{"gene":"NFYA","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"CBF-C (NF-YC) is required together with CBF-A (NF-YB) and CBF-B (NF-YA) to form a CBF/NF-Y–DNA complex. CBF-A and CBF-C interact with each other to form a heterodimer, and CBF-B does not interact with CBF-A or CBF-C individually but associates with the CBF-A–CBF-C complex. All three subunits are present in the protein–DNA complex.","method":"Recombinant protein reconstitution, EMSA/DNA-binding assay, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant subunits, replicated across species (yeast HAP2/HAP3 complementation), multiple orthogonal methods","pmids":["7878029"],"is_preprint":false},{"year":1994,"finding":"The C-terminal HAP2-homology domain of NF-YA (CBF-B) is necessary and sufficient for interaction with NF-YB and for DNA binding. This domain contains two functionally separable subdomains: a 21-amino-acid stretch mediating subunit association and a distinct short segment mediating DNA interaction. DNA-binding mutants of NF-YA act as dominant repressors of NF-Y–DNA complex formation and NF-Y-dependent transcription.","method":"Protein affinity columns with amino acid substitution mutants, dominant-negative functional assays, transcription reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with in vitro binding and functional transcription assays, multiple orthogonal methods in one study","pmids":["8051128"],"is_preprint":false},{"year":1996,"finding":"CBF-B (NF-YA) interacts simultaneously with both subunits of the CBF-A–CBF-C heterodimer (NF-YB and NF-YC) to form a heterotrimeric molecule. The evolutionarily conserved histone-fold-like segment of CBF-C (NF-YC), homologous to H2A, is required for CBF-DNA complex formation and mediates interaction with CBF-A (NF-YB). Two separate domains in CBF-C interact with CBF-B (NF-YA), flanking the CBF-A interaction domain, suggesting a tridentate interaction surface.","method":"Cross-linking, immunoprecipitation, mutational analysis, yeast two-hybrid, in vitro DNA-binding assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (cross-linking, IP, two-hybrid, in vitro assays) with systematic mutagenesis","pmids":["8754798"],"is_preprint":false},{"year":1996,"finding":"Transcriptional activation by the CBF/NF-Y heterotrimer is mediated by two distinct activation domains: one in CBF-B (NF-YB) and one in CBF-C (NF-YC); these act additively in vitro. CBF-A (NF-YA) itself does not contribute an activation domain in this assay. Both activation domains are glutamine- and hydrophobic-residue-rich, similar to Sp1.","method":"In vitro transcription reconstitution with purified recombinant CBF subunit deletion mutants in CBF-depleted nuclear extracts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro transcription system with defined deletion mutants, multiple promoter templates tested","pmids":["8662945"],"is_preprint":false},{"year":2001,"finding":"NF-YA protein is induced after DNA damage (MMS, UV, ionizing radiation) and directly binds to the CCAAT box in the GADD45 promoter. NF-YA binding at this CCAAT motif, together with Oct-1, is required for p53-independent induction of GADD45 transcription following DNA damage.","method":"EMSA, site-directed mutagenesis of promoter elements, Western blot of induced NF-YA protein, reporter gene assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus mutagenesis plus reporter assays, single lab, multiple orthogonal methods","pmids":["11420680"],"is_preprint":false},{"year":2003,"finding":"NF-YA protein is induced by the DNA-alkylating agent MMS and directly binds to inverted CCAAT motifs in the hOGG1 promoter to activate OGG1 transcription; site-directed mutations of these CCAAT boxes abrogate promoter induction.","method":"Gel shift and supershift assay, site-directed mutagenesis, Western blot, luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA/supershift plus mutagenesis plus reporter assay, single lab","pmids":["14688259"],"is_preprint":false},{"year":2005,"finding":"NF-Ya overexpression in primitive hematopoietic cells activates transcription of multiple HOX4 paralogs, Notch-1, LEF-1, and telomerase RNA, and HSCs overexpressing NF-Ya show increased in vivo repopulating ability after bone marrow transplantation, establishing NF-Ya as a regulator of HSC self-renewal.","method":"Retroviral overexpression, in vitro transcription assays, single/sequential bone marrow transplantation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cellular and in vivo phenotype with gene expression targets identified, single lab","pmids":["16081537"],"is_preprint":false},{"year":2008,"finding":"NF-YA protein levels are regulated post-translationally by ubiquitylation and acetylation. Four C-terminal lysines are ubiquitylation targets (mutation stabilizes the protein). Two of these lysines are acetylated in vitro by p300, indicating competition between ubiquitylation and acetylation. A degradation-resistant NF-YA leads to sustained expression of mitotic cyclin complexes and increased cell proliferation.","method":"Site-directed mutagenesis of lysines, cycloheximide chase/stability assay, in vitro acetylation by p300, cell cycle and proliferation assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro acetylation assay with mutagenesis, functional consequence (degradation resistance → proliferation), multiple methods, single lab","pmids":["18815279"],"is_preprint":false},{"year":2009,"finding":"Tuberin deficiency causes decreased NF-YA protein expression and redistribution of NF-YA from the nucleus to the cytoplasm, leading to loss of OGG1 transcription. Restoration of tuberin (via adenoviral Ad-TSC2) rescues nuclear NF-YA localization and OGG1 expression.","method":"siRNA knockdown, adenoviral rescue, Western blot, immunostaining/fractionation","journal":"Journal of molecular signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization change with functional consequence (OGG1 loss), rescue experiment, single lab","pmids":["20040097"],"is_preprint":false},{"year":2010,"finding":"Transcriptional activation of RGS4 in confluent PC6 cells is mediated by NF-YA binding to an inverted CCAAT box element (ICE) in the RGS4 promoter. NF-YA nuclear levels increase at confluence, acetylation of NF-YA increases, and dominant-negative NF-YA represses RGS4 promoter activity. NF-YA cooperates with C/EBPβ while Bcl6 (also acetylated) acts as a repressor at a nearby site.","method":"Chromatin immunoprecipitation, dominant-negative overexpression, luciferase reporter assay, Western blot of nuclear fractions","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus dominant negative, single lab, multiple methods","pmids":["20630860"],"is_preprint":false},{"year":2010,"finding":"TAT-fused NF-Ya protein enters the nucleus of human CD34+ hematopoietic cells and activates the NF-Ya target gene HOXB4, increasing proliferation 4-fold and enhancing engraftment in NOD-SCID IL2Rγ-null mice.","method":"Protein transduction (TAT fusion), real-time PCR, luciferase reporter, xenograft transplantation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional nuclear entry confirmed by target gene activation plus in vivo engraftment, single lab","pmids":["20616221"],"is_preprint":false},{"year":2012,"finding":"The short isoform of NF-YA (NF-YAs) is highly expressed in mouse ESCs and declines upon differentiation. A dominant-negative NF-YA mutant reduces expression of stem cell genes. NF-Y binding is required for NANOG association to its genomic loci (30–50% of NANOG peaks contain NF-Y sites). Protein transduction of TAT-NF-YAs compensates for LIF withdrawal in ESC cultures.","method":"Dominant-negative overexpression, protein transduction, bioinformatics analysis of ChIP-seq data, cell culture differentiation assays","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative with gene expression readout, ChIP-seq correlation, protein transduction rescue, single lab","pmids":["22969033"],"is_preprint":false},{"year":2013,"finding":"NF-YA binds to two CCAAT boxes in the proximal EZH2 promoter in epithelial ovarian cancer (EOC) cells (enhanced compared to normal cells), and NF-YA knockdown downregulates EZH2 expression, decreases H3K27Me3 levels, and suppresses EOC cell growth in vitro and in a xenograft model.","method":"Chromatin immunoprecipitation (ChIP), siRNA knockdown, Western blot, luciferase reporter assay, xenograft mouse model","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus KD plus in vivo xenograft, single lab, multiple orthogonal methods","pmids":["23360797"],"is_preprint":false},{"year":2014,"finding":"p21 directly binds NF-YA and inhibits CDK2–NF-YA interaction at the CCAAT box region of the PLK1 promoter. Upon adriamycin-induced DNA damage, p21 recruitment to this region displaces CDK2 and suppresses PLK1 transcription. NF-YA knockdown abolishes p21-mediated PLK1 repression and impairs p53-mediated protection from mitotic death.","method":"Co-immunoprecipitation, in vitro direct binding assay, chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro direct binding plus reciprocal Co-IP plus ChIP plus reporter assay, multiple orthogonal methods, single lab","pmids":["24407240"],"is_preprint":false},{"year":2014,"finding":"Paeoniflorin (PF) significantly increases NF-YA expression, which upregulates molecules of the ubiquitin-proteasome system (molecular chaperones, CHIP) and autophagy (TFEB), promoting clearance of mutant androgen receptor in SBMA models.","method":"Western blot, behavioral/pathological assays in SBMA mouse model, cell-based assays","journal":"Human molecular genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — NF-YA role inferred from expression increase after PF treatment; mechanism linking NF-YA to proteasome genes not directly demonstrated in this abstract","pmids":["24549037"],"is_preprint":false},{"year":2015,"finding":"ZHX2 interacts with NF-YA (co-IP) and reduces NF-Y binding to the MDR1 promoter (ChIP), thereby repressing NF-Y-mediated MDR1 transcription. Knockdown of NF-YA or mutation of the NF-Y binding site in the MDR1 promoter eliminates ZHX2-mediated repression.