{"gene":"NFYC","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"Recombinant CBF-C (NF-YC) is required together with CBF-A (NF-YA) and CBF-B (NF-YB) to form a CBF-DNA complex at CCAAT motifs; CBF-C is present in the protein-DNA complex along with the other two subunits. CBF-A and CBF-C interact directly to form a heterodimer, and CBF-B does not interact with either subunit individually but associates with the CBF-A/CBF-C complex. CBF-C can substitute for a yeast homolog to allow HAP2/HAP3 binding to CCAAT-containing DNA.","method":"Recombinant protein reconstitution, EMSA (electrophoretic mobility shift assay), immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with purified recombinant proteins, multiple orthogonal methods (EMSA, Co-IP), replicated with yeast homologs","pmids":["7878029"],"is_preprint":false},{"year":1996,"finding":"The evolutionarily conserved histone-fold motif (H2A-like) of CBF-C (NF-YC) is necessary for formation of the CBF-DNA complex. Two separate interaction domains within this motif contact CBF-B, flanking the single CBF-A interaction domain. A 'tridentate' surface generated by the CBF-A/CBF-C heterodimer interacts with a 21-amino-acid subunit interaction domain of CBF-B to form the heterotrimer. CBF-B interacts simultaneously with both CBF-A and CBF-C.","method":"Cross-linking, immunoprecipitation, deletion mutagenesis, in vitro binding assays, yeast two-hybrid","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with mutagenesis and multiple orthogonal methods (cross-linking, IP, yeast two-hybrid, in vitro assays) in single rigorous study","pmids":["8754798"],"is_preprint":false},{"year":1996,"finding":"CBF-C (NF-YC) contains a transcription activation domain in its C-terminal glutamine- and hydrophobic-residue-rich region; deletion of this domain (residues 114–309) reduces transcriptional activation to ~50% of wild-type. The activation domains of CBF-B and CBF-C act additively in vitro.","method":"In vitro transcription reconstitution with purified recombinant CBF subunits and CBF-depleted nuclear extracts, deletion mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro transcription system with mutagenesis, single lab but rigorous reconstitution approach","pmids":["8662945"],"is_preprint":false},{"year":1997,"finding":"NF-YC interacts with TBP (TATA-binding protein) in solution, both alone and when complexed with NF-YB. Short stretches within the evolutionarily conserved domain of NF-YC adjacent to the histone-fold motif are necessary for TBP binding. TBP point mutants in the HS2 helix (previously defective in NC2 binding) are also unable to bind NF-YC.","method":"Immunopurification of TFIID, sedimentation velocity centrifugation, in vitro binding assays, TBP mutant analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interactions tested with TBP mutants and multiple biochemical fractionation methods, single lab","pmids":["9153318"],"is_preprint":false},{"year":1997,"finding":"The histone-fold domain of human NF-YC is sufficient, together with the corresponding conserved domains of NF-YA and NF-YB, to form a functional CCAAT-binding mini-NF-Y complex.","method":"EMSA with bacterially expressed recombinant domain fragments","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with purified proteins but single lab, single method described in abstract","pmids":["9249075"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the NF-YC/NF-YB subcomplex shows that the core domains of NF-YC and NF-YB interact through histone-fold motifs, closely related to H2A/H2B and NC2α/NC2β families. An αC helix unique to NF-YC is required both for NF-Y trimerization (interaction with NF-YA) and serves as a target surface for regulatory proteins such as MYC and p53.","method":"X-ray crystallography, structural modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with detailed functional interpretation of domain interactions and regulatory surfaces","pmids":["12401788"],"is_preprint":false},{"year":2004,"finding":"NF-YC localizes to 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 cell-cycle regulated, increasing at the onset of S phase in serum-restimulated NIH3T3 cells.","method":"Immunofluorescence of endogenous and GFP/Flag-tagged NF-YC, cell cycle synchronization","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by imaging of endogenous and tagged protein with