{"gene":"NFYC","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1995,"finding":"Recombinant CBF-C (NF-YC) is required together with CBF-A (NF-YB) and CBF-B (NF-YA) to form a protein-DNA complex at CCAAT motifs; CBF-C interacts directly with CBF-A to form a heterodimer, and CBF-B associates only with the pre-formed CBF-A–CBF-C complex. CBF-C can substitute for its yeast homologue HAP5 to permit HAP2/HAP3 binding to CCAAT DNA.","method":"Recombinant protein reconstitution, EMSA, immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified recombinant proteins, multiple orthogonal methods, foundational study","pmids":["7878029"],"is_preprint":false},{"year":1996,"finding":"Mutational analysis of CBF-C (NF-YC) showed that its evolutionarily conserved histone-fold motif (similar to histone H2A) is necessary for formation of the CBF-DNA complex. The histone-fold motif mediates interaction with CBF-A; two additional domains flanking this region interact with CBF-B. CBF-B interacts simultaneously with both CBF-A and CBF-C to form a heterotrimeric molecule.","method":"Cross-linking, immunoprecipitation, in vitro binding assays, yeast two-hybrid, mutational analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — extensive mutagenesis combined with multiple in vitro and in vivo binding assays","pmids":["8754798"],"is_preprint":false},{"year":1996,"finding":"CBF-C (NF-YC) contains a transcriptional activation domain in its C-terminal glutamine- and hydrophobic-residue-rich region that acts additively with the activation domain of CBF-B in an in vitro reconstituted transcription system.","method":"In vitro transcription reconstitution with purified recombinant CBF subunits and deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro transcription with defined deletion mutants","pmids":["8662945"],"is_preprint":false},{"year":1997,"finding":"NF-YC (and NF-YB) interact directly with TBP; short stretches within the evolutionarily conserved domains of NF-YC and NF-YB, adjacent to their histone-fold motifs, are necessary for TBP binding. TBP single-amino-acid mutants in the HS2 helix that are defective in NC2 binding are also unable to bind NF-YC.","method":"Immunopurification of TFIID, sedimentation velocity centrifugation, direct binding assays, TBP point mutants","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including mutagenesis and biochemical fractionation","pmids":["9153318"],"is_preprint":false},{"year":1997,"finding":"The conserved yeast-homology domain of human NF-YC, expressed in bacteria and combined with the corresponding conserved domains of NF-YA and NF-YB, forms a minimal CCAAT-binding complex (mini-NF-Y) as shown by EMSA.","method":"Bacterial expression, EMSA","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 — reconstitution in vitro, single study","pmids":["9249075"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the NF-YC/NF-YB (CBF-C/CBF-A) subcomplex revealed that the core domains of both proteins interact through histone-fold motifs closely related to the H2A/H2B pair. The alphaC helix of NF-YC is important both for NF-Y trimerization and as a surface for regulatory protein interactions (e.g., MYC, p53). Structural modeling highlighted how NF-YB/NF-YC interact with DNA in a non-sequence-specific manner within the full NF-Y/CCAAT complex.","method":"X-ray crystallography, structural modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional domain mapping","pmids":["12401788"],"is_preprint":false},{"year":2004,"finding":"NF-YC localizes in both the cytoplasm and nucleus, and its nuclear localization is determined by interaction with its heterodimerization partner NF-YB. Nuclear accumulation of NF-YC is regulated during the cell cycle of serum-restimulated cells, peaking at the onset of S phase.","method":"Immunofluorescence of endogenous and GFP/Flag-tagged NF-Y subunits, cell cycle synchronization (serum restimulation)","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with functional cell-cycle consequence, endogenous and tagged protein validated","pmids":["14712092"],"is_preprint":false},{"year":2009,"finding":"The NF-YC locus produces at least four isoforms (37 kDa and 50 kDa being mutually exclusive) via dual promoters and alternative splicing. The 37-kDa isoform specifically regulates basal levels of G1/S-blocking and pro-apoptotic genes. The NF-YC promoter P2 is induced in response to DNA damage in a p53-dependent manner. Different NF-YC isoforms form preferential pairings with NF-YA isoforms