":"Showed LCOR de-represses PLCL1 by antagonizing RUNX1, restraining lipid accumulation and tumor progression in clear cell renal cell carcinoma, adding a tissue-specific regulatory axis.","evidence":"Co-IP, ChIP-qPCR, reporter assays, gain/loss of function in vitro and in vivo renal tumor models","pmids":["40083699"],"confidence":"Medium","gaps":["Single-lab finding without reciprocal structural validation of LCOR-RUNX1 binding","Whether de-repression involves displacement of corepressors not defined"]},{"year":null,"claim":"The molecular determinants that switch LCOR/PALI1 between corepressor, coactivator, and PRC2-stimulatory functions across cell contexts remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating LXXLL, CtBP, and HTH modules","No unified explanation for context-dependent activation versus repression","Relationship between LCoR and PALI1 isoforms in vivo unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,6,12,16]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,16]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":["PRC2.1 (PALI1-containing)"],"partners":["ESR1","HDAC6","CTBP1","KLF6","RIP140","CEBPB","PPARG","RUNX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JN0","full_name":"Ligand-dependent corepressor","aliases":["Mblk1-related protein 2"],"length_aa":433,"mass_kda":47.0,"function":"May act as transcription activator that binds DNA elements with the sequence 5'-CCCTATCGATCGATCTCTACCT-3' (By similarity). Repressor of ligand-dependent transcription activation by target nuclear receptors. Repressor of ligand-dependent transcription activation by ESR1, ESR2, NR3C1, PGR, RARA, RARB, RARG, RXRA and VDR","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96JN0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LCOR","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTBP1","stoichiometry":0.2},{"gene":"CTBP2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LCOR","total_profiled":1310},"omim":[{"mim_id":"617934","title":"AE-BINDING PROTEIN 2; 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binding assays, site-directed mutagenesis of coactivator binding pocket residues\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro binding assays with mutagenesis plus in vivo co-immunoprecipitation, replicated across multiple receptor contexts in a single rigorous study\",\n      \"pmids\": [\"12535528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LCoR represses agonist-activated nuclear receptor signaling via HDAC-dependent mechanisms; repression is abolished by the HDAC inhibitor trichostatin A in a receptor-dependent fashion, and LCoR binds directly to specific HDACs both in vitro and in vivo.\",\n      \"method\": \"HDAC inhibitor (TSA) treatment assays, in vitro binding, co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (inhibitor pharmacology, in vitro direct binding, in vivo Co-IP) in a single rigorous study\",\n      \"pmids\": [\"12535528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LCoR represses transcription via an HDAC-independent mechanism by recruiting CtBP corepressors through two consensus CtBP-binding motifs, and LCoR colocalizes with CtBPs in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, confocal colocalization, mutational analysis of CtBP-binding motifs\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated in vitro and in vivo with motif mutagenesis, nuclear colocalization confirmed by imaging\",\n      \"pmids\": [\"12535528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LCoR interacts directly with HDAC6 in vitro via its central domain, and HDAC6 is partially nuclear in ERα-expressing MCF7 cells where it colocalizes with LCoR and augments LCoR-mediated corepression of estrogen-inducible reporter genes; this interaction requires a central domain of LCoR, and LCoR mutants lacking this domain show attenuated repression.\",\n      \"method\": \"In vitro GST pull-down, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), re-ChIP, confocal colocalization, siRNA knockdown, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vitro binding, ChIP, re-ChIP, domain mutagenesis, knockdown) in a single study\",\n      \"pmids\": [\"19744931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Despite being co-recruited to ERα target gene promoters, LCoR and HDAC6 failed to co-immunoprecipitate, indicating they are part of distinct complexes on these genes.\",\n      \"method\": \"Co-immunoprecipitation, re-ChIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP negative result confirmed by re-ChIP, single lab\",\n      \"pmids\": [\"19744931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"siRNA-mediated knockdown of LCoR or HDAC6 unexpectedly reduced expression of some endogenous estrogen target genes, suggesting that LCoR and HDAC6 can also function to enhance expression of certain target genes.