functional link to cell cycle; single lab, two approaches","pmids":["14712092"],"is_preprint":false},{"year":2009,"finding":"The NF-YC locus generates at least four alternatively spliced isoforms (37- and 50-kDa being mutually exclusive) arising from two promoters (P1 and P2). P2 is induced by DNA damage in a p53-dependent manner and exclusively drives the 50-kDa isoform. The 37-kDa isoform specifically suppresses basal levels of G1/S-blocking and pro-apoptotic genes but not G2/M promoters. Different NF-YA/NF-YC isoform pairings show distinct transcriptional activities on selected promoters.","method":"Transient transfection, chromatin immunoprecipitation (ChIP), RT-PCR, isoform-specific functional inactivation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional transfections with isoform-specific knockdown, single lab, multiple orthogonal methods","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 ligand-bound MR, inhibits MR transactivation, and is sequentially recruited to the ENaC gene promoter together with MR. NF-YC inhibits the aldosterone-induced N/C intramolecular interaction of MR, thereby altering MR conformation to repress transcription. siRNA depletion of NF-YC potentiates hormonal activation of endogenous MR target genes. The corepressor function is selective for MR and does not affect androgen, progesterone, or glucocorticoid receptors.","method":"Yeast two-hybrid, mammalian two-hybrid, coimmunoprecipitation, fluorescence subcellular imaging, siRNA knockdown, ChIP, transient transfection reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, two-hybrid, siRNA with endogenous target genes, imaging), single lab but comprehensive mechanistic dissection","pmids":["20054001"],"is_preprint":false},{"year":2023,"finding":"The NFYC-37 isoform (but not NFYC-50) promotes bladder cancer cell proliferation and tumor growth. NFYC-37 interacts with CBP and SREBP2 to activate mevalonate pathway transcription and cholesterol biosynthesis. NFYC-50 recruits the arginine methyltransferase CARM1 more than NFYC-37, leading to CBP methylation that prevents the CBP-SREBP2 interaction and inhibits the mevalonate pathway.","method":"CRISPR-Cas9 functional screen, co-immunoprecipitation, reporter assays, ChIP, xenograft tumor models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus Co-IP and ChIP mechanistic follow-up, single lab, multiple methods","pmids":["37561631"],"is_preprint":false},{"year":2023,"finding":"In Drosophila eye imaginal discs, NF-YC knockdown leads to extended expression of Cyclin A and Cyclin B into the non-proliferative region (NPR) and decreased expression of the transcriptional cofactor Eyes absent (Eya), without affecting Dpp or Hh signaling. NF-YC restricts CycA/CycB expression to enable G1 cell-cycle synchronization in the NPR.","method":"RNAi knockdown in Drosophila, immunofluorescence, genetic epistasis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean in vivo knockdown with specific phenotypic readouts and pathway placement, single lab, single organism model","pmids":["37569581"],"is_preprint":false},{"year":2026,"finding":"In glioblastoma cells, NFYC binds the KLF1 promoter and positively regulates KLF1 expression; KLF1 in turn directly activates LDHA transcription. This NFYC-KLF1-LDHA axis promotes aerobic glycolysis and tumor growth. KLF1 knockdown partially reverses NFYC oncogenic effects and vice versa.","method":"ChIP assay, dual-luciferase reporter assay, siRNA/shRNA knockdown, overexpression, Seahorse metabolic flux analysis, xenograft model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter directly demonstrate promoter binding and transactivation; genetic epistasis via double knockdown; single lab","pmids":["42039141"],"is_preprint":false}],"current_model":"NF-YC (CBF-C) is the histone-fold (H2A-like) subunit of the heterotrimeric NF-Y/CBF transcription factor: it dimerizes with NF-YB via their histone-fold motifs and presents a hybrid surface that recruits NF-YB to form the full heterotrimer required for CCAAT-box binding; its αC helix mediates trimerization and contacts regulatory proteins such as MYC and p53; its C-terminal glutamine-rich domain contributes an autonomous transcriptional activation domain that acts additively with the NF-YB domain; it interacts with TBP/TFIID to link CCAAT-bound NF-Y to the basal transcription machinery; its nuclear localization is NF-YB-dependent and cell-cycle regulated, accumulating at S-phase onset; individual isoforms (37 kDa vs. 50 kDa, generated by alternative splicing and dual promoters) have distinct transcriptional activities and regulate specific gene sets including DNA-damage-response genes; outside the NF-Y complex, NF-YC acts as an agonist-dependent corepressor of the mineralocorticoid receptor by altering its N/C conformation, and the NFYC-37 isoform interacts with CBP and SREBP2 to activate mevalonate pathway transcription in cancer cells."