and display different transcriptional activities on selected promoters.","method":"Transient transfections, chromatin immunoprecipitation (ChIP), RT-PCR, specific functional inactivation of the 37-kDa isoform","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, KD, promoter assays) in one study","pmids":["19690168"],"is_preprint":false},{"year":2010,"finding":"NF-YC functions as an agonist-dependent corepressor of the mineralocorticoid receptor (MR). NF-YC physically interacts with MR in a hormone-sensitive manner (confirmed by yeast two-hybrid, mammalian two-hybrid, co-immunoprecipitation, and fluorescence imaging). NF-YC inhibits the aldosterone-induced N/C interaction of MR. Endogenous NF-YC is recruited to the ENaC gene promoter along with MR and SRC-1 in an aldosterone-dependent manner. siRNA knockdown of NF-YC potentiated hormonal activation of endogenous MR target genes.","method":"Yeast two-hybrid, mammalian two-hybrid, co-immunoprecipitation, fluorescence imaging, ChIP, siRNA knockdown, transient transfection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction confirmation by multiple methods plus ChIP and functional knockdown","pmids":["20054001"],"is_preprint":false},{"year":2018,"finding":"siRNA silencing of NFYC in skeletal muscle cells (L6 myotubes) increased constitutive levels of IL6 and LIF mRNA, identifying NFYC as a transcriptional repressor of these cytokine genes downstream of AMPK signaling.","method":"siRNA knockdown, qRT-PCR, actinomycin D transcriptional block experiments","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined transcriptional readout; single lab","pmids":["29688769"],"is_preprint":false},{"year":2023,"finding":"The NFYC-37 isoform (but not NFYC-50) interacts with CBP and SREBP2 to activate mevalonate pathway gene transcription and promote cholesterol biosynthesis in bladder cancer cells. NFYC-50 preferentially recruits CARM1 to methylate CBP, which prevents CBP-SREBP2 interaction and inhibits the mevalonate pathway.","method":"CRISPR-Cas9 functional screen, co-immunoprecipitation, ChIP, loss- and gain-of-function experiments, xenograft tumor models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — CRISPR screen plus reciprocal Co-IP and ChIP with isoform-specific mechanistic dissection","pmids":["37561631"],"is_preprint":false},{"year":2026,"finding":"NFYC directly binds the KLF1 promoter and positively regulates KLF1 expression, which in turn activates LDHA transcription to drive aerobic glycolysis in glioblastoma cells. Knockdown of NFYC reduced KLF1 and LDHA expression, suppressed glycolytic flux, and inhibited tumor growth in xenografts.","method":"Dual-luciferase reporter assay, ChIP, siRNA/shRNA knockdown, Seahorse metabolic assay, xenograft model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus functional rescue in vitro and in vivo; single lab","pmids":["42039141"],"is_preprint":false},{"year":2006,"finding":"A point mutation in the NFYC gene generates an antigenic peptide presented by HLA-B*5201 that is recognized by autologous cytolytic T lymphocytes (CTL) on a human squamous cell lung carcinoma; precursors of CTL recognizing the mutated NF-YC peptide were detected at ~1/30,000 CD8 cells in a tumor-draining lymph node.","method":"CTL recognition assay, sequencing of tumor-derived NFYC mutation, HLA restriction mapping","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — direct identification of tumor-specific mutant peptide with functional T cell assay","pmids":["16287085"],"is_preprint":false}],"current_model":"NFYC (CBF-C) is an obligate subunit of the heterotrimeric NF-Y (CBF) transcription factor complex: its histone-fold domain (H2A-like) heterodimerizes with NF-YB (H2B-like) to form a nuclear-localized dimer whose nuclear import depends on NF-YB interaction, and this dimer recruits NF-YA to complete the trimer that binds CCAAT-box promoter elements; NFYC additionally carries a C-terminal glutamine-rich transcriptional activation domain, directly contacts TBP/TFIID, and through isoform-specific alternative splicing (37 kDa vs. 50 kDa) differentially regulates G1/S and DNA-damage response genes; it also functions as an agonist-dependent corepressor of the mineralocorticoid receptor and, via isoform-selective interactions with CBP and SREBP2, activates the mevalonate/cholesterol biosynthesis pathway in cancer cells."