\",\n      \"method\": \"siRNA knockdown, RT-qPCR of endogenous target gene expression in MCF7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean siRNA knockdown with specific gene expression readout, single lab, single method\",\n      \"pmids\": [\"19744931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LCoR interacts with the transcription factor KLF6 via its C-terminal domain (identified by yeast two-hybrid); LCoR and KLF6 co-occupy the CDKN1A and CDH1 promoters in cancer cells and LCoR contributes to KLF6-mediated transcriptional repression via HDAC- and CtBP1-dependent mechanisms.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation (ChIP), reporter assay with HDAC inhibitor TSA, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — yeast two-hybrid interaction confirmed by Co-IP and ChIP occupancy, functional repression validated by siRNA and inhibitor, multiple orthogonal methods\",\n      \"pmids\": [\"22277651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LCoR repression of CDKN1A is mediated through its N-terminal domain (CtBP recruitment) and central domain (HDAC recruitment), as revealed by domain-deletion analysis.\",\n      \"method\": \"Mutational/deletion analysis of LCoR domains, reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional reporter readout, single lab\",\n      \"pmids\": [\"22277651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-199a directly represses LCOR expression by targeting its mRNA, thereby suppressing LCOR-primed interferon response pathways and promoting stem cell properties in mammary stem cells and breast cancer stem cells.\",\n      \"method\": \"miRNA overexpression/inhibition, luciferase reporter assay for direct miR-199a targeting of LCOR 3'-UTR, rescue experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct 3'-UTR reporter validation of miR-199a→LCOR targeting, rescue experiments linking LCOR loss to IFN response attenuation, multiple cell and in vivo models\",\n      \"pmids\": [\"28530657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LCOR primes interferon (IFN) responses in mammary epithelial and breast cancer cells; its loss (via miR-199a-mediated repression) protects stem-like cells from IFN-induced differentiation and senescence.\",\n      \"method\": \"LCOR knockdown/overexpression, IFN stimulation assays, gene expression profiling, in vivo tumor initiation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with specific IFN-pathway phenotype, validated in multiple model systems including in vivo\",\n      \"pmids\": [\"28530657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LCoR interacts with RIP140 (receptor-interacting protein 140) via the helix-turn-helix (HTH) domain of LCoR and the N- and C-terminal regions of RIP140; this interaction is required for LCoR-mediated inhibition of gene expression and reduction of breast cancer cell proliferation.\",\n      \"method\": \"In vitro interaction assay, co-immunoprecipitation, proximity ligation assay, confocal microscopy, mutagenesis of HTH domain, siRNA knockdown of RIP140\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (in vitro binding, reciprocal Co-IP, PLA, confocal) plus functional rescue by siRNA, single lab but rigorous\",\n      \"pmids\": [\"28414308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The helix-turn-helix (HTH) domain of LCoR is required for transcriptional repression and inhibition of estrogen-induced target gene expression, as shown by mutagenesis analysis.\",\n      \"method\": \"Mutagenesis of HTH domain, reporter gene assays, endogenous gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"28414308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LCoR interacts with and represses the transcription factor C/EBPβ through its C-terminal HTH domain, suppressing C/EBPβ transcriptional activity on C/EBPα and PPARγ2 promoters by recruiting CtBPs and modulating histone modifications, thereby inhibiting early adipogenesis.\",\n      \"method\": \"Affinity purification/mass spectrometry, co-immunoprecipitation, reporter assay, ChIP, overexpression and knockdown in 3T3-L1 adipocytes, rescue with C/EBPα or PPARγ2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — interaction identified by unbiased AP-MS, confirmed by Co-IP and ChIP, domain mutagenesis, functional rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"28972158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LCOR and LCORL gene loci encode vertebrate-specific PRC2.1-associated proteins PALI1 and PALI2, respectively. PALI1 (encoded by LCOR) promotes PRC2 methyltransferase activity (H3K27 mono-, di-, and tri-methylation) in vitro and in vivo, and is essential for mouse development; PALI1 defines a PRC2.1 subtype mutually exclusive with and antagonistic to the PRC2.2 (AEBP2/JARID2) subtype.\",\n      \"method\": \"Biochemical reconstitution of PRC2 complexes, in vitro methyltransferase assay, genetic knockout (Pali1-null mice), ChIP-seq, co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with methyltransferase activity assay, confirmed by ChIP-seq and genetic knockout with developmental phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"29628311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LCoR acts as a coactivator (not corepressor) for PPARγ-RXRα heterodimers at the Muc1 promoter; LCoR interacts with PPARγ and RXRα via adjacent non-canonical protein motifs in a synergistic fashion, and this coactivator function is inhibited by the RXRα AF2 domain when bound by rexinoid ligand.