},"narrative":{"mechanistic_narrative":"NFYC (NF-YC/CBF-C) is the histone-fold subunit of the heterotrimeric NF-Y/CBF transcription factor that binds CCAAT-box promoter elements [PMID:7878029]. It uses its evolutionarily conserved histone-fold motif to dimerize directly with NF-YB, and the resulting NF-YC/NF-YB heterodimer presents a composite 'tridentate' surface that recruits NF-YA to assemble the full DNA-binding heterotrimer; the histone-fold domains alone, together with the conserved domains of the other subunits, suffice to reconstitute CCAAT binding [PMID:8754798, PMID:9249075, PMID:12401788]. The crystal structure of the NF-YC/NF-YB subcomplex shows histone-fold pairing closely related to H2A/H2B, with an NF-YC-specific αC helix that both mediates trimerization with NF-YA and serves as a docking surface for regulatory proteins such as MYC and p53 [PMID:12401788]. NFYC contributes to transcriptional output through a C-terminal glutamine- and hydrophobic-residue-rich activation domain that acts additively with the NF-YB activation domain [PMID:8662945], and it bridges CCAAT-bound NF-Y to the basal machinery by contacting TBP/TFIID through residues adjacent to its histone-fold motif [PMID:9153318]. Its nuclear accumulation depends on NF-YB and is cell-cycle regulated, rising at the onset of S phase [PMID:14712092], and alternatively spliced/dual-promoter isoforms (37- vs 50-kDa) have distinct transcriptional activities, with the p53-inducible 50-kDa form and the 37-kDa form differentially controlling DNA-damage-response, G1/S and pro-apoptotic gene sets [PMID:19690168]. Beyond the canonical complex, NFYC acts as an agonist-dependent corepressor of the mineralocorticoid receptor by disrupting its N/C intramolecular conformation [PMID:20054001], and in cancer the NFYC-37 isoform interacts with CBP and SREBP2 to activate mevalonate-pathway/cholesterol-biosynthesis transcription [PMID:37561631]; NFYC also drives oncogenic transcriptional programs via a KLF1–LDHA glycolytic axis [PMID:42039141].","teleology":[{"year":1995,"claim":"Established that NFYC is an obligate subunit of the CCAAT-binding factor and defined the order of subunit assembly, answering how the trimer is built.","evidence":"Recombinant reconstitution, EMSA and immunoprecipitation, with yeast homolog substitution","pmids":["7878029"],"confidence":"High","gaps":["Atomic-resolution contacts not resolved","DNA-bound conformation not defined"]},{"year":1996,"claim":"Mapped the histone-fold motif as the interaction module that contacts both NF-YA and NF-YB, explaining at domain resolution how NF-YC nucleates heterotrimer formation.","evidence":"Cross-linking, immunoprecipitation, deletion mutagenesis, in vitro binding and yeast two-hybrid","pmids":["8754798"],"confidence":"High","gaps":["Did not define DNA-contacting residues","Quantitative affinities not determined"]},{"year":1996,"claim":"Identified an autonomous C-terminal Q-rich activation domain in NFYC that adds to NF-YB activity, distinguishing NF-YC's contribution to transactivation from its structural role.","evidence":"In vitro transcription reconstitution with CBF-depleted nuclear extracts and deletion mutagenesis","pmids":["8662945"],"confidence":"High","gaps":["Coactivators engaged by the Q-rich domain not identified","In vivo promoter dependence not tested"]},{"year":1997,"claim":"Connected CCAAT-bound NF-Y to the basal transcription machinery by showing NFYC binds TBP/TFIID through a region adjacent to its histone fold.","evidence":"TFIID immunopurification, sedimentation velocity, in vitro binding and TBP HS2 mutant analysis","pmids":["9153318"],"confidence":"Medium","gaps":["Single lab, not reciprocally validated in cells","Functional consequence on PIC assembly not measured"]},{"year":1997,"claim":"Demonstrated the histone-fold domain