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing that NF-YC is an obligate subunit of the CCAAT-binding trimer resolved how the three CBF subunits assemble: NF-YC heterodimerizes with NF-YB first, and NF-YA then joins the preformed dimer to enable DNA binding.","evidence":"Recombinant protein reconstitution, EMSA, immunoprecipitation; functional complementation of yeast HAP5","pmids":["7878029"],"confidence":"High","gaps":["Stoichiometry of the trimer on DNA not resolved","No structural data at this stage"]},{"year":1996,"claim":"Mutagenesis defined the histone-fold motif of NF-YC as the minimal determinant for NF-YB interaction and identified flanking regions required for NF-YA contact, establishing the domain architecture of the trimer, while a separate study showed NF-YC harbors a C-terminal glutamine-rich transactivation domain that acts additively with that of NF-YA.","evidence":"Cross-linking, yeast two-hybrid, deletion mutagenesis; reconstituted in vitro transcription","pmids":["8754798","8662945"],"confidence":"High","gaps":["Activation domain targets on general transcription machinery unknown","No crystal structure yet"]},{"year":1997,"claim":"Demonstrating that NF-YC (and NF-YB) directly contact TBP via residues adjacent to their histone folds linked the NF-Y trimer mechanistically to the basal transcription apparatus and suggested overlap with the NC2 binding surface on TBP.","evidence":"Immunopurification of TFIID, sedimentation velocity, TBP point-mutant binding assays","pmids":["9153318"],"confidence":"High","gaps":["Whether NF-Y and NC2 compete for TBP in vivo not tested","Structural basis of TBP–NF-YC contact unresolved"]},{"year":2002,"claim":"The crystal structure of the NF-YB/NF-YC dimer confirmed the H2A/H2B-like histone-fold architecture and identified the αC helix of NF-YC as a surface for both trimer assembly and regulatory protein interactions (MYC, p53), providing a structural framework for understanding NF-Y function.","evidence":"X-ray crystallography, structural modeling","pmids":["12401788"],"confidence":"High","gaps":["Full trimer–DNA co-crystal not yet available","Regulatory interactions with MYC/p53 mapped structurally but not validated functionally in this study"]},{"year":2004,"claim":"Showing that NF-YC nuclear accumulation depends on NF-YB interaction and peaks at S-phase onset connected NF-Y assembly dynamics to cell-cycle control.","evidence":"Immunofluorescence of endogenous and tagged NF-YC, serum-restimulation cell-cycle synchronization","pmids":["14712092"],"confidence":"High","gaps":["Nuclear import signal and importin pathway not identified","Whether cytoplasmic NF-YC has independent functions unknown"]},{"year":2009,"claim":"Discovery that the NFYC locus produces mutually exclusive 37-kDa and 50-kDa isoforms via alternative promoters/splicing, with the 37-kDa isoform specifically regulating G1/S and pro-apoptotic genes and its P2 promoter being p53-inducible, revealed isoform-level functional diversification of NF-Y.","evidence":"ChIP, RT-PCR, transient transfection, specific functional inactivation of 37-kDa isoform","pmids":["19690168"],"confidence":"High","gaps":["Isoform-specific interactomes not comprehensively mapped","In vivo isoform-specific knockout models lacking"]},{"year":2010,"claim":"Identification of NF-YC as an agonist-dependent corepressor of the mineralocorticoid receptor expanded NF-YC function beyond CCAAT-box promoter activation to nuclear receptor coregulation.","evidence":"Yeast/mammalian two-hybrid, co-IP, ChIP at ENaC promoter, siRNA knockdown potentiating MR target genes","pmids":["20054001"],"confidence":"High","gaps":["Whether corepression requires the full NF-Y trimer or involves NF-YC alone not resolved","Structural basis of MR–NF-YC interaction unknown"]},{"year":2018,"claim":"Knockdown experiments in muscle cells showed NF-YC represses IL6 and LIF transcription, linking it to AMPK-mediated cytokine regulation and demonstrating a repressive role outside the classical CCAAT-activation paradigm.","evidence":"siRNA knockdown in L6 myotubes, qRT-PCR, actinomycin D chase","pmids":["29688769"],"confidence":"Medium","gaps":["Whether repression is direct (NF-YC on IL6/LIF promoters) not shown by ChIP","Single cell-type study"]},{"year":2023,"claim":"Mechanistic dissection of the two major NF-YC isoforms showed that the 37-kDa isoform activates mevalonate/cholesterol biosynthesis via CBP–SREBP2 interaction, while the 50-kDa isoform recruits CARM1 to methylate CBP and suppress this pathway, establishing an isoform-switch model for metabolic reprogramming in cancer.","evidence":"CRISPR-Cas9 