\",\n      \"method\": \"Reporter assays, co-immunoprecipitation, Lcor-null mouse placenta analysis (Muc1 expression), mutagenesis of AF2 domain\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, reporter assays, and in vivo genetic (null mouse) validation, single lab\",\n      \"pmids\": [\"29463649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KLF6 is a component of Muc1 regulation in cooperation with PPARγ, RXRα, and LCoR in placental cells.\",\n      \"method\": \"Reporter assays, co-immunoprecipitation in placental context\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, reporter assay and Co-IP without extensive mechanistic follow-up for this specific interaction in placenta\",\n      \"pmids\": [\"29463649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LCOR functions as a master transcriptional activator of antigen processing/presentation machinery (APM) genes by binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner; loss of LCOR in cancer stem cells reduces APM expression and drives immune escape.\",\n      \"method\": \"Genetic modification of LCOR expression (overexpression/knockdown), ChIP at ISRE elements, gene expression profiling, in vivo tumor immunotherapy models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct ISRE binding, genetic loss-of-function with APM phenotype, in vivo validation with immunotherapy models, multiple orthogonal methods\",\n      \"pmids\": [\"35301507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LCOR interacts with RUNX1 transcriptional suppressor and relieves RUNX1-mediated repression of PLCL1, leading to increased PLCL1 expression that inhibits lipid accumulation and tumor progression in clear cell renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation (LCOR-RUNX1 interaction), ChIP-qPCR, reporter assays, overexpression/knockdown in vitro and in vivo tumor models\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for protein interaction, ChIP and reporter assays for functional mechanism, in vivo tumor model, single lab\",\n      \"pmids\": [\"40083699\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LCOR (Ligand-dependent Corepressor) is a multifunctional transcriptional coregulator that: (1) is recruited to agonist-bound nuclear receptors (e.g., ERα) via an LXXLL motif and represses their activity by directly binding HDACs (including HDAC3 and HDAC6) and recruiting CtBP corepressors through consensus binding motifs; (2) also acts as a non-receptor transcription factor corepressor by interacting with KLF6 and C/EBPβ via its C-terminal HTH domain to repress target genes including CDKN1A and adipogenic regulators; (3) interacts with RIP140 (requiring HTH domain) to co-regulate gene expression and cell proliferation; (4) acts as a context-dependent coactivator of PPARγ-RXRα at certain promoters via non-canonical motifs; (5) encodes the PRC2.1-associated protein PALI1, which promotes PRC2 H3K27 methyltransferase activity and defines a PRC2 subtype antagonistic to AEBP2/JARID2-containing PRC2.2; (6) acts as an IFN-independent transcriptional activator of antigen processing/presentation machinery (APM) genes by binding ISREs, with its expression regulated by miR-199a; and (7) relieves RUNX1-mediated repression of PLCL1 to restrain lipid accumulation in renal cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LCOR is a multifunctional transcriptional coregulator that controls gene expression through context-dependent corepression, coactivation, and chromatin modification [#0, #13]. In its founding role, LCoR is recruited to agonist-bound nuclear receptors including estrogen receptor alpha through a single LXXLL motif and represses receptor signaling by two parallel routes: an HDAC-dependent mechanism involving direct binding to histone deacetylases (including HDAC6 via its central domain) and an HDAC-independent mechanism through recruitment of CtBP corepressors at consensus CtBP-binding motifs [#0, #1, #2, #3]. Beyond nuclear receptors, LCoR uses its C-terminal helix-turn-helix (HTH) domain to engage sequence-specific transcription factors — KLF6 at the CDKN1A and CDH1 promoters, C/EBPβ to suppress adipogenic genes, and RIP140 to restrain breast cancer cell proliferation — combining N-terminal CtBP recruitment and central-domain HDAC recruitment to effect repression [#6, #10, #12, #11]. The LCOR locus also encodes PALI1, a PRC2.1-associated subunit that stimulates PRC2 H3K27 methyltransferase activity and defines a PRC2 subtype antagonistic to AEBP2/JARID2-containing PRC2.2, and Pali1-null mice are embryonic-lethal [#13]. In an opposing transcriptional capacity, LCOR acts as an interferon-independent activator that binds ISRE elements to drive antigen processing/presentation machinery gene expression; this activity is silenced by miR-199a, whose targeting of the LCOR 3'-UTR licenses immune escape and stem-like properties in breast cancer [#8, #9, #16]. LCoR can also operate as a coactivator of PPARγ-RXRα heterodimers at the Muc1 promoter [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established LCoR as a ligand-dependent corepressor by showing how it docks onto activated nuclear receptors and the dual machinery it uses to silence them, defining its founding mechanism.