alone suffices for CCAAT binding, defining a minimal functional NF-Y core.","evidence":"EMSA with bacterially expressed recombinant domain fragments","pmids":["9249075"],"confidence":"Medium","gaps":["Single method","Activity of mini-complex on chromatin not tested"]},{"year":2002,"claim":"Provided the structural basis for NF-YC/NF-YB histone-fold pairing and identified the NF-YC αC helix as both the trimerization element and a regulatory docking surface for MYC and p53.","evidence":"X-ray crystallography of the NF-YC/NF-YB subcomplex with structural modeling","pmids":["12401788"],"confidence":"High","gaps":["Structure of NF-YA-bound trimer on DNA not solved","Direct MYC/p53 contacts not co-crystallized"]},{"year":2004,"claim":"Showed NFYC nuclear entry is NF-YB-dependent and cell-cycle regulated, linking complex assembly to S-phase timing.","evidence":"Immunofluorescence of endogenous and tagged NF-YC with cell-cycle synchronization in NIH3T3","pmids":["14712092"],"confidence":"Medium","gaps":["Import machinery/NLS not mapped","Single cell system"]},{"year":2009,"claim":"Revealed isoform-specific NFYC function: dual promoters and alternative splicing generate 37- and 50-kDa forms with distinct, p53-linked control of DNA-damage and cell-cycle gene sets.","evidence":"Transient transfection, ChIP, RT-PCR and isoform-specific functional inactivation","pmids":["19690168"],"confidence":"Medium","gaps":["Mechanism distinguishing isoform target selectivity unresolved","Single lab"]},{"year":2010,"claim":"Defined a non-canonical role for NFYC as a selective, agonist-dependent corepressor of the mineralocorticoid receptor acting by altering MR N/C conformation.","evidence":"Two-hybrid, Co-IP, imaging, siRNA on endogenous targets, ChIP and reporter assays","pmids":["20054001"],"confidence":"High","gaps":["Whether this function is NF-Y-complex-independent not fully resolved","Structural basis of MR conformational change not determined"]},{"year":2023,"claim":"Linked NFYC isoforms to cancer metabolism, with NFYC-37 driving CBP/SREBP2-dependent mevalonate-pathway transcription and NFYC-50 antagonizing it via CARM1-mediated CBP methylation.","evidence":"CRISPR-Cas9 screen, Co-IP, ChIP, reporter assays and xenografts in bladder cancer","pmids":["37561631"],"confidence":"Medium","gaps":["Generality beyond bladder cancer untested","Direct CBP methylation site not mapped"]},{"year":2023,"claim":"Established an in vivo developmental role for NF-YC in restricting Cyclin A/B expression to enforce G1 synchronization, independent of Dpp/Hh signaling.","evidence":"RNAi knockdown, immunofluorescence and genetic epistasis in Drosophila eye discs","pmids":["37569581"],"confidence":"Medium","gaps":["Direct target promoters not defined","Single organism model"]},{"year":2026,"claim":"Identified an oncogenic NFYC-KLF1-LDHA transcriptional axis promoting aerobic glycolysis in glioblastoma.","evidence":"ChIP, dual-luciferase reporter, knockdown/overexpression, Seahorse flux and xenograft","pmids":["42039141"],"confidence":"Medium","gaps":["Direct vs NF-Y-complex-mediated KLF1 regulation not separated","Single tumor type"]},{"year":null,"claim":"How NFYC switches between canonical NF-Y CCAAT-driven transcription and its complex-independent roles (MR corepression, isoform-specific metabolic and glycolytic programs) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism distinguishing complex-dependent from complex-independent activities","Isoform-specific partner selectivity unexplained","No structure of the DNA-bound trimer with regulatory cofactors"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,7,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[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]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,7,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9,11]}],"complexes":["NF-Y/CBF heterotrimer"],"partners":["NFYB","NFYA","TBP","MYC","P53","CBP","SREBP2","MR"],"other_free_text":[]}},"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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CBF-A and CBF-C interact directly to form a heterodimer, and CBF-B does not interact with either subunit individually but associates with the CBF-A/CBF-C complex. CBF-C can substitute for a yeast homolog to allow HAP2/HAP3 binding to CCAAT-containing DNA.