screen, co-IP, ChIP, gain/loss-of-function, xenograft models in bladder cancer cells","pmids":["37561631"],"confidence":"High","gaps":["Whether the isoform switch operates in non-cancer tissues unknown","Upstream signals controlling isoform ratio not identified"]},{"year":2026,"claim":"Demonstration that NF-YC directly activates KLF1 transcription to drive LDHA-dependent aerobic glycolysis in glioblastoma broadened the metabolic roles of NF-YC beyond cholesterol to glycolytic reprogramming.","evidence":"ChIP, dual-luciferase reporter, Seahorse metabolic assay, shRNA knockdown, xenograft model","pmids":["42039141"],"confidence":"Medium","gaps":["Which NF-YC isoform is responsible not determined","Single tumor type studied"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the full NF-Y trimer on DNA at atomic resolution, the upstream signals and splicing regulators that control the 37-kDa vs. 50-kDa isoform ratio, and the physiological significance of isoform-specific functions in normal tissues versus cancer.","evidence":"","pmids":[],"confidence":"High","gaps":["Full NF-Y trimer–CCAAT co-crystal structure not yet reported","In vivo isoform-specific knockout phenotypes unknown","Mechanism of NF-YC-mediated transcriptional repression at IL6/LIF and MR targets remains indirect"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,7,8,10,11]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,7,10,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10,11]}],"complexes":["NF-Y (CBF) heterotrimer"],"partners":["NFYB","NFYA","TBP","NR3C2","CBP","SREBF2","CARM1"],"other_free_text":[]},"mechanistic_narrative":"NFYC encodes the C subunit of the heterotrimeric NF-Y (CBF) transcription factor, a master regulator of CCAAT-box-dependent gene expression that controls cell-cycle progression, DNA-damage responses, lipid metabolism, and cytokine expression. Its histone-fold domain (H2A-like) heterodimerizes with NF-YB (H2B-like) to form a platform that recruits NF-YA, completing the CCAAT-binding trimer; nuclear import of NFYC depends on NF-YB interaction, and its nuclear accumulation peaks at S-phase onset [PMID:7878029, PMID:8754798, PMID:14712092]. NFYC carries a C-terminal glutamine-rich activation domain that synergizes with NF-YA and directly contacts TBP/TFIID, and its isoform-specific alternative splicing (37 kDa vs. 50 kDa) confers distinct transcriptional outputs: the 37-kDa isoform activates mevalonate/cholesterol biosynthesis genes via CBP–SREBP2, whereas the 50-kDa isoform recruits CARM1 to methylate CBP and suppress this pathway [PMID:8662945, PMID:9153318, PMID:19690168, PMID:37561631]. Beyond CCAAT-dependent promoter activation, NFYC functions as an agonist-dependent corepressor of the mineralocorticoid receptor and represses IL6/LIF cytokine transcription downstream of AMPK signaling [PMID:20054001, PMID:29688769]."},"prefetch_data":{"uniprot":{"accession":"Q13952","full_name":"Nuclear transcription factor Y subunit gamma","aliases":["CAAT box DNA-binding protein subunit C","Nuclear transcription factor Y subunit C","NF-YC","Transactivator HSM-1/2"],"length_aa":458,"mass_kda":50.3,"function":"Component of the sequence-specific heterotrimeric transcription factor (NF-Y) which specifically recognizes a 5'-CCAAT-3' box motif found in the promoters of its target genes. NF-Y can function as both an activator and a repressor, depending on its interacting cofactors","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13952/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NFYC","classification":"Common Essential","n_dependent_lines":1153,"n_total_lines":1208,"dependency_fraction":0.9544701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NFYC","total_profiled":1310},"omim":[{"mim_id":"621274","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 152; CCDC152","url":"https://www.omim.org/entry/621274"},{"mim_id":"607268","title":"CHROMATIN ACCESSIBILITY COMPLEX, SUBUNIT 1; CHRAC1","url":"https://www.omim.org/entry/607268"},{"mim_id":"605344","title":"NUCLEAR TRANSCRIPTION FACTOR Y, GAMMA; NFYC","url":"https://www.omim.org/entry/605344"},{"mim_id":"604764","title":"ZINC FINGER AND HOMEODOMAIN PROTEIN 1; ZHX1","url":"https://www.omim.org/entry/604764"},{"mim_id":"600005","title":"CLASS II MAJOR HISTOCOMPATIBILITY COMPLEX TRANSACTIVATOR; CIITA","url":"https://www.omim.org/entry/600005"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NFYC"},"hgnc":{"alias_symbol":["CBF-C","NF-YC"],"prev_symbol":[]},"alphafold":{"accession":"Q13952","domains":[{"cath_id":"1.10.20.10","chopping":"15-115","consensus_level":"high","plddt":94.1462,"start":15,"end":115}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13952","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13952-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13952-F1-predicted_aligned_error_v6.png","plddt_mean":49.