\",\n      \"evidence\": \"In vitro binding, coactivator-pocket mutagenesis, HDAC-inhibitor (TSA) pharmacology, Co-IP, and confocal colocalization with CtBPs\",\n      \"pmids\": [\"12535528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific HDACs were engaged was not fully resolved\", \"Genome-wide receptor targets not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the central-domain HDAC6 interaction and revealed that LCoR-HDAC6 co-recruitment can both repress and, unexpectedly, enhance some endogenous estrogen target genes, indicating context-dependent output.\",\n      \"evidence\": \"GST pull-down, Co-IP, ChIP/re-ChIP, siRNA knockdown and RT-qPCR in MCF7 cells\",\n      \"pmids\": [\"19744931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LCoR and HDAC6 did not co-IP on target genes, leaving the complex composition unclear\", \"Basis for gene-specific activation versus repression unexplained\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended LCoR function beyond nuclear receptors by identifying KLF6 as a direct partner, showing LCoR acts as a corepressor for sequence-specific transcription factors at cell-cycle and adhesion genes.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, ChIP at CDKN1A/CDH1, TSA reporter assays, domain-deletion analysis, siRNA\",\n      \"pmids\": [\"22277651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of KLF6-LCoR repression not tested\", \"Whether HTH domain directly contacts KLF6 not mapped at residue level\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped the HTH domain as the interaction surface for RIP140 and C/EBPβ, linking LCoR to control of breast cancer proliferation and adipogenesis, and showed miR-199a represses LCOR to attenuate IFN priming and promote stemness.\",\n      \"evidence\": \"AP-MS, reciprocal Co-IP, PLA, HTH mutagenesis, ChIP, 3'-UTR luciferase reporter, knockdown/overexpression and in vivo tumor-initiation models\",\n      \"pmids\": [\"28414308\", \"28972158\", \"28530657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of HTH-partner binding not solved\", \"Mechanism by which LCOR primes IFN responses not detailed at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed two new dimensions: the LCOR-encoded PALI1 is a PRC2.1 subunit that stimulates H3K27 methylation and is required for development, and LCoR can act as a coactivator of PPARγ-RXRα, broadening its mechanistic repertoire beyond repression.\",\n      \"evidence\": \"Biochemical reconstitution and in vitro methyltransferase assays, ChIP-seq, Pali1-null mice; Co-IP, reporter assays, and Lcor-null placenta analysis for PPARγ-RXRα coactivation\",\n      \"pmids\": [\"29628311\", \"29463649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between PALI1/PRC2 function and the corepressor LCoR isoform not integrated\", \"Determinants switching LCoR between corepressor and coactivator modes unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined LCOR as an IFN-independent transcriptional activator that binds ISRE elements to drive antigen processing/presentation machinery, mechanistically explaining how its miR-199a-mediated loss enables tumor immune escape.\",\n      \"evidence\": \"ChIP at ISRE elements, genetic gain/loss of function, expression profiling, in vivo immunotherapy tumor models\",\n      \"pmids\": [\"35301507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors enabling ISRE-bound activation versus repression not identified\", \"How the same protein selects activator versus corepressor targets unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed LCOR de-represses PLCL1 by antagonizing RUNX1, restraining lipid accumulation and tumor progression in clear cell renal cell carcinoma, adding a tissue-specific regulatory axis.\",\n      \"evidence\": \"Co-IP, ChIP-qPCR, reporter assays, gain/loss of function in vitro and in vivo renal tumor models\",\n      \"pmids\": [\"40083699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without reciprocal structural validation of LCOR-RUNX1 binding\", \"Whether de-repression involves displacement of corepressors not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular determinants that switch LCOR/PALI1 between corepressor, coactivator, and PRC2-stimulatory functions across cell contexts remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating LXXLL, CtBP, and HTH modules\", \"No unified explanation for context-dependent activation versus repression\", \"Relationship between LCoR and PALI1 isoforms in vivo unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 6, 12, 16]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 16]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"PRC2.1 (PALI1-containing)\"\n    ],\n    \"partners\": [\n      \"ESR1\",\n      \"HDAC6\",\n      \"CtBP1\",\n      \"KLF6\",\n      \"RIP140\",\n      \"CEBPB\",\n      \"PPARG\",\n      \"RUNX1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}