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown, mutagenesis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus reporter mutagenesis, single lab, multiple orthogonal methods","pmids":["25473899"],"is_preprint":false},{"year":2016,"finding":"NF-YA overexpression upregulates EZH2 expression in melanoma cells, leading to enhanced STAT3 methylation/activation and increased VEGF secretion and angiogenesis. EZH2 knockdown attenuates NF-YA-induced angiogenesis.","method":"Overexpression/knockdown, Western blot, VEGF ELISA, in vitro angiogenesis assays","journal":"Oncology reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional link established by KD/OE but no direct ChIP or binding assay for NF-YA→EZH2 in this context; single lab, single methods per step","pmids":["27109360"],"is_preprint":false},{"year":2016,"finding":"The two NF-YA splice isoforms have distinct roles in myoblast fate: NF-YAs enhances proliferation while NF-YAl boosts differentiation. NF-YAl directly activates Mef2D, Six genes, and p57kip2 (Cdkn1c) via NF-Y binding to CCAAT promoters; it also reduces expression of lncRNA Kcnq1ot1, a negative regulator of Cdkn1c transcription.","method":"Overexpression of isoforms, expression profiling, bioinformatic analysis of CCAAT in regulated promoters, NF-Y binding assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific overexpression with defined transcriptional targets and CCAAT binding, single lab","pmids":["26921500"],"is_preprint":false},{"year":2018,"finding":"NF-YA contains two cell-penetrating peptide (CPP) sequences within its DNA-binding alpha-helices (A1 and A2), overlapping with nuclear localization signals, that allow nanomolar-concentration entry into cells without carrier peptides. Internalized NF-YA trimerizes with NF-YB/NF-YC and binds to CCAAT target DNA. Protein transfection into C2C12 myoblasts inhibits differentiation to myotubes.","method":"Protein transduction experiments, mutagenesis of CPP regions, EMSA for DNA binding after transduction, C2C12 differentiation assay","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis identifying CPPs, functional CCAAT binding post-transduction, differentiation phenotype; single lab","pmids":["30296497"],"is_preprint":false},{"year":2018,"finding":"Ser320 of NF-YA (phosphorylatable by CDK2) makes structural contacts with the DNA phosphate backbone. Ser320 phosphorylation is the major NF-YA phospho-isoform in HeLa cells, increases upon mitotic arrest, and Ser320Ala/Glu mutants reduce DNA binding (EMSA) and transactivation of CCAAT-dependent MDR1 and RHOB promoters. Ser326 phosphorylation does not affect DNA binding.","method":"EMSA with Ala/Glu phosphomimetic mutants, transactivation assays, high-throughput proteomics phospho-site confirmation, phylogenetic analysis","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis plus in vitro EMSA plus functional transcription assays plus structural context, single lab, multiple orthogonal methods","pmids":["30589568"],"is_preprint":false},{"year":2019,"finding":"NF-YA directly binds the CCAAT box in the SOX2 promoter (confirmed by EMSA and ChIP) and transcriptionally activates SOX2 expression in cervical cancer stem cells; overexpression of NF-YA in SiHa and C33A cells increases SOX2 transcription and protein.","method":"Dual-luciferase reporter assay, mutagenesis, EMSA, chromatin immunoprecipitation, overexpression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus ChIP plus reporter with mutagenesis, single lab","pmids":["31365524"],"is_preprint":false},{"year":2019,"finding":"NF-YA overexpression confers resistance to glutamine deprivation by increasing GLUL mRNA/protein expression (key glutamine biosynthetic enzyme) and preventing activation of pro-apoptotic CHOP/DDIT3. GLUL inhibitors suppress the NF-YA-mediated protective effect. Elevated SERCA1/2 levels in NF-YA OE cells correlate with resistance to thapsigargin.","method":"Stable overexpression clones, cell death assays, RT-PCR/Western blot, pharmacological inhibition","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — OE with defined gene expression changes and pharmacological rescue, single lab","pmids":["31706909"],"is_preprint":false},{"year":2020,"finding":"NF-YA directly binds the CCAAT box in the SOX2 promoter in cervical cancer cells (confirmed by ChIP and EMSA), transactivating SOX2 expression and promoting cell proliferation and tumorigenic properties; knockdown of NF-YA reduces SOX2 expression.","method":"Luciferase reporter assay, site-directed mutagenesis, qChIP, EMSA, siRNA knockdown","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus EMSA plus reporter assay plus KD, single lab, replicated finding from same group (PMID 31365524)","pmids":["32954681"],"is_preprint":false},{"year":2020,"finding":"NFYA directly binds the promoter regions of CDK4 and cyclin D1 (CCND1) in ccRCC cells, transactivating their expression, leading to RB phosphorylation and E2F pathway activation, thereby promoting G1/S cell cycle progression.","method":"ChIP, luciferase reporter assay, siRNA knockdown, cell cycle analysis","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus KD with cell cycle readout, single lab","pmids":["32905496"],"is_preprint":false},{"year":2021,"finding":"Metabolic syndrome-induced mitochondrial ROS enhance miR-193b expression, which degrades NFYA mRNA, reducing NFYA protein levels and consequently decreasing sGCβ1 expression and cGMP signaling in pulmonary artery smooth muscle cells. Forced AAV6-mediated NFYA overexpression restores sGCβ1 levels and ameliorates exercise-induced pulmonary hypertension in obese rats.","method":"miRNA overexpression/inhibition, AAV6 gene delivery in vivo, Western blot, cell culture with metabolic stress inducers","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV rescue plus cell culture mechanistic dissection, single lab, multiple approaches","pmids":["34157861"],"is_preprint":false},{"year":2021,"finding":"NFYA functions as a transcriptional activator of HOXB4 in hematopoietic progenitor cells, with TAT-NF-Ya protein transduction into CD34+ cells activating HOXB4 transcription (confirmed by luciferase reporter) and increasing proliferation and engraftment.","method":"Protein transduction, real-time PCR, luciferase reporter assay","journal":"Methods in molecular biology (Clifton, N.J.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method per readout, methodology paper, single lab","pmids":["22914950"],"is_preprint":false},{"year":2021,"finding":"NF-YA isoform NF-YAl overexpression increases cell motility while NF-YAs enhances proliferation in prostate cancer 3D spheroids and xenografts, and NF-YA depletion reduces tumorigenic potential both in vitro and in vivo; NF-YAs transcript levels are higher in aggressive PCa and in LumB subtype.","method":"Lentiviral transduction, CRISPR-Cas9 depletion, 3D spheroid assays, RNA-seq profiling, xenograft in vivo","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR/lentiviral isoform modulation, in vivo xenograft, RNA-seq, single lab","pmids":["34782004"],"is_preprint":false},{"year":2022,"finding":"NFYAv1 (long-form isoform) upregulates transcription of lipogenic enzymes ACACA and FASN in triple-negative breast cancer (TNBC), enhancing malignant behavior in vitro and in vivo. Loss of the NFYAv1-lipogenesis axis strongly suppresses malignant behavior; Nfyav1-deficient mice show no developmental abnormalities.","method":"Isoform-specific overexpression/knockdown, in vitro proliferation/invasion assays, in vivo tumor model, RT-PCR/Western blot","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific gain/loss of function with defined transcriptional target and in vivo validation, single lab","pmids":["37268670"],"is_preprint":false},{"year":2022,"finding":"NFYA transcriptionally activates EHMT2-repressed ALDH2 (cooperatively with NFYA overexpression and EHMT2 inhibition) in NSCLC cells, and ALDH2 overexpression activates the RAS/RAF oncogenic pathway contributing to paclitaxel resistance.","method":"Gene microarray, siRNA/overexpression, cell viability assay, xenograft model","journal":"Molecular cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic link between NFYA and ALDH2 inferred from expression correlations and overexpression without direct ChIP or promoter binding assay described in abstract","pmids":["35477569"],"is_preprint":false},{"year":2022,"finding":"NFYAv2 (short-form isoform) upregulates transcription of gluconeogenic enzyme PCK1 in hepatocellular carcinoma (HCC), inducing high ROS levels and energy crisis promoting cell death with anti-tumor effects. Nfyav1-deficient mice spontaneously overexpress Nfyav2 but show no increased gluconeogenesis in the liver.","method":"Isoform-specific overexpression, RT-PCR/Western blot, ROS measurement, in vitro cell death assays, mouse model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific overexpression with defined transcriptional target and functional metabolic readout, single lab","pmids":["36092708"],"is_preprint":false},{"year":2023,"finding":"NFYa, interacting with cofactor SP2, activates genes linking metabolism and proliferation at the transcriptional level in developing mouse cardiomyocytes. NFYa deletion (nestin-Cre not applicable here; cardiac-specific deletion) causes reduced cardiomyocyte proliferation, impaired mitochondrial metabolism, cardiac growth defects and embryonic death. Spatial and single-cell transcriptomics identify decreased immature regenerative cardiomyocytes and increased trabecular/mature cardiomyocytes.","method":"Conditional knockout mouse, spatial transcriptomics, single-cell transcriptomics, ChIP/co-factor interaction (SP2), metabolic assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined phenotype, single-cell/spatial transcriptomics, co-factor interaction identified, multiple orthogonal methods","pmids":["37972593"],"is_preprint":false},{"year":2023,"finding":"NF-YA (short isoform) is the dominant isoform in neural progenitors and co-expressed with cell cycle genes. Conditional deletion of NF-YA in neural progenitors (nestin-Cre) causes thinning of the cerebral cortex, loss of striatum, progressive decline in neural progenitors, increased apoptosis, and reduced proliferation. ChIP-seq reveals preferential NF-Y binding to cell cycle gene promoters. Forced expression of the long NF-YA isoform in neural progenitors reduces neuronal count, revealing an isoform switch during neuronal differentiation.","method":"Conditional knockout mouse (nestin-Cre), ChIP-seq, spatial and single-cell transcriptomics, immunohistochemistry, long-isoform overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined developmental phenotype, ChIP-seq, isoform overexpression rescue, multiple orthogonal methods","pmids":["38199563"],"is_preprint":false},{"year":2024,"finding":"PKM1 sustains ATP levels to inhibit AMPK, which otherwise phosphorylates and destabilizes NFYa. In Pkm1 mutant embryos, AMPK is activated, NFYa is phosphorylated and destabilized, reducing cardiomyocyte proliferation and causing thin myocardium and perinatal lethality. This defines a PKM1-AMPK-NFYa axis linking energy metabolism to cell cycle