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NFYC","jax_strain_url":"https://www.jax.org/strain/search?query=NFYC"},"sequence":{"accession":"Q13952","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13952.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13952/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13952"}},"corpus_meta":[{"pmid":"7878029","id":"PMC_7878029","title":"Recombinant rat CBF-C, the third 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CCAAT motifs; CBF-C interacts directly with CBF-A to form a heterodimer, and CBF-B associates only with the pre-formed CBF-A–CBF-C complex. CBF-C can substitute for its yeast homologue HAP5 to permit HAP2/HAP3 binding to CCAAT DNA.\",\n      \"method\": \"Recombinant protein reconstitution, EMSA, immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified recombinant proteins, multiple orthogonal methods, foundational study\",\n      \"pmids\": [\"7878029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mutational analysis of CBF-C (NF-YC) showed that its evolutionarily conserved histone-fold motif (similar to histone H2A) is necessary for formation of the CBF-DNA complex. The histone-fold motif mediates interaction with CBF-A; two additional domains flanking this region interact with CBF-B. CBF-B interacts simultaneously with both CBF-A and CBF-C to form a heterotrimeric molecule.\",\n      \"method\": \"Cross-linking, immunoprecipitation, in vitro binding assays, yeast two-hybrid, mutational analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — extensive mutagenesis combined with multiple in vitro and in vivo binding assays\",\n      \"pmids\": [\"8754798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CBF-C (NF-YC) contains a transcriptional activation domain in its C-terminal glutamine- and hydrophobic-residue-rich region that acts additively with the activation domain of CBF-B in an in vitro reconstituted transcription system.\",\n      \"method\": \"In vitro transcription reconstitution with purified recombinant CBF subunits and deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro transcription with defined deletion mutants\",\n      \"pmids\": [\"8662945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NF-YC (and NF-YB) interact directly with TBP; short stretches within the evolutionarily conserved domains of NF-YC and NF-YB, adjacent to their histone-fold motifs, are necessary for TBP binding. TBP single-amino-acid mutants in the HS2 helix that are defective in NC2 binding are also unable to bind NF-YC.\",\n      \"method\": \"Immunopurification of TFIID, sedimentation velocity centrifugation, direct binding assays, TBP point mutants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including mutagenesis and biochemical fractionation\",\n      \"pmids\": [\"9153318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The conserved yeast-homology domain of human NF-YC, expressed in bacteria and combined with the corresponding conserved domains of NF-YA and NF-YB, forms a minimal CCAAT-binding complex (mini-NF-Y) as shown by EMSA.\",\n      \"method\": \"Bacterial expression, EMSA\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in vitro, single study\",\n      \"pmids\": [\"9249075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the NF-YC/NF-YB (CBF-C/CBF-A) subcomplex revealed that the core domains of both proteins interact through histone-fold motifs closely related to the H2A/H2B pair. The alphaC helix of NF-YC is important both for NF-Y trimerization and as a surface for regulatory protein interactions (e.g., MYC, p53). Structural modeling highlighted how NF-YB/NF-YC interact with DNA in a non-sequence-specific manner within the full NF-Y/CCAAT complex.\",\n      \"method\": \"X-ray crystallography, structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional domain mapping\",\n      \"pmids\": [\"12401788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NF-YC localizes in both the cytoplasm and nucleus, and its nuclear localization is determined by interaction with its heterodimerization partner NF-YB. Nuclear accumulation of NF-YC is regulated during the cell cycle of serum-restimulated cells, peaking at the onset of S phase.