Affinage

NFYC

Nuclear transcription factor Y subunit gamma · UniProt Q13952

Length
458 aa
Mass
50.3 kDa
Annotated
2026-06-10
35 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 High

    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

    PMID:7878029

    Open questions at the time
    • Atomic-resolution contacts not resolved
    • DNA-bound conformation not defined
  2. 1996 High

    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

    PMID:8754798

    Open questions at the time
    • Did not define DNA-contacting residues
    • Quantitative affinities not determined
  3. 1996 High

    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

    PMID:8662945

    Open questions at the time
    • Coactivators engaged by the Q-rich domain not identified
    • In vivo promoter dependence not tested
  4. 1997 Medium

    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

    PMID:9153318

    Open questions at the time
    • Single lab, not reciprocally validated in cells
    • Functional consequence on PIC assembly not measured
  5. 1997 Medium

    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

    PMID:9249075

    Open questions at the time
    • Single method
    • Activity of mini-complex on chromatin not tested
  6. 2002 High

    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

    PMID:12401788

    Open questions at the time
    • Structure of NF-YA-bound trimer on DNA not solved
    • Direct MYC/p53 contacts not co-crystallized
  7. 2004 Medium

    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

    PMID:14712092

    Open questions at the time
    • Import machinery/NLS not mapped
    • Single cell system
  8. 2009 Medium

    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

    PMID:19690168

    Open questions at the time
    • Mechanism distinguishing isoform target selectivity unresolved
    • Single lab
  9. 2010 High

    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

    PMID:20054001

    Open questions at the time
    • Whether this function is NF-Y-complex-independent not fully resolved
    • Structural basis of MR conformational change not determined
  10. 2023 Medium

    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

    PMID:37561631

    Open questions at the time
    • Generality beyond bladder cancer untested
    • Direct CBP methylation site not mapped
  11. 2023 Medium

    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

    PMID:37569581

    Open questions at the time
    • Direct target promoters not defined
    • Single organism model
  12. 2026 Medium

    Identified an oncogenic NFYC-KLF1-LDHA transcriptional axis promoting aerobic glycolysis in glioblastoma.

    Evidence ChIP, dual-luciferase reporter, knockdown/overexpression, Seahorse flux and xenograft

    PMID:42039141

    Open questions at the time
    • Direct vs NF-Y-complex-mediated KLF1 regulation not separated
    • Single tumor type

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 3 GO:0140110 transcription regulator activity 3 GO:0042393 histone binding 1 GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2
Partners
CBPMRMYCNFYANFYBP53SREBP2TBP
Complex memberships
NF-Y/CBF heterotrimer

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 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. Recombinant protein reconstitution, EMSA (electrophoretic mobility shift assay), immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 7878029
1996 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. Cross-linking, immunoprecipitation, deletion mutagenesis, in vitro binding assays, yeast two-hybrid Molecular and cellular biology High 8754798
1996 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. In vitro transcription reconstitution with purified recombinant CBF subunits and CBF-depleted nuclear extracts, deletion mutagenesis The Journal of biological chemistry High 8662945
1997 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. Immunopurification of TFIID, sedimentation velocity centrifugation, in vitro binding assays, TBP mutant analysis Nucleic acids research Medium 9153318
1997 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. EMSA with bacterially expressed recombinant domain fragments Gene Medium 9249075
2002 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. X-ray crystallography, structural modeling The Journal of biological chemistry High 12401788
2004 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. Immunofluorescence of endogenous and GFP/Flag-tagged NF-YC, cell cycle synchronization Cell cycle (Georgetown, Tex.) Medium 14712092
2009 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. Transient transfection, chromatin immunoprecipitation (ChIP), RT-PCR, isoform-specific functional inactivation The Journal of biological chemistry Medium 19690168
2010 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. Yeast two-hybrid, mammalian two-hybrid, coimmunoprecipitation, fluorescence subcellular imaging, siRNA knockdown, ChIP, transient transfection reporter assays The Journal of biological chemistry High 20054001
2023 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. CRISPR-Cas9 functional screen, co-immunoprecipitation, reporter assays, ChIP, xenograft tumor models Cell reports Medium 37561631
2023 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. RNAi knockdown in Drosophila, immunofluorescence, genetic epistasis International journal of molecular sciences Medium 37569581
2026 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. ChIP assay, dual-luciferase reporter assay, siRNA/shRNA knockdown, overexpression, Seahorse metabolic flux analysis, xenograft model Frontiers in cell and developmental biology Medium 42039141