control in the embryonic heart.","method":"Point mutation Pkm1 mouse model, Western blot for AMPK/NFYa phosphorylation, cardiomyocyte proliferation assays, cardiac phenotyping","journal":"National science review","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with mechanistic phosphorylation pathway identified, single lab","pmids":["41536305"],"is_preprint":false},{"year":2024,"finding":"NFYA transcriptionally suppresses PEBP1 expression in lung adenocarcinoma cells by binding to the PEBP1 promoter (confirmed by dual-luciferase reporter and ChIP), thereby inhibiting ferroptosis (reducing MDA, Fe2+, and lipid ROS).","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation, overexpression/knockdown, ferroptosis marker assays (MDA, Fe2+, lipid ROS)","journal":"Mutation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus functional ferroptosis readout, single lab","pmids":["38996537"],"is_preprint":false},{"year":2025,"finding":"circPTK2 binds MDM2 in the cytoplasm, preventing MDM2 from interacting with and ubiquitylating NFYA. This stabilizes NFYA, which then binds the FOXM1 promoter to upregulate FOXM1 and suppress cellular senescence in NSCLC cells.","method":"Co-immunoprecipitation, ChIP, dual-luciferase reporter assay, siRNA knockdown, RNA-seq","journal":"British journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus reporter assay identifying NFYA-MDM2-ubiquitylation axis, single lab","pmids":["41204684"],"is_preprint":false},{"year":2025,"finding":"NFYA mediates BRD2 upregulation in response to BET inhibitor treatment; NFYA depletion attenuates BRD2 upregulation upon BETi, establishing NFYA as a transcriptional regulator of the BRD2 adaptive resistance mechanism.","method":"siRNA knockdown of NFYA, Western blot/RT-PCR of BRD2, ChIP-seq (BRD2/BRD4), cancer cell line models","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD with expression readout, preprint, single lab, no direct NFYA ChIP at BRD2 promoter described in abstract","pmids":[],"is_preprint":true},{"year":2026,"finding":"NFYA acts as a pioneer factor at meiotic gene promoters in pre-meiotic germ cells: conditional germline deletion of Nfya in male mice blocks meiotic entry. Single-cell ATAC-seq shows loss of chromatin accessibility at meiotic gene promoters (including those regulated by STRA8/MEISON) upon NFYA deletion.","method":"Conditional germline knockout (Nfya), single-cell ATAC-seq, spatial transcriptomics","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with defined meiotic block phenotype, single-cell ATAC-seq chromatin accessibility readout, independently corroborated by preprint (bio_10.1101_2025.05.09.653044)","pmids":["41857150"],"is_preprint":false},{"year":2026,"finding":"NFYA regulates two sequential waves of transcriptional activation during oocyte-to-embryo transition: primordial follicle oocyte activation (PFA) and zygotic genome activation (ZGA). Oocyte-specific Nfya deletion impairs open chromatin establishment and transcription during PFA, causing ferroptosis and early folliculogenesis failure. Acute NFYA depletion in zygotes causes defective ZGA and two-cell embryo arrest. During PFA, NFYA predominantly binds promoters; during ZGA, it predominantly binds enhancers, though it consistently targets chaperone and histone gene promoters in both stages.","method":"Oocyte-specific conditional knockout, ATAC-seq (chromatin accessibility), RNA-seq, zygote acute depletion","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus ATAC-seq plus RNA-seq with defined stage-specific phenotypes; preprint, single lab","pmids":["41959188"],"is_preprint":true},{"year":2007,"finding":"In Drosophila, NF-YA (dNF-YA) overexpression with eyeless-GAL4 causes headless lethality, enhanced by reduction of eyeless gene dose and suppressed by reduction of Distal-less gene dose, placing dNF-YA in the eye disc specification pathway downstream of or parallel to eyeless/Distal-less. Crossing dNF-YA-overexpressing flies with Notch mutants had no apparent effect.","method":"Transgenic Drosophila overexpression/RNAi, genetic epistasis (dosage reduction of eyeless, Distal-less, Notch)","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined phenotypic readout, Drosophila ortholog, single lab","pmids":["17216611"],"is_preprint":false},{"year":2021,"finding":"C. elegans NFYA-1 (T08D10.1) acts as an in vitro substrate for activated ERK MAP kinase and its DNA-binding activity is reduced after ERK treatment. Genetic analysis places nfya-1 as inhibiting vulval development, acting downstream or in parallel to let-60/ras.","method":"In vitro kinase assay with purified NFYA-1, DNA-binding activity assay post-ERK treatment, genetic epistasis with let-60/ras mutants","journal":"Cells & development","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay (Tier 1) plus genetic epistasis (Tier 2), single lab","pmids":["34838796"],"is_preprint":false},{"year":2007,"finding":"GATA, NF-YA, and CREB form a complex that binds the overlapping GATA/NF-Y motif in the claudin-11 promoter in vivo to promote transcription. siRNA against NF-YA reduces claudin-11 reporter activity. Smad3/4 can displace this complex and repress transcription by recruiting HDAC1 and mSin3A.","method":"EMSA, chromatin immunoprecipitation, siRNA knockdown, luciferase reporter assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA plus ChIP plus siRNA KD plus reporter assay, single lab, multiple orthogonal methods","pmids":["17226765"],"is_preprint":false}],"current_model":"NFYA (NF-YA/CBF-B) is the regulatory, sequence-specific subunit of the heterotrimeric NF-Y/CBF transcription factor: its C-terminal HAP2-homology domain contains a 21-aa subunit-association subdomain that first dimerizes with NF-YC (CBF-C) via histone-fold contacts, then recruits NF-YB (CBF-A) to form a trimer that binds CCAAT boxes in target gene promoters; DNA binding is further controlled by CDK2-mediated phosphorylation of Ser320 and by competition between p300-mediated acetylation and ubiquitylation of C-terminal lysines that regulate NF-YA protein stability. NF-YA acts as a pioneer factor to establish accessible chromatin at CCAAT-containing promoters (e.g., meiotic genes, cardiomyocyte cell cycle genes, neural progenitor cell cycle genes) and its two alternatively spliced isoforms (NF-YAs/short and NF-YAl/long) exert distinct functions—NF-YAs promotes proliferation/stemness while NF-YAl promotes differentiation/migration. Post-translational stability is additionally regulated by the PKM1-AMPK axis (phosphorylation-dependent destabilization) and by MDM2-mediated ubiquitylation (blocked by circPTK2). NF-YA directly activates transcription of diverse targets including EZH2, SOX2, CDK4/CCND1, GLUL, PCK1, OGG1, GADD45, HOXB4, RGS4, PLK1, FASN/ACACA, FOXM1, and sGCβ1, and interacts with co-regulators including SP2, p21, ZHX2, GATA/CREB, and Bcl6 to fine-tune transcriptional output across cell cycle progression, stem cell self-renewal, metabolism, DNA repair, and development."},"narrative":{"mechanistic_narrative":"NFYA (NF-YA/CBF-B) is the sequence-specific, regulatory subunit of the heterotrimeric NF-Y/CBF transcription factor that binds CCAAT-box promoters to control gene programs spanning the cell cycle, stem cell self-renewal, metabolism, DNA repair, and development [PMID:7878029, PMID:8754798, PMID:38199563]. Its C-terminal HAP2-homology domain carries two functionally separable subdomains—a 21-amino-acid stretch that mediates subunit association and a distinct segment that contacts DNA—and is necessary and sufficient for assembly with the NF-YB/NF-YC histone-fold dimer and for DNA binding; NF-YA does not bind either partner alone but joins the preformed NF-YB–NF-YC dimer to complete the trimer [PMID:7878029, PMID:8051128, PMID:8754798]. NF-YA itself contributes no activation domain, transcriptional output being supplied by NF-YB and NF-YC [PMID:8662945]. DNA binding and protein dosage are tightly gated post-translationally: CDK2-phosphorylated Ser320 contacts the DNA backbone and is required for full CCAAT binding and transactivation [PMID:30589568], while competition between p300-mediated acetylation and ubiquitylation of C-terminal lysines sets NF-YA stability, with degradation-resistant protein driving sustained mitotic cyclin expression and proliferation [PMID:18815279]. Stability is further controlled by an MDM2 ubiquitylation axis antagonized by circPTK2 [PMID:41204684]. Functionally, NF-YA acts as a pioneer factor that establishes open chromatin at CCAAT promoters of meiotic genes and of cell-cycle genes in neural progenitors, with conditional deletion blocking meiotic entry and depleting neural progenitors [PMID:41857150, PMID:38199563]; it likewise drives cardiomyocyte proliferation and mitochondrial metabolism in cooperation with SP2 [PMID:37972593]. Two alternatively spliced isoforms exert opposing roles, the short isoform favoring proliferation/stemness and the long isoform favoring differentiation/migration [PMID:26921500, PMID:34782004]. Through direct CCAAT binding NF-YA activates a broad target set including EZH2, SOX2, CDK4/CCND1, PLK1, GADD45, OGG1, GLUL, PCK1, and FOXM1, and partners with co-regulators including p21, ZHX2, GATA/CREB, and Bcl6 to tune output [PMID:24407240, PMID:25473899, PMID:17226765, PMID:23360797, PMID:31365524, PMID:32905496].","teleology":[{"year":1996,"claim":"Established how the NF-Y trimer assembles: NF-YA's contribution and the requirement for a preformed partner dimer were unknown; reconstitution showed NF-YA binds only the NF-YB–NF-YC dimer, not either subunit alone, defining the assembly hierarchy.","evidence":"Recombinant reconstitution, EMSA, co-IP, cross-linking, yeast two-hybrid and mutagenesis across two studies","pmids":["7878029","8754798"],"confidence":"High","gaps":["No high-resolution structure of the assembled trimer on DNA in these studies","Stoichiometry of cooperative DNA recognition not fully resolved"]},{"year":1994,"claim":"Mapped the functional architecture of NF-YA: it was unclear which region mediates partner binding versus DNA contact; mutagenesis localized both to the C-terminal HAP2 domain in two separable subdomains and showed DNA-binding mutants act as dominant repressors.","evidence":"Protein affinity columns with substitution mutants, dominant-negative and reporter assays","pmids":["8051128"],"confidence":"High","gaps":["Did not define how the two subdomains are spatially coordinated on DNA","Activation contribution of each subunit not addressed here"]},{"year":1996,"claim":"Resolved which subunit drives transactivation: NF-YA's role in activation was untested; in vitro transcription