\",\n      \"method\": \"Immunofluorescence of endogenous and GFP/Flag-tagged NF-Y subunits, cell cycle synchronization (serum restimulation)\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional cell-cycle consequence, endogenous and tagged protein validated\",\n      \"pmids\": [\"14712092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The NF-YC locus produces at least four isoforms (37 kDa and 50 kDa being mutually exclusive) via dual promoters and alternative splicing. The 37-kDa isoform specifically regulates basal levels of G1/S-blocking and pro-apoptotic genes. The NF-YC promoter P2 is induced in response to DNA damage in a p53-dependent manner. Different NF-YC isoforms form preferential pairings with NF-YA isoforms and display different transcriptional activities on selected promoters.\",\n      \"method\": \"Transient transfections, chromatin immunoprecipitation (ChIP), RT-PCR, specific functional inactivation of the 37-kDa isoform\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, KD, promoter assays) in one study\",\n      \"pmids\": [\"19690168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NF-YC functions as an agonist-dependent corepressor of the mineralocorticoid receptor (MR). NF-YC physically interacts with MR in a hormone-sensitive manner (confirmed by yeast two-hybrid, mammalian two-hybrid, co-immunoprecipitation, and fluorescence imaging). NF-YC inhibits the aldosterone-induced N/C interaction of MR. Endogenous NF-YC is recruited to the ENaC gene promoter along with MR and SRC-1 in an aldosterone-dependent manner. siRNA knockdown of NF-YC potentiated hormonal activation of endogenous MR target genes.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, co-immunoprecipitation, fluorescence imaging, ChIP, siRNA knockdown, transient transfection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmation by multiple methods plus ChIP and functional knockdown\",\n      \"pmids\": [\"20054001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"siRNA silencing of NFYC in skeletal muscle cells (L6 myotubes) increased constitutive levels of IL6 and LIF mRNA, identifying NFYC as a transcriptional repressor of these cytokine genes downstream of AMPK signaling.\",\n      \"method\": \"siRNA knockdown, qRT-PCR, actinomycin D transcriptional block experiments\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined transcriptional readout; single lab\",\n      \"pmids\": [\"29688769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The NFYC-37 isoform (but not NFYC-50) interacts with CBP and SREBP2 to activate mevalonate pathway gene transcription and promote cholesterol biosynthesis in bladder cancer cells. NFYC-50 preferentially recruits CARM1 to methylate CBP, which prevents CBP-SREBP2 interaction and inhibits the mevalonate pathway.\",\n      \"method\": \"CRISPR-Cas9 functional screen, co-immunoprecipitation, ChIP, loss- and gain-of-function experiments, xenograft tumor models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen plus reciprocal Co-IP and ChIP with isoform-specific mechanistic dissection\",\n      \"pmids\": [\"37561631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NFYC directly binds the KLF1 promoter and positively regulates KLF1 expression, which in turn activates LDHA transcription to drive aerobic glycolysis in glioblastoma cells. Knockdown of NFYC reduced KLF1 and LDHA expression, suppressed glycolytic flux, and inhibited tumor growth in xenografts.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP, siRNA/shRNA knockdown, Seahorse metabolic assay, xenograft model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional rescue in vitro and in vivo; single lab\",\n      \"pmids\": [\"42039141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A point mutation in the NFYC gene generates an antigenic peptide presented by HLA-B*5201 that is recognized by autologous cytolytic T lymphocytes (CTL) on a human squamous cell lung carcinoma; precursors of CTL recognizing the mutated NF-YC peptide were detected at ~1/30,000 CD8 cells in a tumor-draining lymph node.