\",\n      \"method\": \"Recombinant protein reconstitution, EMSA (electrophoretic mobility shift assay), immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with purified recombinant proteins, multiple orthogonal methods (EMSA, Co-IP), replicated with yeast homologs\",\n      \"pmids\": [\"7878029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The evolutionarily conserved histone-fold motif (H2A-like) of CBF-C (NF-YC) is necessary for formation of the CBF-DNA complex. Two separate interaction domains within this motif contact CBF-B, flanking the single CBF-A interaction domain. A 'tridentate' surface generated by the CBF-A/CBF-C heterodimer interacts with a 21-amino-acid subunit interaction domain of CBF-B to form the heterotrimer. CBF-B interacts simultaneously with both CBF-A and CBF-C.\",\n      \"method\": \"Cross-linking, immunoprecipitation, deletion mutagenesis, in vitro binding assays, yeast two-hybrid\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with mutagenesis and multiple orthogonal methods (cross-linking, IP, yeast two-hybrid, in vitro assays) in single rigorous study\",\n      \"pmids\": [\"8754798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CBF-C (NF-YC) contains a transcription activation domain in its C-terminal glutamine- and hydrophobic-residue-rich region; deletion of this domain (residues 114–309) reduces transcriptional activation to ~50% of wild-type. The activation domains of CBF-B and CBF-C act additively in vitro.\",\n      \"method\": \"In vitro transcription reconstitution with purified recombinant CBF subunits and CBF-depleted nuclear extracts, deletion mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro transcription system with mutagenesis, single lab but rigorous reconstitution approach\",\n      \"pmids\": [\"8662945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NF-YC interacts with TBP (TATA-binding protein) in solution, both alone and when complexed with NF-YB. Short stretches within the evolutionarily conserved domain of NF-YC adjacent to the histone-fold motif are necessary for TBP binding. TBP point mutants in the HS2 helix (previously defective in NC2 binding) are also unable to bind NF-YC.\",\n      \"method\": \"Immunopurification of TFIID, sedimentation velocity centrifugation, in vitro binding assays, TBP mutant analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interactions tested with TBP mutants and multiple biochemical fractionation methods, single lab\",\n      \"pmids\": [\"9153318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The histone-fold domain of human NF-YC is sufficient, together with the corresponding conserved domains of NF-YA and NF-YB, to form a functional CCAAT-binding mini-NF-Y complex.\",\n      \"method\": \"EMSA with bacterially expressed recombinant domain fragments\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with purified proteins but single lab, single method described in abstract\",\n      \"pmids\": [\"9249075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the NF-YC/NF-YB subcomplex shows that the core domains of NF-YC and NF-YB interact through histone-fold motifs, closely related to H2A/H2B and NC2α/NC2β families. An αC helix unique to NF-YC is required both for NF-Y trimerization (interaction with NF-YA) and serves as a target surface for regulatory proteins such as MYC and p53.\",\n      \"method\": \"X-ray crystallography, structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with detailed functional interpretation of domain interactions and regulatory surfaces\",\n      \"pmids\": [\"12401788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NF-YC localizes to 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 cell-cycle regulated, increasing at the onset of S phase in serum-restimulated NIH3T3 cells.\",\n      \"method\": \"Immunofluorescence of endogenous and GFP/Flag-tagged NF-YC, cell cycle synchronization\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by imaging of endogenous and tagged protein with functional link to cell cycle; single lab, two approaches\",\n      \"pmids\": [\"14712092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The NF-YC locus generates at least four alternatively spliced isoforms (37- and 50-kDa being mutually exclusive) arising from two promoters (P1 and P2). P2 is induced by DNA damage in a p53-dependent manner and exclusively drives the 50-kDa isoform. The 37-kDa isoform specifically suppresses basal levels of G1/S-blocking and pro-apoptotic genes but not G2/M promoters. Different NF-YA/NF-YC isoform pairings show distinct transcriptional activities on selected promoters.