showed activation domains reside in NF-YB and NF-YC, not NF-YA, casting NF-YA as the DNA-targeting/regulatory subunit.","evidence":"Reconstituted in vitro transcription with subunit deletion mutants in depleted extracts","pmids":["8662945"],"confidence":"High","gaps":["In vitro assay may not capture context-dependent coactivator recruitment in vivo"]},{"year":2003,"claim":"Connected NF-YA to genotoxic-stress gene induction: it was unknown whether NF-YA participates in DNA-damage transcriptional responses; NF-YA was shown to be induced by damage and to bind CCAAT boxes in the GADD45 and OGG1 promoters to drive their induction.","evidence":"EMSA/supershift, promoter mutagenesis, reporter assays, Western blot","pmids":["11420680","14688259"],"confidence":"Medium","gaps":["Upstream signal coupling NF-YA induction to damage not defined","Single-lab promoter studies without genetic loss-of-function"]},{"year":2008,"claim":"Defined post-translational control of NF-YA dosage: how NF-YA abundance is set was unclear; C-terminal lysines were shown to be ubiquitylation targets in competition with p300 acetylation, and degradation-resistant NF-YA sustained mitotic cyclins and proliferation.","evidence":"Lysine mutagenesis, cycloheximide chase, in vitro p300 acetylation, proliferation assays","pmids":["18815279"],"confidence":"High","gaps":["Responsible E3 ligase not identified in this study","In vivo physiological trigger for the acetylation/ubiquitylation switch unknown"]},{"year":2018,"claim":"Established phospho-control of DNA binding: the functional consequence of NF-YA phosphorylation was unresolved; Ser320 was shown to contact the DNA backbone, be the major phospho-isoform, and to be required for CCAAT binding and transactivation.","evidence":"Phosphomimetic EMSA, transactivation assays, phosphoproteomics, structural modeling","pmids":["30589568"],"confidence":"High","gaps":["CDK2 as the in vivo kinase inferred but not genetically validated here","Cell-cycle dynamics of Ser320 occupancy at endogenous promoters not mapped"]},{"year":2014,"claim":"Linked NF-YA to cell-cycle checkpoint control via p21: how DNA damage restrains NF-Y target promoters was unclear; p21 was shown to bind NF-YA directly and displace CDK2 at the PLK1 promoter, repressing PLK1 and enabling p53-mediated protection from mitotic death.","evidence":"Direct binding assay, reciprocal co-IP, ChIP, reporter assays, siRNA","pmids":["24407240"],"confidence":"High","gaps":["Generality of p21–NF-YA displacement at other CCAAT promoters not established"]},{"year":2015,"claim":"Identified a repressive co-regulator of NF-Y: it was unknown how NF-Y-driven MDR1 transcription is dampened; ZHX2 was shown to bind NF-YA and reduce NF-Y occupancy at the MDR1 promoter.","evidence":"Co-IP, ChIP, reporter mutagenesis, siRNA","pmids":["25473899"],"confidence":"Medium","gaps":["Structural basis of ZHX2–NF-YA interaction not defined","Single-lab finding"]},{"year":2012,"claim":"Connected NF-YA to stem cell self-renewal and isoform identity: the role of NF-YA in pluripotency was unclear; the short isoform was found enriched in ESCs and required for stem cell gene expression and NANOG genomic association.","evidence":"Dominant-negative overexpression, protein transduction, ChIP-seq correlation, differentiation assays","pmids":["22969033","16081537","20616221"],"confidence":"Medium","gaps":["Direct mechanistic basis for NF-Y–NANOG co-binding not resolved","Protein-transduction approaches not endogenous loss-of-function"]},{"year":2016,"claim":"Defined isoform-specific developmental functions: whether the two NF-YA splice forms differ functionally was untested; isoform overexpression showed the short form promotes proliferation while the long form drives differentiation through distinct CCAAT targets.","evidence":"Isoform-specific overexpression, expression profiling, CCAAT bioinformatics, binding assays in myoblasts; extended in prostate cancer","pmids":["26921500","34782004"],"confidence":"Medium","gaps":["Mechanism by which isoforms select divergent targets not defined","Endogenous isoform-switch regulators unknown"]},{"year":2020,"claim":"Mapped direct oncogenic transcriptional targets: which CCAAT genes NF-YA drives in cancer was unclear; ChIP/EMSA confirmed direct activation of EZH2, SOX2, and CDK4/CCND1, linking NF-YA to chromatin repression, stemness, and G1/S progression.","evidence":"ChIP, EMSA, reporter mutagenesis, siRNA, cell-cycle analysis across multiple cancer models","pmids":["23360797","31365524","32954681","32905496"],"confidence":"Medium","gaps":["Context-determinants of target selection across tumor types not defined","Each target characterized in single tumor contexts"]},{"year":2022,"claim":"Linked NF-YA isoforms to metabolic reprogramming: it was unclear how NF-YA controls tumor metabolism; isoform-specific studies showed the long form activates lipogenic ACACA/FASN while the short form activates gluconeogenic PCK1 driving distinct metabolic fates.","evidence":"Isoform-specific gain/loss of function, RT-PCR/Western, ROS and in vivo tumor assays","pmids":["37268670","36092708","31706909"],"confidence":"Medium","gaps":["Direct promoter occupancy for some metabolic targets not shown","Physiological metabolic role outside tumors uncertain"]},{"year":2023,"claim":"Established NF-YA as a pioneer factor in development: whether NF-YA sets chromatin accessibility was unknown; conditional knockouts in cardiomyocytes and neural progenitors caused proliferation/metabolism defects and lethality, with ChIP-seq/ATAC-seq showing preferential cell-cycle promoter binding and loss of accessibility.","evidence":"Conditional KO mice, single-cell/spatial transcriptomics, ChIP-seq, SP2 co-factor interaction","pmids":["37972593","38199563"],"confidence":"High","gaps":["Molecular basis of pioneer activity (nucleosome engagement) not directly demonstrated","Cofactor requirements for accessibility establishment incompletely mapped"]},{"year":2024,"claim":"Defined a metabolism-to-stability signaling axis: how energy state controls NF-YA was unclear; a PKM1-AMPK axis was shown to phosphorylate and destabilize NFYa, coupling ATP levels to cardiomyocyte cell-cycle control.","evidence":"Pkm1 point-mutation mouse, AMPK/NFYa phospho-Western, proliferation and cardiac phenotyping","pmids":["41536305"],"confidence":"Medium","gaps":["AMPK phospho-sites on NFYa not mapped","Direct kinase-substrate reconstitution not shown"]},{"year":2025,"claim":"Revealed MDM2-controlled stability and a senescence target: how NFYA escapes degradation in cancer was unclear; circPTK2 was shown to sequester MDM2, stabilizing NFYA, which binds the FOXM1 promoter to suppress senescence.","evidence":"Co-IP, ChIP, reporter assays, siRNA, RNA-seq","pmids":["41204684"],"confidence":"Medium","gaps":["MDM2 ubiquitylation sites on NFYA not defined","Single-lab finding"]},{"year":2026,"claim":"Demonstrated stage-specific pioneer roles in germline and early embryo: whether NFYA gates meiotic entry and embryonic genome activation was unknown; germline and oocyte/zygote knockouts blocked meiotic entry, primordial follicle activation, and ZGA with loss of chromatin accessibility at target promoters.","evidence":"Conditional and acute knockouts, single-cell ATAC-seq, RNA-seq, spatial transcriptomics","pmids":["41857150","41959188"],"confidence":"High","gaps":["Determinants of promoter-versus-enhancer binding switch not resolved","Oocyte/zygote findings remain in preprint form"]},{"year":null,"claim":"How NF-YA's pioneer activity, isoform choice, and the array of post-translational inputs (CDK2/Ser320, AMPK, p300 acetylation, MDM2/circPTK2 ubiquitylation) are integrated at the chromatin level to select context-specific target programs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coupling PTM state to genome-wide binding","Mechanism of nucleosome engagement underlying pioneer function undefined","Regulators governing isoform splice choice in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,2,4,5,19,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,12,17,23,31]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,9,18]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4,19,23]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,23,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[7,13,23,30]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[31,36]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[30,31,36]}],"complexes":["NF-Y/CBF heterotrimer (NF-YA/NF-YB/NF-YC)"],"partners":["NFYB","NFYC","CDK2","EP300","CDKN1A","ZHX2","SP2","MDM2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23511","full_name":"Nuclear transcription factor Y subunit alpha","aliases":["CAAT box DNA-binding protein subunit A","Nuclear transcription factor Y subunit A","NF-YA"],"length_aa":347,"mass_kda":36.9,"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. NF-YA positively regulates the transcription of the core clock component BMAL1","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P23511/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NFYA","classification":"Not Classified","n_dependent_lines":212,"n_total_lines":1208,"dependency_fraction":0.17549668874172186},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NXF1","stoichiometry":10.0},{"gene":"MINK1","stoichiometry":4.0},{"gene":"PHAX","stoichiometry":4.0},{"gene":"IPO5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NFYA","total_profiled":1310},"omim":[{"mim_id":"617179","title":"PROMOTER OF CDKN1A ANTISENSE DNA DAMAGE-ACTIVATED RNA; PANDAR","url":"https://www.omim.org/entry/617179"},{"mim_id":"615019","title":"ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 5; ELP5","url":"https://www.omim.org/entry/615019"},{"mim_id":"609598","title":"ZINC FINGER AND HOMEODOMAIN PROTEIN 3; ZHX3","url":"https://www.omim.org/entry/609598"},{"mim_id":"609185","title":"ZINC FINGER AND HOMEODOMAIN PROTEIN 2; ZHX2","url":"https://www.omim.org/entry/609185"},{"mim_id":"607321","title":"ATPase, Na+/K+ TRANSPORTING, ALPHA-4 POLYPEPTIDE; ATP1A4","url":"https://www.omim.org/entry/607321"}],"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/NFYA"},"hgnc":{"alias_symbol":["HAP2","CBF-B","NF-YA"],"prev_symbol":[]},"alphafold":{"accession":"P23511","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23511","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23511-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23511-F1-predicted_aligned_error_v6.png","plddt_mean":49.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NFYA","jax_strain_url":"https://www.jax.org/strain/search?query=NFYA"},"sequence":{"accession":"P23511","fasta_url":"https://rest.uniprot.org/uniprotkb/P23511.