\",\n      \"method\": \"CTL recognition assay, sequencing of tumor-derived NFYC mutation, HLA restriction mapping\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct identification of tumor-specific mutant peptide with functional T cell assay\",\n      \"pmids\": [\"16287085\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NFYC (CBF-C) is an obligate subunit of the heterotrimeric NF-Y (CBF) transcription factor complex: its histone-fold domain (H2A-like) heterodimerizes with NF-YB (H2B-like) to form a nuclear-localized dimer whose nuclear import depends on NF-YB interaction, and this dimer recruits NF-YA to complete the trimer that binds CCAAT-box promoter elements; NFYC additionally carries a C-terminal glutamine-rich transcriptional activation domain, directly contacts TBP/TFIID, and through isoform-specific alternative splicing (37 kDa vs. 50 kDa) differentially regulates G1/S and DNA-damage response genes; it also functions as an agonist-dependent corepressor of the mineralocorticoid receptor and, via isoform-selective interactions with CBP and SREBP2, activates the mevalonate/cholesterol biosynthesis pathway in cancer cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NFYC encodes the C subunit of the heterotrimeric NF-Y (CBF) transcription factor, a master regulator of CCAAT-box-dependent gene expression that controls cell-cycle progression, DNA-damage responses, lipid metabolism, and cytokine expression. Its histone-fold domain (H2A-like) heterodimerizes with NF-YB (H2B-like) to form a platform that recruits NF-YA, completing the CCAAT-binding trimer; nuclear import of NFYC depends on NF-YB interaction, and its nuclear accumulation peaks at S-phase onset [PMID:7878029, PMID:8754798, PMID:14712092]. NFYC carries a C-terminal glutamine-rich activation domain that synergizes with NF-YA and directly contacts TBP/TFIID, and its isoform-specific alternative splicing (37 kDa vs. 50 kDa) confers distinct transcriptional outputs: the 37-kDa isoform activates mevalonate/cholesterol biosynthesis genes via CBP–SREBP2, whereas the 50-kDa isoform recruits CARM1 to methylate CBP and suppress this pathway [PMID:8662945, PMID:9153318, PMID:19690168, PMID:37561631]. Beyond CCAAT-dependent promoter activation, NFYC functions as an agonist-dependent corepressor of the mineralocorticoid receptor and represses IL6/LIF cytokine transcription downstream of AMPK signaling [PMID:20054001, PMID:29688769].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that NF-YC is an obligate subunit of the CCAAT-binding trimer resolved how the three CBF subunits assemble: NF-YC heterodimerizes with NF-YB first, and NF-YA then joins the preformed dimer to enable DNA binding.\",\n      \"evidence\": \"Recombinant protein reconstitution, EMSA, immunoprecipitation; functional complementation of yeast HAP5\",\n      \"pmids\": [\"7878029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the trimer on DNA not resolved\", \"No structural data at this stage\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mutagenesis defined the histone-fold motif of NF-YC as the minimal determinant for NF-YB interaction and identified flanking regions required for NF-YA contact, establishing the domain architecture of the trimer, while a separate study showed NF-YC harbors a C-terminal glutamine-rich transactivation domain that acts additively with that of NF-YA.\",\n      \"evidence\": \"Cross-linking, yeast two-hybrid, deletion mutagenesis; reconstituted in vitro transcription\",\n      \"pmids\": [\"8754798\", \"8662945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activation domain targets on general transcription machinery unknown\", \"No crystal structure yet\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating that NF-YC (and NF-YB) directly contact TBP via residues adjacent to their histone folds linked the NF-Y trimer mechanistically to the basal transcription apparatus and suggested overlap with the NC2 binding surface on TBP.\",\n      \"evidence\": \"Immunopurification of TFIID, sedimentation velocity, TBP point-mutant binding assays\",\n      \"pmids\": [\"9153318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NF-Y and NC2 compete for TBP in vivo not tested\", \"Structural basis of TBP–NF-YC contact unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The crystal structure of the NF-YB/NF-YC dimer confirmed the H2A/H2B-like histone-fold architecture and identified the αC helix of NF-YC as a surface for both trimer assembly and regulatory protein interactions (MYC, p53), providing a structural framework for understanding NF-Y function.\",\n      \"evidence\": \"X-ray crystallography, structural modeling\",\n      \"pmids\": [\"12401788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full trimer–DNA co-crystal not yet available\", \"Regulatory interactions with MYC/p53 mapped structurally but not validated functionally in this study\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that NF-YC nuclear accumulation depends on NF-YB interaction and peaks at S-phase onset connected NF-Y assembly dynamics to cell-cycle control.