\",\n      \"method\": \"Transient transfection, chromatin immunoprecipitation (ChIP), RT-PCR, isoform-specific functional inactivation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional transfections with isoform-specific knockdown, single lab, multiple orthogonal methods\",\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 ligand-bound MR, inhibits MR transactivation, and is sequentially recruited to the ENaC gene promoter together with MR. NF-YC inhibits the aldosterone-induced N/C intramolecular interaction of MR, thereby altering MR conformation to repress transcription. siRNA depletion of NF-YC potentiates hormonal activation of endogenous MR target genes. The corepressor function is selective for MR and does not affect androgen, progesterone, or glucocorticoid receptors.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, coimmunoprecipitation, fluorescence subcellular imaging, siRNA knockdown, ChIP, transient transfection reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, two-hybrid, siRNA with endogenous target genes, imaging), single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"20054001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The NFYC-37 isoform (but not NFYC-50) promotes bladder cancer cell proliferation and tumor growth. NFYC-37 interacts with CBP and SREBP2 to activate mevalonate pathway transcription and cholesterol biosynthesis. NFYC-50 recruits the arginine methyltransferase CARM1 more than NFYC-37, leading to CBP methylation that prevents the CBP-SREBP2 interaction and inhibits the mevalonate pathway.\",\n      \"method\": \"CRISPR-Cas9 functional screen, co-immunoprecipitation, reporter assays, ChIP, xenograft tumor models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus Co-IP and ChIP mechanistic follow-up, single lab, multiple methods\",\n      \"pmids\": [\"37561631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Drosophila eye imaginal discs, NF-YC knockdown leads to extended expression of Cyclin A and Cyclin B into the non-proliferative region (NPR) and decreased expression of the transcriptional cofactor Eyes absent (Eya), without affecting Dpp or Hh signaling. NF-YC restricts CycA/CycB expression to enable G1 cell-cycle synchronization in the NPR.\",\n      \"method\": \"RNAi knockdown in Drosophila, immunofluorescence, genetic epistasis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean in vivo knockdown with specific phenotypic readouts and pathway placement, single lab, single organism model\",\n      \"pmids\": [\"37569581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In glioblastoma cells, NFYC binds the KLF1 promoter and positively regulates KLF1 expression; KLF1 in turn directly activates LDHA transcription. This NFYC-KLF1-LDHA axis promotes aerobic glycolysis and tumor growth. KLF1 knockdown partially reverses NFYC oncogenic effects and vice versa.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, siRNA/shRNA knockdown, overexpression, Seahorse metabolic flux analysis, xenograft model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter directly demonstrate promoter binding and transactivation; genetic epistasis via double knockdown; single lab\",\n      \"pmids\": [\"42039141\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NF-YC (CBF-C) is the histone-fold (H2A-like) subunit of the heterotrimeric NF-Y/CBF transcription factor: it dimerizes with NF-YB via their histone-fold motifs and presents a hybrid surface that recruits NF-YB to form the full heterotrimer required for CCAAT-box binding; its αC helix mediates trimerization and contacts regulatory proteins such as MYC and p53; its C-terminal glutamine-rich domain contributes an autonomous transcriptional activation domain that acts additively with the NF-YB domain; it interacts with TBP/TFIID to link CCAAT-bound NF-Y to the basal transcription machinery; its nuclear localization is NF-YB-dependent and cell-cycle regulated, accumulating at S-phase onset; individual isoforms (37 kDa vs. 50 kDa, generated by alternative splicing and dual promoters) have distinct transcriptional activities and regulate specific gene sets including