Affinage

NFYC

Nuclear transcription factor Y subunit gamma · UniProt Q13952

Length
458 aa
Mass
50.3 kDa
Annotated
2026-04-29
42 papers in source corpus 13 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1995 High

    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

    PMID:7878029

    Open questions at the time
    • Stoichiometry of the trimer on DNA not resolved
    • No structural data at this stage
  2. 1996 High

    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

    PMID:8662945 PMID:8754798

    Open questions at the time
    • Activation domain targets on general transcription machinery unknown
    • No crystal structure yet
  3. 1997 High

    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

    PMID:9153318

    Open questions at the time
    • Whether NF-Y and NC2 compete for TBP in vivo not tested
    • Structural basis of TBP–NF-YC contact unresolved
  4. 2002 High

    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

    PMID:12401788

    Open questions at the time
    • Full trimer–DNA co-crystal not yet available
    • Regulatory interactions with MYC/p53 mapped structurally but not validated functionally in this study
  5. 2004 High

    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

    PMID:14712092

    Open questions at the time
    • Nuclear import signal and importin pathway not identified
    • Whether cytoplasmic NF-YC has independent functions unknown
  6. 2009 High

    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

    PMID:19690168

    Open questions at the time
    • Isoform-specific interactomes not comprehensively mapped
    • In vivo isoform-specific knockout models lacking
  7. 2010 High

    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

    PMID:20054001

    Open questions at the time
    • Whether corepression requires the full NF-Y trimer or involves NF-YC alone not resolved
    • Structural basis of MR–NF-YC interaction unknown
  8. 2018 Medium

    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

    PMID:29688769

    Open questions at the time
    • Whether repression is direct (NF-YC on IL6/LIF promoters) not shown by ChIP
    • Single cell-type study
  9. 2023 High

    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

    PMID:37561631

    Open questions at the time
    • Whether the isoform switch operates in non-cancer tissues unknown
    • Upstream signals controlling isoform ratio not identified
  10. 2026 Medium

    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

    PMID:42039141

    Open questions at the time
    • Which NF-YC isoform is responsible not determined
    • Single tumor type studied

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2
Partners
CARM1CBPNFYANFYBNR3C2SREBF2TBP
Complex memberships
NF-Y (CBF) heterotrimer

Evidence

Reading pass · 13 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-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. Recombinant protein reconstitution, EMSA, immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 7878029
1996 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. Cross-linking, immunoprecipitation, in vitro binding assays, yeast two-hybrid, mutational analysis Molecular and cellular biology High 8754798
1996 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. In vitro transcription reconstitution with purified recombinant CBF subunits and deletion mutants The Journal of biological chemistry High 8662945
1997 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. Immunopurification of TFIID, sedimentation velocity centrifugation, direct binding assays, TBP point mutants Nucleic acids research High 9153318
1997 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. Bacterial expression, EMSA Gene Medium 9249075
2002 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. X-ray crystallography, structural modeling The Journal of biological chemistry High 12401788
2004 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. Immunofluorescence of endogenous and GFP/Flag-tagged NF-Y subunits, cell cycle synchronization (serum restimulation) Cell cycle (Georgetown, Tex.) High 14712092
2009 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. Transient transfections, chromatin immunoprecipitation (ChIP), RT-PCR, specific functional inactivation of the 37-kDa isoform The Journal of biological chemistry High 19690168
2010 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. Yeast two-hybrid, mammalian two-hybrid, co-immunoprecipitation, fluorescence imaging, ChIP, siRNA knockdown, transient transfection The Journal of biological chemistry High 20054001
2018 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. siRNA knockdown, qRT-PCR, actinomycin D transcriptional block experiments American journal of physiology. Endocrinology and metabolism Medium 29688769
2023 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. CRISPR-Cas9 functional screen, co-immunoprecipitation, ChIP, loss- and gain-of-function experiments, xenograft tumor models Cell reports High 37561631
2026 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. Dual-luciferase reporter assay, ChIP, siRNA/shRNA knockdown, Seahorse metabolic assay, xenograft model Frontiers in cell and developmental biology Medium 42039141
2006 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. CTL recognition assay, sequencing of tumor-derived NFYC mutation, HLA restriction mapping International journal of cancer Medium 16287085

Source papers

Stage 0 corpus · 42 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 233 12401788
2016 The NF-YC-RGL2 module integrates GA and ABA signalling to regulate seed germination in Arabidopsis. Nature communications 189 27624486
2019 Arabidopsis ABF3 and ABF4 Transcription Factors Act with the NF-YC Complex to Regulate SOC1 Expression and Mediate Drought-Accelerated Flowering. Molecular plant 163 30639313
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 124 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 92 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 67 25965574
2023 Gibberellin signaling modulates flowering via the DELLA-BRAHMA-NF-YC module in Arabidopsis. The Plant cell 53 37294919
2016 NUCLEAR FACTOR Y, Subunit C (NF-YC) Transcription Factors Are Positive Regulators of Photomorphogenesis in Arabidopsis thaliana. PLoS genetics 53 27685091
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 51 16287085
1997 Cloning and expression of human NF-YC. Gene 41 9249075
2015 The overexpression of an Amaranthus hypochondriacus NF-YC gene modifies growth and confers water deficit stress resistance in Arabidopsis. Plant science : an international journal of experimental plant biology 39 26475185
2010 TaNF-YC11, one of the light-upregulated NF-YC members in Triticum aestivum, is co-regulated with photosynthesis-related genes. Functional & integrative genomics 38 20111976
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
2016 NF-YC in glioma cell proliferation and tumor growth and its role as an independent predictor of patient survival. Neuroscience letters 22 27495011
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 21 29688769
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
2024 Molecular condensation of the CO/NF-YB/NF-YC/FT complex gates floral transition in Arabidopsis. The EMBO journal 13 39567828
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
1996 Chromosomal assignment and tissue expression of CBF-C/NFY-C, the third subunit of the mammalian CCAAT-binding factor. Genomics 11 8921405
2023 NFYC-37 promotes tumor growth by activating the mevalonate pathway in bladder cancer. Cell reports 10 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 10 24014123
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
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
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 4 37569581
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