\",\n      \"evidence\": \"Immunofluorescence of endogenous and tagged NF-YC, serum-restimulation cell-cycle synchronization\",\n      \"pmids\": [\"14712092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear import signal and importin pathway not identified\", \"Whether cytoplasmic NF-YC has independent functions unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Discovery that the NFYC locus produces mutually exclusive 37-kDa and 50-kDa isoforms via alternative promoters/splicing, with the 37-kDa isoform specifically regulating G1/S and pro-apoptotic genes and its P2 promoter being p53-inducible, revealed isoform-level functional diversification of NF-Y.\",\n      \"evidence\": \"ChIP, RT-PCR, transient transfection, specific functional inactivation of 37-kDa isoform\",\n      \"pmids\": [\"19690168\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific interactomes not comprehensively mapped\", \"In vivo isoform-specific knockout models lacking\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of NF-YC as an agonist-dependent corepressor of the mineralocorticoid receptor expanded NF-YC function beyond CCAAT-box promoter activation to nuclear receptor coregulation.\",\n      \"evidence\": \"Yeast/mammalian two-hybrid, co-IP, ChIP at ENaC promoter, siRNA knockdown potentiating MR target genes\",\n      \"pmids\": [\"20054001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether corepression requires the full NF-Y trimer or involves NF-YC alone not resolved\", \"Structural basis of MR–NF-YC interaction unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Knockdown experiments in muscle cells showed NF-YC represses IL6 and LIF transcription, linking it to AMPK-mediated cytokine regulation and demonstrating a repressive role outside the classical CCAAT-activation paradigm.\",\n      \"evidence\": \"siRNA knockdown in L6 myotubes, qRT-PCR, actinomycin D chase\",\n      \"pmids\": [\"29688769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether repression is direct (NF-YC on IL6/LIF promoters) not shown by ChIP\", \"Single cell-type study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mechanistic dissection of the two major NF-YC isoforms showed that the 37-kDa isoform activates mevalonate/cholesterol biosynthesis via CBP–SREBP2 interaction, while the 50-kDa isoform recruits CARM1 to methylate CBP and suppress this pathway, establishing an isoform-switch model for metabolic reprogramming in cancer.\",\n      \"evidence\": \"CRISPR-Cas9 screen, co-IP, ChIP, gain/loss-of-function, xenograft models in bladder cancer cells\",\n      \"pmids\": [\"37561631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the isoform switch operates in non-cancer tissues unknown\", \"Upstream signals controlling isoform ratio not identified\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstration that NF-YC directly activates KLF1 transcription to drive LDHA-dependent aerobic glycolysis in glioblastoma broadened the metabolic roles of NF-YC beyond cholesterol to glycolytic reprogramming.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, Seahorse metabolic assay, shRNA knockdown, xenograft model\",\n      \"pmids\": [\"42039141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which NF-YC isoform is responsible not determined\", \"Single tumor type studied\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the full NF-Y trimer on DNA at atomic resolution, the upstream signals and splicing regulators that control the 37-kDa vs. 50-kDa isoform ratio, and the physiological significance of isoform-specific functions in normal tissues versus cancer.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full NF-Y trimer–CCAAT co-crystal structure not yet reported\", \"In vivo isoform-specific knockout phenotypes unknown\", \"Mechanism of NF-YC-mediated transcriptional repression at IL6/LIF and MR targets remains indirect\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 7, 8, 10, 11]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 7, 10, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [\n      \"NF-Y (CBF) heterotrimer\"\n    ],\n    \"partners\": [\n      \"NFYB\",\n      \"NFYA\",\n      \"TBP\",\n      \"NR3C2\",\n      \"CBP\",\n      \"SREBF2\",\n      \"CARM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}