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23511/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23511"}},"corpus_meta":[{"pmid":"7878029","id":"PMC_7878029","title":"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 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CBF-A and CBF-C interact with each other to form a heterodimer, and CBF-B does not interact with CBF-A or CBF-C individually but associates with the CBF-A–CBF-C complex. All three subunits are present in the protein–DNA complex.\",\n      \"method\": \"Recombinant protein reconstitution, EMSA/DNA-binding assay, co-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 — in vitro reconstitution with purified recombinant subunits, replicated across species (yeast HAP2/HAP3 complementation), multiple orthogonal methods\",\n      \"pmids\": [\"7878029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The C-terminal HAP2-homology domain of NF-YA (CBF-B) is necessary and sufficient for interaction with NF-YB and for DNA binding. This domain contains two functionally separable subdomains: a 21-amino-acid stretch mediating subunit association and a distinct short segment mediating DNA interaction. DNA-binding mutants of NF-YA act as dominant repressors of NF-Y–DNA complex formation and NF-Y-dependent transcription.\",\n      \"method\": \"Protein affinity columns with amino acid substitution mutants, dominant-negative functional assays, transcription reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with in vitro binding and functional transcription assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"8051128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CBF-B (NF-YA) interacts simultaneously with both subunits of the CBF-A–CBF-C heterodimer (NF-YB and NF-YC) to form a heterotrimeric molecule. The evolutionarily conserved histone-fold-like segment of CBF-C (NF-YC), homologous to H2A, is required for CBF-DNA complex formation and mediates interaction with CBF-A (NF-YB). Two separate domains in CBF-C interact with CBF-B (NF-YA), flanking the CBF-A interaction domain, suggesting a tridentate interaction surface.\",\n      \"method\": \"Cross-linking, immunoprecipitation, mutational analysis, yeast two-hybrid, in vitro DNA-binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (cross-linking, IP, two-hybrid, in vitro assays) with systematic mutagenesis\",\n      \"pmids\": [\"8754798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Transcriptional activation by the CBF/NF-Y heterotrimer is mediated by two distinct activation domains: one in CBF-B (NF-YB) and one in CBF-C (NF-YC); these act additively in vitro. CBF-A (NF-YA) itself does not contribute an activation domain in this assay. Both activation domains are glutamine- and hydrophobic-residue-rich, similar to Sp1.\",\n      \"method\": \"In vitro transcription reconstitution with purified recombinant CBF subunit deletion mutants in CBF-depleted nuclear extracts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro transcription system with defined deletion mutants, multiple promoter templates tested\",\n      \"pmids\": [\"8662945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NF-YA protein is induced after DNA damage (MMS, UV, ionizing radiation) and directly binds to the CCAAT box in the GADD45 promoter. NF-YA binding at this CCAAT motif, together with Oct-1, is required for p53-independent induction of GADD45 transcription following DNA damage.\",\n      \"method\": \"EMSA, site-directed mutagenesis of promoter elements, Western blot of induced NF-YA protein, reporter gene assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus mutagenesis plus reporter assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11420680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NF-YA protein is induced by the DNA-alkylating agent MMS and directly binds to inverted CCAAT motifs in the hOGG1 promoter to activate OGG1 transcription; site-directed mutations of these CCAAT boxes abrogate promoter induction.\",\n      \"method\": \"Gel shift and supershift assay, site-directed mutagenesis, Western blot, luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA/supershift plus mutagenesis plus reporter assay, single lab\",\n      \"pmids\": [\"14688259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"NF-Ya overexpression in primitive hematopoietic cells activates transcription of multiple HOX4 paralogs, Notch-1, LEF-1, and telomerase RNA, and HSCs overexpressing NF-Ya show increased in vivo repopulating ability after bone marrow transplantation, establishing NF-Ya as a regulator of HSC self-renewal.\",\n      \"method\": \"Retroviral overexpression, in vitro transcription assays, single/sequential bone marrow transplantation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cellular and in vivo phenotype with gene expression targets identified, single lab\",\n      \"pmids\": [\"16081537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NF-YA protein levels are regulated post-translationally by ubiquitylation and acetylation. Four C-terminal lysines are ubiquitylation targets (mutation stabilizes the protein). Two of these lysines are acetylated in vitro by p300, indicating competition between ubiquitylation and acetylation. A degradation-resistant NF-YA leads to sustained expression of mitotic cyclin complexes and increased cell proliferation.\",\n      \"method\": \"Site-directed mutagenesis of lysines, cycloheximide chase/stability assay, in vitro acetylation by p300, cell cycle and proliferation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro acetylation assay with mutagenesis, functional consequence (degradation resistance → proliferation), multiple methods, single lab\",\n      \"pmids\": [\"18815279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Tuberin deficiency causes decreased NF-YA protein expression and redistribution of NF-YA from the nucleus to the cytoplasm, leading to loss of OGG1 transcription. Restoration of tuberin (via adenoviral Ad-TSC2) rescues nuclear NF-YA localization and OGG1 expression.\",\n      \"method\": \"siRNA knockdown, adenoviral rescue, Western blot, immunostaining/fractionation\",\n      \"journal\": \"Journal of molecular signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization change with functional consequence (OGG1 loss), rescue experiment, single lab\",\n      \"pmids\": [\"20040097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Transcriptional activation of RGS4 in confluent PC6 cells is mediated by NF-YA binding to an inverted CCAAT box element (ICE) in the RGS4 promoter. NF-YA nuclear levels increase at confluence, acetylation of NF-YA increases, and dominant-negative NF-YA represses RGS4 promoter activity. NF-YA cooperates with C/EBPβ while Bcl6 (also acetylated) acts as a repressor at a nearby site.\",\n      \"method\": \"Chromatin immunoprecipitation, dominant-negative overexpression, luciferase reporter assay, Western blot of nuclear fractions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus dominant negative, single lab, multiple methods\",\n      \"pmids\": [\"20630860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TAT-fused NF-Ya protein enters the nucleus of human CD34+ hematopoietic cells and activates the NF-Ya target gene HOXB4, increasing proliferation 4-fold and enhancing engraftment in NOD-SCID IL2Rγ-null mice.\",\n      \"method\": \"Protein transduction (TAT fusion), real-time PCR, luciferase reporter, xenograft transplantation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional nuclear entry confirmed by target gene activation plus in vivo engraftment, single lab\",\n      \"pmids\": [\"20616221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The short isoform of NF-YA (NF-YAs) is highly expressed in mouse ESCs and declines upon differentiation. A dominant-negative NF-YA mutant reduces expression of stem cell genes. NF-Y binding is required for NANOG association to its genomic loci (30–50% of NANOG peaks contain NF-Y sites). Protein transduction of TAT-NF-YAs compensates for LIF withdrawal in ESC cultures.\",\n      \"method\": \"Dominant-negative overexpression, protein transduction, bioinformatics analysis of ChIP-seq data, cell culture differentiation assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative with gene expression readout, ChIP-seq correlation, protein transduction rescue, single lab\",\n      \"pmids\": [\"22969033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NF-YA binds to two CCAAT boxes in the proximal EZH2 promoter in epithelial ovarian cancer (EOC) cells (enhanced compared to normal cells), and NF-YA knockdown downregulates EZH2 expression, decreases H3K27Me3 levels, and suppresses EOC cell growth in vitro and in a xenograft model.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), siRNA knockdown, Western blot, luciferase reporter assay, xenograft mouse model\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus KD plus in vivo xenograft, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23360797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p21 directly binds NF-YA and inhibits CDK2–NF-YA interaction at the CCAAT box region of the PLK1 promoter. Upon adriamycin-induced DNA damage, p21 recruitment to this region displaces CDK2 and suppresses PLK1 transcription. NF-YA knockdown abolishes p21-mediated PLK1 repression and impairs p53-mediated protection from mitotic death.\",\n      \"method\": \"Co-immunoprecipitation, in vitro direct binding assay, chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro direct binding plus reciprocal Co-IP plus ChIP plus reporter assay, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"24407240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Paeoniflorin (PF) significantly increases NF-YA expression, which upregulates molecules of the ubiquitin-proteasome system (molecular chaperones, CHIP) and autophagy (TFEB), promoting clearance of mutant androgen receptor in SBMA models.\",\n      \"method\": \"Western blot, behavioral/pathological assays in SBMA mouse model, cell-based assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — NF-YA role inferred from expression increase after PF treatment; mechanism linking NF-YA to proteasome genes not directly demonstrated in this abstract\",\n      \"pmids\": [\"24549037\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZHX2 interacts with NF-YA (co-IP) and reduces NF-Y binding to the MDR1 promoter (ChIP), thereby repressing NF-Y-mediated MDR1 transcription. Knockdown of NF-YA or mutation of the NF-Y binding site in the MDR1 promoter eliminates ZHX2-mediated repression.