DNA-damage-response genes; outside the NF-Y complex, NF-YC acts as an agonist-dependent corepressor of the mineralocorticoid receptor by altering its N/C conformation, and the NFYC-37 isoform interacts with CBP and SREBP2 to activate mevalonate pathway transcription in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NFYC (NF-YC/CBF-C) is the histone-fold subunit of the heterotrimeric NF-Y/CBF transcription factor that binds CCAAT-box promoter elements [#0]. It uses its evolutionarily conserved histone-fold motif to dimerize directly with NF-YB, and the resulting NF-YC/NF-YB heterodimer presents a composite 'tridentate' surface that recruits NF-YA to assemble the full DNA-binding heterotrimer; the histone-fold domains alone, together with the conserved domains of the other subunits, suffice to reconstitute CCAAT binding [#1, #4, #5]. The crystal structure of the NF-YC/NF-YB subcomplex shows histone-fold pairing closely related to H2A/H2B, with an NF-YC-specific \\u03b1C helix that both mediates trimerization with NF-YA and serves as a docking surface for regulatory proteins such as MYC and p53 [#5]. NFYC contributes to transcriptional output through a C-terminal glutamine- and hydrophobic-residue-rich activation domain that acts additively with the NF-YB activation domain [#2], and it bridges CCAAT-bound NF-Y to the basal machinery by contacting TBP/TFIID through residues adjacent to its histone-fold motif [#3]. Its nuclear accumulation depends on NF-YB and is cell-cycle regulated, rising at the onset of S phase [#6], and alternatively spliced/dual-promoter isoforms (37- vs 50-kDa) have distinct transcriptional activities, with the p53-inducible 50-kDa form and the 37-kDa form differentially controlling DNA-damage-response, G1/S and pro-apoptotic gene sets [#7]. Beyond the canonical complex, NFYC acts as an agonist-dependent corepressor of the mineralocorticoid receptor by disrupting its N/C intramolecular conformation [#8], and in cancer the NFYC-37 isoform interacts with CBP and SREBP2 to activate mevalonate-pathway/cholesterol-biosynthesis transcription [#9]; NFYC also drives oncogenic transcriptional programs via a KLF1\\u2013LDHA glycolytic axis [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that NFYC is an obligate subunit of the CCAAT-binding factor and defined the order of subunit assembly, answering how the trimer is built.\",\n      \"evidence\": \"Recombinant reconstitution, EMSA and immunoprecipitation, with yeast homolog substitution\",\n      \"pmids\": [\"7878029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution contacts not resolved\", \"DNA-bound conformation not defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapped the histone-fold motif as the interaction module that contacts both NF-YA and NF-YB, explaining at domain resolution how NF-YC nucleates heterotrimer formation.\",\n      \"evidence\": \"Cross-linking, immunoprecipitation, deletion mutagenesis, in vitro binding and yeast two-hybrid\",\n      \"pmids\": [\"8754798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define DNA-contacting residues\", \"Quantitative affinities not determined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified an autonomous C-terminal Q-rich activation domain in NFYC that adds to NF-YB activity, distinguishing NF-YC's contribution to transactivation from its structural role.\",\n      \"evidence\": \"In vitro transcription reconstitution with CBF-depleted nuclear extracts and deletion mutagenesis\",\n      \"pmids\": [\"8662945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivators engaged by the Q-rich domain not identified\", \"In vivo promoter dependence not tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Connected CCAAT-bound NF-Y to the basal transcription machinery by showing NFYC binds TBP/TFIID through a region adjacent to its histone fold.\",\n      \"evidence\": \"TFIID immunopurification, sedimentation velocity, in vitro binding and TBP HS2 mutant analysis\",\n      \"pmids\": [\"9153318\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not reciprocally validated in cells\", \"Functional consequence on PIC assembly not measured\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated the histone-fold domain alone suffices for CCAAT binding, defining a minimal functional NF-Y core.