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Recombinant rat CBF-C, the third subunit of CBF/NFY, allows formation of a protein-DNA complex with CBF-A and CBF-B and with yeast HAP2 and HAP3. Proceedings of the National Academy of Sciences of the United States of America 253 7878029
2002 The NF-YB/NF-YC structure gives insight into DNA binding and transcription regulation by CCAAT factor NF-Y. The Journal of biological chemistry 235 12401788
1996 Determination of functional domains in the C subunit of the CCAAT-binding factor (CBF) necessary for formation of a CBF-DNA complex: CBF-B interacts simultaneously with both the CBF-A and CBF-C subunits to form a heterotrimeric CBF molecule. Molecular and cellular biology 130 8754798
2017 CONSTANS Imparts DNA Sequence Specificity to the Histone Fold NF-YB/NF-YC Dimer. The Plant cell 129 28526714
2014 Overexpression of a NF-YC transcription factor from bermudagrass confers tolerance to drought and salinity in transgenic rice. Plant biotechnology journal 103 25283804
1997 CCAAT binding NF-Y-TBP interactions: NF-YB and NF-YC require short domains adjacent to their histone fold motifs for association with TBP basic residues. Nucleic acids research 103 9153318
2015 QQS orphan gene regulates carbon and nitrogen partitioning across species via NF-YC interactions. Proceedings of the National Academy of Sciences of the United States of America 94 26554020
2004 Cell cycle regulation of NF-YC nuclear localization. Cell cycle (Georgetown, Tex.) 91 14712092
1996 The transcriptional activity of the CCAAT-binding factor CBF is mediated by two distinct activation domains, one in the CBF-B subunit and the other in the CBF-C subunit. The Journal of biological chemistry 70 8662945
2015 Cross-Species Genomics Identifies TAF12, NFYC, and RAD54L as Choroid Plexus Carcinoma Oncogenes. Cancer cell 68 25965574
2006 A point mutation in the NFYC gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human squamous cell lung carcinoma. International journal of cancer 52 16287085
1997 Cloning and expression of human NF-YC. Gene 41 9249075
2009 NF-YC complexity is generated by dual promoters and alternative splicing. The Journal of biological chemistry 31 19690168
2018 Overexpression of a NF-YC Gene Results in Enhanced Drought and Salt Tolerance in Transgenic Seashore Paspalum. Frontiers in plant science 30 30298080
2010 NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor. The Journal of biological chemistry 29 20054001
2018 IL6 and LIF mRNA expression in skeletal muscle is regulated by AMPK and the transcription factors NFYC, ZBTB14, and SP1. American journal of physiology. Endocrinology and metabolism 23 29688769
2016 NF-YC in glioma cell proliferation and tumor growth and its role as an independent predictor of patient survival. Neuroscience letters 23 27495011
2011 Altered expression of NFY-C and RORA in colorectal adenocarcinomas. Acta histochemica 21 22104449
2016 The garlic NF-YC gene, AsNF-YC8, positively regulates non-ionic hyperosmotic stress tolerance in tobacco. Protoplasma 15 27650870
2021 LncRNA NFYC-AS1 promotes the development of lung adenocarcinomas through autophagy, apoptosis, and MET/c-Myc oncogenic proteins. Annals of translational medicine 14 34926665
2019 Nuclear Factor Y (NF-Y) Modulates Encystation in Entamoeba via Stage-Specific Expression of the NF-YB and NF-YC Subunits. mBio 14 31213550
2022 Five Rice Seed-Specific NF-YC Genes Redundantly Regulate Grain Quality and Seed Germination via Interfering Gibberellin Pathway. International journal of molecular sciences 13 35955515
2023 NFYC-37 promotes tumor growth by activating the mevalonate pathway in bladder cancer. Cell reports 11 37561631
2013 Upregulated expression of NF-YC contributes to neuronal apoptosis via proapoptotic protein bim in rats' brain hippocampus following middle cerebral artery occlusion (MCAO). Journal of molecular neuroscience : MN 11 24014123
1996 Chromosomal assignment and tissue expression of CBF-C/NFY-C, the third subunit of the mammalian CCAAT-binding factor. Genomics 11 8921405
2024 The pancancer overexpressed NFYC Antisense 1 controls cell cycle mitotic progression through in cis and in trans modes of action. Cell death & disease 5 38467619
2023 SNHG12/NFYC-AS1 Acted as the Sponge for hsa-miR-199a-5p to Promote the Expression of S100A8/S100A7/XDH and was Involved in the Progression of Diabetic Foot Ulcers. Molecular biotechnology 5 36920714
2023 Cell Cycle Regulation by NF-YC in Drosophila Eye Imaginal Disc: Implications for Synchronization in the Non-Proliferative Region. International journal of molecular sciences 5 37569581
2022 Identification of an autophagy-related 12-lncRNA signature and evaluation of NFYC-AS1 as a pro-cancer factor in lung adenocarcinoma. Frontiers in genetics 5 36105077
2021 The transcription factor NFYC positively regulates expression of MHCIa in the red-spotted grouper (Epinephelus akaara). Developmental and comparative immunology 2 34600022
2026 Exploring the NF-YC gene family in Astragalus membranaceus: characterization, evolutionary relationships, and expression pattern analysis under MeJA treatment. BMC genomic data 0 41792606
2026 NFYC upregulates KLF1 expression and activate LDHA to drive glycolysis and tumor growth in glioblastoma cells. Frontiers in cell and developmental biology 0 42039141
2025 Integrating datasets to dissect NFYC-AS1 RNA- and transcription-dependent functions: comparative transcriptome profiling of knockdown strategies. Data in brief 0 40322504
2025 Genome-Wide Identification and Expression of NF-YC Transcription Factors in Blueberry Under Abiotic Stress Conditions. International journal of molecular sciences 0 40943428
2022 Corrigendum: Identification of an autophagy-related 12-lncRNA signature and evaluation of NFYC-AS1 as a pro-cancer factor in lung adenocarcinoma. Frontiers in genetics 0 36386796

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