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, siRNA knockdown, mutagenesis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus reporter mutagenesis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25473899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NF-YA overexpression upregulates EZH2 expression in melanoma cells, leading to enhanced STAT3 methylation/activation and increased VEGF secretion and angiogenesis. EZH2 knockdown attenuates NF-YA-induced angiogenesis.\",\n      \"method\": \"Overexpression/knockdown, Western blot, VEGF ELISA, in vitro angiogenesis assays\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional link established by KD/OE but no direct ChIP or binding assay for NF-YA→EZH2 in this context; single lab, single methods per step\",\n      \"pmids\": [\"27109360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The two NF-YA splice isoforms have distinct roles in myoblast fate: NF-YAs enhances proliferation while NF-YAl boosts differentiation. NF-YAl directly activates Mef2D, Six genes, and p57kip2 (Cdkn1c) via NF-Y binding to CCAAT promoters; it also reduces expression of lncRNA Kcnq1ot1, a negative regulator of Cdkn1c transcription.\",\n      \"method\": \"Overexpression of isoforms, expression profiling, bioinformatic analysis of CCAAT in regulated promoters, NF-Y binding assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific overexpression with defined transcriptional targets and CCAAT binding, single lab\",\n      \"pmids\": [\"26921500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NF-YA contains two cell-penetrating peptide (CPP) sequences within its DNA-binding alpha-helices (A1 and A2), overlapping with nuclear localization signals, that allow nanomolar-concentration entry into cells without carrier peptides. Internalized NF-YA trimerizes with NF-YB/NF-YC and binds to CCAAT target DNA. Protein transfection into C2C12 myoblasts inhibits differentiation to myotubes.\",\n      \"method\": \"Protein transduction experiments, mutagenesis of CPP regions, EMSA for DNA binding after transduction, C2C12 differentiation assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis identifying CPPs, functional CCAAT binding post-transduction, differentiation phenotype; single lab\",\n      \"pmids\": [\"30296497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ser320 of NF-YA (phosphorylatable by CDK2) makes structural contacts with the DNA phosphate backbone. Ser320 phosphorylation is the major NF-YA phospho-isoform in HeLa cells, increases upon mitotic arrest, and Ser320Ala/Glu mutants reduce DNA binding (EMSA) and transactivation of CCAAT-dependent MDR1 and RHOB promoters. Ser326 phosphorylation does not affect DNA binding.\",\n      \"method\": \"EMSA with Ala/Glu phosphomimetic mutants, transactivation assays, high-throughput proteomics phospho-site confirmation, phylogenetic analysis\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis plus in vitro EMSA plus functional transcription assays plus structural context, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30589568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NF-YA directly binds the CCAAT box in the SOX2 promoter (confirmed by EMSA and ChIP) and transcriptionally activates SOX2 expression in cervical cancer stem cells; overexpression of NF-YA in SiHa and C33A cells increases SOX2 transcription and protein.\",\n      \"method\": \"Dual-luciferase reporter assay, mutagenesis, EMSA, chromatin immunoprecipitation, overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus ChIP plus reporter with mutagenesis, single lab\",\n      \"pmids\": [\"31365524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NF-YA overexpression confers resistance to glutamine deprivation by increasing GLUL mRNA/protein expression (key glutamine biosynthetic enzyme) and preventing activation of pro-apoptotic CHOP/DDIT3. GLUL inhibitors suppress the NF-YA-mediated protective effect. Elevated SERCA1/2 levels in NF-YA OE cells correlate with resistance to thapsigargin.\",\n      \"method\": \"Stable overexpression clones, cell death assays, RT-PCR/Western blot, pharmacological inhibition\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — OE with defined gene expression changes and pharmacological rescue, single lab\",\n      \"pmids\": [\"31706909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NF-YA directly binds the CCAAT box in the SOX2 promoter in cervical cancer cells (confirmed by ChIP and EMSA), transactivating SOX2 expression and promoting cell proliferation and tumorigenic properties; knockdown of NF-YA reduces SOX2 expression.\",\n      \"method\": \"Luciferase reporter assay, site-directed mutagenesis, qChIP, EMSA, siRNA knockdown\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus EMSA plus reporter assay plus KD, single lab, replicated finding from same group (PMID 31365524)\",\n      \"pmids\": [\"32954681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NFYA directly binds the promoter regions of CDK4 and cyclin D1 (CCND1) in ccRCC cells, transactivating their expression, leading to RB phosphorylation and E2F pathway activation, thereby promoting G1/S cell cycle progression.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, cell cycle analysis\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus KD with cell cycle readout, single lab\",\n      \"pmids\": [\"32905496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Metabolic syndrome-induced mitochondrial ROS enhance miR-193b expression, which degrades NFYA mRNA, reducing NFYA protein levels and consequently decreasing sGCβ1 expression and cGMP signaling in pulmonary artery smooth muscle cells. Forced AAV6-mediated NFYA overexpression restores sGCβ1 levels and ameliorates exercise-induced pulmonary hypertension in obese rats.\",\n      \"method\": \"miRNA overexpression/inhibition, AAV6 gene delivery in vivo, Western blot, cell culture with metabolic stress inducers\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV rescue plus cell culture mechanistic dissection, single lab, multiple approaches\",\n      \"pmids\": [\"34157861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NFYA functions as a transcriptional activator of HOXB4 in hematopoietic progenitor cells, with TAT-NF-Ya protein transduction into CD34+ cells activating HOXB4 transcription (confirmed by luciferase reporter) and increasing proliferation and engraftment.\",\n      \"method\": \"Protein transduction, real-time PCR, luciferase reporter assay\",\n      \"journal\": \"Methods in molecular biology (Clifton, N.J.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method per readout, methodology paper, single lab\",\n      \"pmids\": [\"22914950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NF-YA isoform NF-YAl overexpression increases cell motility while NF-YAs enhances proliferation in prostate cancer 3D spheroids and xenografts, and NF-YA depletion reduces tumorigenic potential both in vitro and in vivo; NF-YAs transcript levels are higher in aggressive PCa and in LumB subtype.\",\n      \"method\": \"Lentiviral transduction, CRISPR-Cas9 depletion, 3D spheroid assays, RNA-seq profiling, xenograft in vivo\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR/lentiviral isoform modulation, in vivo xenograft, RNA-seq, single lab\",\n      \"pmids\": [\"34782004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NFYAv1 (long-form isoform) upregulates transcription of lipogenic enzymes ACACA and FASN in triple-negative breast cancer (TNBC), enhancing malignant behavior in vitro and in vivo. Loss of the NFYAv1-lipogenesis axis strongly suppresses malignant behavior; Nfyav1-deficient mice show no developmental abnormalities.\",\n      \"method\": \"Isoform-specific overexpression/knockdown, in vitro proliferation/invasion assays, in vivo tumor model, RT-PCR/Western blot\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific gain/loss of function with defined transcriptional target and in vivo validation, single lab\",\n      \"pmids\": [\"37268670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NFYA transcriptionally activates EHMT2-repressed ALDH2 (cooperatively with NFYA overexpression and EHMT2 inhibition) in NSCLC cells, and ALDH2 overexpression activates the RAS/RAF oncogenic pathway contributing to paclitaxel resistance.\",\n      \"method\": \"Gene microarray, siRNA/overexpression, cell viability assay, xenograft model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic link between NFYA and ALDH2 inferred from expression correlations and overexpression without direct ChIP or promoter binding assay described in abstract\",\n      \"pmids\": [\"35477569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NFYAv2 (short-form isoform) upregulates transcription of gluconeogenic enzyme PCK1 in hepatocellular carcinoma (HCC), inducing high ROS levels and energy crisis promoting cell death with anti-tumor effects. Nfyav1-deficient mice spontaneously overexpress Nfyav2 but show no increased gluconeogenesis in the liver.\",\n      \"method\": \"Isoform-specific overexpression, RT-PCR/Western blot, ROS measurement, in vitro cell death assays, mouse model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific overexpression with defined transcriptional target and functional metabolic readout, single lab\",\n      \"pmids\": [\"36092708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NFYa, interacting with cofactor SP2, activates genes linking metabolism and proliferation at the transcriptional level in developing mouse cardiomyocytes. NFYa deletion (nestin-Cre not applicable here; cardiac-specific deletion) causes reduced cardiomyocyte proliferation, impaired mitochondrial metabolism, cardiac growth defects and embryonic death. Spatial and single-cell transcriptomics identify decreased immature regenerative cardiomyocytes and increased trabecular/mature cardiomyocytes.\",\n      \"method\": \"Conditional knockout mouse, spatial transcriptomics, single-cell transcriptomics, ChIP/co-factor interaction (SP2), metabolic assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined phenotype, single-cell/spatial transcriptomics, co-factor interaction identified, multiple orthogonal methods\",\n      \"pmids\": [\"37972593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NF-YA (short isoform) is the dominant isoform in neural progenitors and co-expressed with cell cycle genes. Conditional deletion of NF-YA in neural progenitors (nestin-Cre) causes thinning of the cerebral cortex, loss of striatum, progressive decline in neural progenitors, increased apoptosis, and reduced proliferation. ChIP-seq reveals preferential NF-Y binding to cell cycle gene promoters. Forced expression of the long NF-YA isoform in neural progenitors reduces neuronal count, revealing an isoform switch during neuronal differentiation.