\",\n      \"evidence\": \"EMSA with bacterially expressed recombinant domain fragments\",\n      \"pmids\": [\"9249075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method\", \"Activity of mini-complex on chromatin not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Provided the structural basis for NF-YC/NF-YB histone-fold pairing and identified the NF-YC \\u03b1C helix as both the trimerization element and a regulatory docking surface for MYC and p53.\",\n      \"evidence\": \"X-ray crystallography of the NF-YC/NF-YB subcomplex with structural modeling\",\n      \"pmids\": [\"12401788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of NF-YA-bound trimer on DNA not solved\", \"Direct MYC/p53 contacts not co-crystallized\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed NFYC nuclear entry is NF-YB-dependent and cell-cycle regulated, linking complex assembly to S-phase timing.\",\n      \"evidence\": \"Immunofluorescence of endogenous and tagged NF-YC with cell-cycle synchronization in NIH3T3\",\n      \"pmids\": [\"14712092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Import machinery/NLS not mapped\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed isoform-specific NFYC function: dual promoters and alternative splicing generate 37- and 50-kDa forms with distinct, p53-linked control of DNA-damage and cell-cycle gene sets.\",\n      \"evidence\": \"Transient transfection, ChIP, RT-PCR and isoform-specific functional inactivation\",\n      \"pmids\": [\"19690168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism distinguishing isoform target selectivity unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined a non-canonical role for NFYC as a selective, agonist-dependent corepressor of the mineralocorticoid receptor acting by altering MR N/C conformation.\",\n      \"evidence\": \"Two-hybrid, Co-IP, imaging, siRNA on endogenous targets, ChIP and reporter assays\",\n      \"pmids\": [\"20054001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this function is NF-Y-complex-independent not fully resolved\", \"Structural basis of MR conformational change not determined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked NFYC isoforms to cancer metabolism, with NFYC-37 driving CBP/SREBP2-dependent mevalonate-pathway transcription and NFYC-50 antagonizing it via CARM1-mediated CBP methylation.\",\n      \"evidence\": \"CRISPR-Cas9 screen, Co-IP, ChIP, reporter assays and xenografts in bladder cancer\",\n      \"pmids\": [\"37561631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality beyond bladder cancer untested\", \"Direct CBP methylation site not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established an in vivo developmental role for NF-YC in restricting Cyclin A/B expression to enforce G1 synchronization, independent of Dpp/Hh signaling.\",\n      \"evidence\": \"RNAi knockdown, immunofluorescence and genetic epistasis in Drosophila eye discs\",\n      \"pmids\": [\"37569581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct target promoters not defined\", \"Single organism model\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified an oncogenic NFYC-KLF1-LDHA transcriptional axis promoting aerobic glycolysis in glioblastoma.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, knockdown/overexpression, Seahorse flux and xenograft\",\n      \"pmids\": [\"42039141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs NF-Y-complex-mediated KLF1 regulation not separated\", \"Single tumor type\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NFYC switches between canonical NF-Y CCAAT-driven transcription and its complex-independent roles (MR corepression, isoform-specific metabolic and glycolytic programs) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism distinguishing complex-dependent from complex-independent activities\", \"Isoform-specific partner selectivity unexplained\", \"No structure of the DNA-bound trimer with regulatory cofactors\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 7, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [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]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 7, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"complexes\": [\"NF-Y/CBF heterotrimer\"],\n    \"partners\": [\"NFYB\", \"NFYA\", \"TBP\", \"MYC\", \"p53\", \"CBP\", \"SREBP2\", \"MR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}