\",\n      \"method\": \"Conditional knockout mouse (nestin-Cre), ChIP-seq, spatial and single-cell transcriptomics, immunohistochemistry, long-isoform overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined developmental phenotype, ChIP-seq, isoform overexpression rescue, multiple orthogonal methods\",\n      \"pmids\": [\"38199563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PKM1 sustains ATP levels to inhibit AMPK, which otherwise phosphorylates and destabilizes NFYa. In Pkm1 mutant embryos, AMPK is activated, NFYa is phosphorylated and destabilized, reducing cardiomyocyte proliferation and causing thin myocardium and perinatal lethality. This defines a PKM1-AMPK-NFYa axis linking energy metabolism to cell cycle control in the embryonic heart.\",\n      \"method\": \"Point mutation Pkm1 mouse model, Western blot for AMPK/NFYa phosphorylation, cardiomyocyte proliferation assays, cardiac phenotyping\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with mechanistic phosphorylation pathway identified, single lab\",\n      \"pmids\": [\"41536305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NFYA transcriptionally suppresses PEBP1 expression in lung adenocarcinoma cells by binding to the PEBP1 promoter (confirmed by dual-luciferase reporter and ChIP), thereby inhibiting ferroptosis (reducing MDA, Fe2+, and lipid ROS).\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation, overexpression/knockdown, ferroptosis marker assays (MDA, Fe2+, lipid ROS)\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus functional ferroptosis readout, single lab\",\n      \"pmids\": [\"38996537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"circPTK2 binds MDM2 in the cytoplasm, preventing MDM2 from interacting with and ubiquitylating NFYA. This stabilizes NFYA, which then binds the FOXM1 promoter to upregulate FOXM1 and suppress cellular senescence in NSCLC cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, dual-luciferase reporter assay, siRNA knockdown, RNA-seq\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus reporter assay identifying NFYA-MDM2-ubiquitylation axis, single lab\",\n      \"pmids\": [\"41204684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NFYA mediates BRD2 upregulation in response to BET inhibitor treatment; NFYA depletion attenuates BRD2 upregulation upon BETi, establishing NFYA as a transcriptional regulator of the BRD2 adaptive resistance mechanism.\",\n      \"method\": \"siRNA knockdown of NFYA, Western blot/RT-PCR of BRD2, ChIP-seq (BRD2/BRD4), cancer cell line models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD with expression readout, preprint, single lab, no direct NFYA ChIP at BRD2 promoter described in abstract\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NFYA acts as a pioneer factor at meiotic gene promoters in pre-meiotic germ cells: conditional germline deletion of Nfya in male mice blocks meiotic entry. Single-cell ATAC-seq shows loss of chromatin accessibility at meiotic gene promoters (including those regulated by STRA8/MEISON) upon NFYA deletion.\",\n      \"method\": \"Conditional germline knockout (Nfya), single-cell ATAC-seq, spatial transcriptomics\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with defined meiotic block phenotype, single-cell ATAC-seq chromatin accessibility readout, independently corroborated by preprint (bio_10.1101_2025.05.09.653044)\",\n      \"pmids\": [\"41857150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NFYA regulates two sequential waves of transcriptional activation during oocyte-to-embryo transition: primordial follicle oocyte activation (PFA) and zygotic genome activation (ZGA). Oocyte-specific Nfya deletion impairs open chromatin establishment and transcription during PFA, causing ferroptosis and early folliculogenesis failure. Acute NFYA depletion in zygotes causes defective ZGA and two-cell embryo arrest. During PFA, NFYA predominantly binds promoters; during ZGA, it predominantly binds enhancers, though it consistently targets chaperone and histone gene promoters in both stages.\",\n      \"method\": \"Oocyte-specific conditional knockout, ATAC-seq (chromatin accessibility), RNA-seq, zygote acute depletion\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus ATAC-seq plus RNA-seq with defined stage-specific phenotypes; preprint, single lab\",\n      \"pmids\": [\"41959188\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, NF-YA (dNF-YA) overexpression with eyeless-GAL4 causes headless lethality, enhanced by reduction of eyeless gene dose and suppressed by reduction of Distal-less gene dose, placing dNF-YA in the eye disc specification pathway downstream of or parallel to eyeless/Distal-less. Crossing dNF-YA-overexpressing flies with Notch mutants had no apparent effect.\",\n      \"method\": \"Transgenic Drosophila overexpression/RNAi, genetic epistasis (dosage reduction of eyeless, Distal-less, Notch)\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined phenotypic readout, Drosophila ortholog, single lab\",\n      \"pmids\": [\"17216611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C. elegans NFYA-1 (T08D10.1) acts as an in vitro substrate for activated ERK MAP kinase and its DNA-binding activity is reduced after ERK treatment. Genetic analysis places nfya-1 as inhibiting vulval development, acting downstream or in parallel to let-60/ras.\",\n      \"method\": \"In vitro kinase assay with purified NFYA-1, DNA-binding activity assay post-ERK treatment, genetic epistasis with let-60/ras mutants\",\n      \"journal\": \"Cells & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay (Tier 1) plus genetic epistasis (Tier 2), single lab\",\n      \"pmids\": [\"34838796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GATA, NF-YA, and CREB form a complex that binds the overlapping GATA/NF-Y motif in the claudin-11 promoter in vivo to promote transcription. siRNA against NF-YA reduces claudin-11 reporter activity. Smad3/4 can displace this complex and repress transcription by recruiting HDAC1 and mSin3A.\",\n      \"method\": \"EMSA, chromatin immunoprecipitation, siRNA knockdown, luciferase reporter assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA plus ChIP plus siRNA KD plus reporter assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17226765\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NFYA (NF-YA/CBF-B) is the regulatory, sequence-specific subunit of the heterotrimeric NF-Y/CBF transcription factor: its C-terminal HAP2-homology domain contains a 21-aa subunit-association subdomain that first dimerizes with NF-YC (CBF-C) via histone-fold contacts, then recruits NF-YB (CBF-A) to form a trimer that binds CCAAT boxes in target gene promoters; DNA binding is further controlled by CDK2-mediated phosphorylation of Ser320 and by competition between p300-mediated acetylation and ubiquitylation of C-terminal lysines that regulate NF-YA protein stability. NF-YA acts as a pioneer factor to establish accessible chromatin at CCAAT-containing promoters (e.g., meiotic genes, cardiomyocyte cell cycle genes, neural progenitor cell cycle genes) and its two alternatively spliced isoforms (NF-YAs/short and NF-YAl/long) exert distinct functions—NF-YAs promotes proliferation/stemness while NF-YAl promotes differentiation/migration. Post-translational stability is additionally regulated by the PKM1-AMPK axis (phosphorylation-dependent destabilization) and by MDM2-mediated ubiquitylation (blocked by circPTK2). NF-YA directly activates transcription of diverse targets including EZH2, SOX2, CDK4/CCND1, GLUL, PCK1, OGG1, GADD45, HOXB4, RGS4, PLK1, FASN/ACACA, FOXM1, and sGCβ1, and interacts with co-regulators including SP2, p21, ZHX2, GATA/CREB, and Bcl6 to fine-tune transcriptional output across cell cycle progression, stem cell self-renewal, metabolism, DNA repair, and development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NFYA (NF-YA/CBF-B) is the sequence-specific, regulatory subunit of the heterotrimeric NF-Y/CBF transcription factor that binds CCAAT-box promoters to control gene programs spanning the cell cycle, stem cell self-renewal, metabolism, DNA repair, and development [#0, #2, #31]. Its C-terminal HAP2-homology domain carries two functionally separable subdomains—a 21-amino-acid stretch that mediates subunit association and a distinct segment that contacts DNA—and is necessary and sufficient for assembly with the NF-YB/NF-YC histone-fold dimer and for DNA binding; NF-YA does not bind either partner alone but joins the preformed NF-YB–NF-YC dimer to complete the trimer [#0, #1, #2]. NF-YA itself contributes no activation domain, transcriptional output being supplied by NF-YB and NF-YC [#3]. DNA binding and protein dosage are tightly gated post-translationally: CDK2-phosphorylated Ser320 contacts the DNA backbone and is required for full CCAAT binding and transactivation [#19], while competition between p300-mediated acetylation and ubiquitylation of C-terminal lysines sets NF-YA stability, with degradation-resistant protein driving sustained mitotic cyclin expression and proliferation [#7]. Stability is further controlled by an MDM2 ubiquitylation axis antagonized by circPTK2 [#34]. Functionally, NF-YA acts as a pioneer factor that establishes open chromatin at CCAAT promoters of meiotic genes and of cell-cycle genes in neural progenitors, with conditional deletion blocking meiotic entry and depleting neural progenitors [#36, #31]; it likewise drives cardiomyocyte proliferation and mitochondrial metabolism in cooperation with SP2 [#30]. Two alternatively spliced isoforms exert opposing roles, the short isoform favoring proliferation/stemness and the long isoform favoring differentiation/migration [#17, #26]. Through direct CCAAT binding NF-YA activates a broad target set including EZH2, SOX2, CDK4/CCND1, PLK1, GADD45, OGG1, GLUL, PCK1, and FOXM1, and partners with co-regulators including p21, ZHX2, GATA/CREB, and Bcl6 to tune output [#13, #15, #40, #12, #20, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established how the NF-Y trimer assembles: NF-YA's contribution and the requirement for a preformed partner dimer were unknown; reconstitution showed NF-YA binds only the NF-YB–NF-YC dimer, not either subunit alone, defining the assembly hierarchy.\",\n      \"evidence\": \"Recombinant reconstitution, EMSA, co-IP, cross-linking, yeast two-hybrid and mutagenesis across two studies\",\n      \"pmids\": [\"7878029\", \"8754798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the assembled trimer on DNA in these studies\", \"Stoichiometry of cooperative DNA recognition not fully resolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Mapped the functional architecture of NF-YA: it was unclear which region mediates partner binding versus DNA contact; mutagenesis localized both to the C-terminal HAP2 domain in two separable subdomains and showed DNA-binding mutants act as dominant repressors.\",\n      \"evidence\": \"Protein affinity columns with substitution mutants, dominant-negative and reporter assays\",\n      \"pmids\": [\"8051128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how the two subdomains are spatially coordinated on DNA\", \"Activation contribution of each subunit not addressed here\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolved which subunit drives transactivation: NF-YA's role in activation was untested; in vitro transcription showed activation domains reside in NF-YB and NF-YC, not NF-YA, casting NF-YA as the DNA-targeting/regulatory subunit.\",\n      \"evidence\": \"Reconstituted in vitro transcription with subunit deletion mutants in depleted extracts\",\n      \"pmids\": [\"8662945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro assay may not capture context-dependent coactivator recruitment in vivo\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected NF-YA to genotoxic-stress gene induction: it was unknown whether NF-YA participates in DNA-damage transcriptional responses; NF-YA was shown to be induced by damage and to bind CCAAT boxes in the GADD45 and OGG1 promoters to drive their induction.\",\n      \"evidence\": \"EMSA/supershift, promoter mutagenesis, reporter assays, Western blot\",\n      \"pmids\": [\"11420680\", \"14688259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal coupling NF-YA induction to damage not defined\", \"Single-lab promoter studies without genetic loss-of-function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined post-translational control of NF-YA dosage: how NF-YA abundance is set was unclear; C-terminal lysines were shown to be ubiquitylation targets in competition with p300 acetylation, and degradation-resistant NF-YA sustained mitotic cyclins and proliferation.\",\n      \"evidence\": \"Lysine mutagenesis, cycloheximide chase, in vitro p300 acetylation, proliferation assays\",\n      \"pmids\": [\"18815279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Responsible E3 ligase not identified in this study\", \"In vivo physiological trigger for the acetylation/ubiquitylation switch unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established phospho-control of DNA binding: the functional consequence of NF-YA phosphorylation was unresolved; Ser320 was shown to contact the DNA backbone, be the major phospho-isoform, and to be required for CCAAT binding and transactivation.\",\n      \"evidence\": \"Phosphomimetic EMSA, transactivation assays, phosphoproteomics, structural modeling\",\n      \"pmids\": [\"30589568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CDK2 as the in vivo kinase inferred but not genetically validated here\", \"Cell-cycle dynamics of Ser320 occupancy at endogenous promoters not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked NF-YA to cell-cycle checkpoint control via p21: how DNA damage restrains NF-Y target promoters was unclear; p21 was shown to bind NF-YA directly and displace CDK2 at the PLK1 promoter, repressing PLK1 and enabling p53-mediated protection from mitotic death.\",\n      \"evidence\": \"Direct binding assay, reciprocal co-IP, ChIP, reporter assays, siRNA\",\n      \"pmids\": [\"24407240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of p21–NF-YA displacement at other CCAAT promoters not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a repressive co-regulator of NF-Y: it was unknown how NF-Y-driven MDR1 transcription is dampened; ZHX2 was shown to bind NF-YA and reduce NF-Y occupancy at the MDR1 promoter.\",\n      \"evidence\": \"Co-IP, ChIP, reporter mutagenesis, siRNA\",\n      \"pmids\": [\"25473899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of ZHX2–NF-YA interaction not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected NF-YA to stem cell self-renewal and isoform identity: the role of NF-YA in pluripotency was unclear; the short isoform was found enriched in ESCs and required for stem cell gene expression and NANOG genomic association.\",\n      \"evidence\": \"Dominant-negative overexpression, protein transduction, ChIP-seq correlation, differentiation assays\",\n      \"pmids\": [\"22969033\", \"16081537\", \"20616221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanistic basis for NF-Y–NANOG co-binding not resolved\", \"Protein-transduction approaches not endogenous loss-of-function\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined isoform-specific developmental functions: whether the two NF-YA splice forms differ functionally was untested; isoform overexpression showed the short form promotes proliferation while the long form drives differentiation through distinct CCAAT targets.\",\n      \"evidence\": \"Isoform-specific overexpression, expression profiling, CCAAT bioinformatics, binding assays in myoblasts; extended in prostate cancer\",\n      \"pmids\": [\"26921500\", \"34782004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which isoforms select divergent targets not defined\", \"Endogenous isoform-switch regulators unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped direct oncogenic transcriptional targets: which CCAAT genes NF-YA drives in cancer was unclear; ChIP/EMSA confirmed direct activation of EZH2, SOX2, and CDK4/CCND1, linking NF-YA to chromatin repression, stemness, and G1/S progression.\",\n      \"evidence\": \"ChIP, EMSA, reporter mutagenesis, siRNA, cell-cycle analysis across multiple cancer models\",\n      \"pmids\": [\"23360797\", \"31365524\", \"32954681\", \"32905496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-determinants of target selection across tumor types not defined\", \"Each target characterized in single tumor contexts\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked NF-YA isoforms to metabolic reprogramming: it was unclear how NF-YA controls tumor metabolism; isoform-specific studies showed the long form activates lipogenic ACACA/FASN while the short form activates gluconeogenic PCK1 driving distinct metabolic fates.\",\n      \"evidence\": \"Isoform-specific gain/loss of function, RT-PCR/Western, ROS and in vivo tumor assays\",\n      \"pmids\": [\"37268670\", \"36092708\", \"31706909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy for some metabolic targets not shown\", \"Physiological metabolic role outside tumors uncertain\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established NF-YA as a pioneer factor in development: whether NF-YA sets chromatin accessibility was unknown; conditional knockouts in cardiomyocytes and neural progenitors caused proliferation/metabolism defects and lethality, with ChIP-seq/ATAC-seq showing preferential cell-cycle promoter binding and loss of accessibility.\",\n      \"evidence\": \"Conditional KO mice, single-cell/spatial transcriptomics, ChIP-seq, SP2 co-factor interaction\",\n      \"pmids\": [\"37972593\", \"38199563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of pioneer activity (nucleosome engagement) not directly demonstrated\", \"Cofactor requirements for accessibility establishment incompletely mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a metabolism-to-stability signaling axis: how energy state controls NF-YA was unclear; a PKM1-AMPK axis was shown to phosphorylate and destabilize NFYa, coupling ATP levels to cardiomyocyte cell-cycle control.\",\n      \"evidence\": \"Pkm1 point-mutation mouse, AMPK/NFYa phospho-Western, proliferation and cardiac phenotyping\",\n      \"pmids\": [\"41536305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"AMPK phospho-sites on NFYa not mapped\", \"Direct kinase-substrate reconstitution not shown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed MDM2-controlled stability and a senescence target: how NFYA escapes degradation in cancer was unclear; circPTK2 was shown to sequester MDM2, stabilizing NFYA, which binds the FOXM1 promoter to suppress senescence.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays, siRNA, RNA-seq\",\n      \"pmids\": [\"41204684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MDM2 ubiquitylation sites on NFYA not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated stage-specific pioneer roles in germline and early embryo: whether NFYA gates meiotic entry and embryonic genome activation was unknown; germline and oocyte/zygote knockouts blocked meiotic entry, primordial follicle activation, and ZGA with loss of chromatin accessibility at target promoters.\",\n      \"evidence\": \"Conditional and acute knockouts, single-cell ATAC-seq, RNA-seq, spatial transcriptomics\",\n      \"pmids\": [\"41857150\", \"41959188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of promoter-versus-enhancer binding switch not resolved\", \"Oocyte/zygote findings remain in preprint form\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NF-YA's pioneer activity, isoform choice, and the array of post-translational inputs (CDK2/Ser320, AMPK, p300 acetylation, MDM2/circPTK2 ubiquitylation) are integrated at the chromatin level to select context-specific target programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coupling PTM state to genome-wide binding\", \"Mechanism of nucleosome engagement underlying pioneer function undefined\", \"Regulators governing isoform splice choice in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 2, 4, 5, 19, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 12, 17, 23, 31]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [4, 20, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 9, 18]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4, 19, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 23, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [7, 13, 23, 30]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [31, 36]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [30, 31, 36]}\n    ],\n    \"complexes\": [\"NF-Y/CBF heterotrimer (NF-YA/NF-YB/NF-YC)\"],\n    \"partners\": [\"NFYB\", \"NFYC\", \"CDK2\", \"EP300\", \"CDKN1A\", \"ZHX2\", \"SP2\", \"MDM2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":8,"faith_pct":75.0}}