{"gene":"NFYB","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1987,"finding":"HAP2 and HAP3 (yeast orthologs of NF-YB/NF-YC) bind interdependently to the CCAAT-containing UAS2 element of CYC1 and form a single protein-DNA complex; binding of either factor is abolished when the other is absent.","method":"Gel mobility shift assay, methylation interference footprinting, beta-galactosidase fusion tagging","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro DNA binding assay with tagged proteins, replicated across multiple labs","pmids":["2826015"],"is_preprint":false},{"year":1988,"finding":"HAP2 and HAP3 (yeast orthologs) form a stable heteromeric complex in the absence of DNA, co-purifying through four chromatographic steps, establishing that complex assembly precedes DNA binding.","method":"Affinity co-purification (LexA-HAP2 / HAP3-beta-galactosidase fusions), multi-step chromatography","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of complex from purified tagged subunits with rigorous controls","pmids":["2832951"],"is_preprint":false},{"year":1989,"finding":"HAP4 (yeast NF-YA-like activator) is a third subunit required for DNA binding by the HAP2/HAP3 heteromer at UAS2; HAP4 provides the principal transcriptional activation domain (acidic region replaceable by GAL4 activation domain).","method":"Genetic analysis, in vitro DNA binding assay, deletion mutagenesis, GAL4 activation domain swap","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 — genetic epistasis combined with in vitro reconstitution and mutagenesis, highly cited foundational study","pmids":["2676721"],"is_preprint":false},{"year":1990,"finding":"Mammalian CBF-A (NF-YB) shares a conserved 90-amino-acid domain with yeast HAP3, establishing evolutionary conservation of the CCAAT-binding subunit.","method":"Protein purification by DNA affinity chromatography, cDNA cloning, sequence alignment, in vitro transcription/translation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct protein purification and sequence identification, foundational cloning paper","pmids":["2266139"],"is_preprint":false},{"year":1993,"finding":"The DNA-binding domain of HAP2 (21 residues with critical histidines and arginines) and a 7-residue region of HAP3 (NF-YB ortholog) form a hybrid CCAAT-binding domain; mutations in HAP3 suppress DNA-binding mutations in HAP2, indicating direct inter-subunit contacts at the DNA interface.","method":"Site-directed mutagenesis, genetic suppressor analysis, in vitro DNA binding assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with inter-subunit suppression demonstrating direct contacts","pmids":["8223474"],"is_preprint":false},{"year":1995,"finding":"Recombinant rat CBF-C (NF-YC) is required together with CBF-A (NF-YB) and CBF-B (NF-YA) to form a CBF-DNA complex; CBF-A and CBF-C interact directly to form a heterodimer, and CBF-B associates only with the CBF-A/CBF-C complex, not with either subunit alone.","method":"Recombinant protein reconstitution, EMSA, co-immunoprecipitation, cross-linking","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — full in vitro reconstitution of trimeric complex with recombinant subunits, multiple orthogonal assays","pmids":["7878029"],"is_preprint":false},{"year":1996,"finding":"The histone fold motif of CBF-C (NF-YC) mediates interaction with CBF-A (NF-YB); the CBF-A/CBF-C heterodimer generates a tridentate interaction surface for CBF-B (NF-YA), defining the assembly order of the heterotrimeric NF-Y complex.","method":"Cross-linking, co-immunoprecipitation, yeast two-hybrid, mutational analysis, in vitro binding assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis combined with multiple interaction assays, clear domain mapping","pmids":["8754798"],"is_preprint":false},{"year":1996,"finding":"NF-YA and NF-YB together (but not separately) bind the CCAAT Y-box of MHC class II gene I-Aβ promoter; antisense constructs against NF-YA or NF-YB each reduce reporter gene expression from the I-Aβ promoter.","method":"EMSA, supershift assay, antisense knockdown with reporter assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal functional evidence with EMSA and reporter, single lab","pmids":["8760361"],"is_preprint":false},{"year":1997,"finding":"NF-YB and NF-YC interact with TBP in solution and associate with TFIID; short conserved stretches adjacent to their histone fold motifs are necessary for TBP binding; TBP basic-residue mutants defective in NC2 binding also fail to bind NF-YB and NF-YC.","method":"Immunopurification of holo-TFIID, sedimentation velocity centrifugation, in vitro interaction assays, mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods with domain mapping and mutagenesis","pmids":["9153318"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of the NF-YC/NF-YB subcomplex reveals that the core domains interact via histone fold motifs closely related to H2A/H2B; the αC helix of NF-YC is essential for NF-Y trimerization and serves as a binding surface for regulatory proteins such as MYC and p53.","method":"X-ray crystallography, structural modeling of NF-YB/NF-YC/DNA and full NF-Y/CCAAT complex","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation by modeling; highly cited","pmids":["12401788"],"is_preprint":false},{"year":2002,"finding":"MADS-box protein OsMADS18 forms a ternary complex with rice NF-YB1 (and mouse NF-YB as NF-YB/NF-YC dimer) through MADS and I regions; NF-YB's histone fold motif mediates this interaction; a D99S mutation in the HFM α2-helix of OsNF-YB1 restores NF-YA interaction but not DNA binding, separating these functions.","method":"Yeast two-hybrid, co-immunoprecipitation in vivo and in vitro, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro and in vivo interaction assays combined with mutagenesis separating distinct functions","pmids":["11971906"],"is_preprint":false},{"year":2010,"finding":"Dysbindin physically interacts with NF-YB in mouse brain; the Dysbindin-NF-YB complex binds the MARCKS promoter via NF-YB's CCAAT-binding activity and represses MARCKS transcription; knockdown of either protein increases MARCKS expression.","method":"Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation, DNA chip/reporter assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal assays (Y2H, IP, ChIP, reporter) in single lab","pmids":["20098743"],"is_preprint":false},{"year":2011,"finding":"IER5 binds the Cdc25B promoter and represses Cdc25B transcription through NF-YB and the co-activator p300 in AML cells; IER5 overexpression causes G2/M arrest via reduction of Cdc25B expression dependent on NF-YB and p300 displacement.","method":"ChIP, reporter assay, knockdown/overexpression with flow cytometry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay with functional phenotypic readout in single lab","pmids":["22132193"],"is_preprint":false},{"year":2015,"finding":"NFYB is a direct transcriptional target of E2F1; NFYB knockdown enhances E2F1-induced apoptosis, indicating NFYB mediates a pro-survival joint transcriptional program downstream of E2F1.","method":"Genome-wide expression analysis, NFYB knockdown, apoptosis assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — expression profiling combined with functional knockdown and apoptosis readout, single lab","pmids":["26039627"],"is_preprint":false},{"year":2017,"finding":"NFYB transactivates the E2F1 gene promoter in oxaliplatin-resistant colorectal cancer cells; the NFYB→E2F1→CHK1 axis suppresses oxaliplatin-induced apoptosis and maintains tumorigenicity in vitro and in vivo.","method":"Knockdown/overexpression, transcriptome profiling, in vitro and in vivo phenotype assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement confirmed by gene knockdown cascade with functional in vitro/in vivo readouts","pmids":["29203250"],"is_preprint":false},{"year":2020,"finding":"C. elegans NFYB-1 (NF-Y beta subunit) regulates mitochondrial gene expression, oxygen consumption, mitochondrial morphology, and cardiolipin levels; NFYB-1 represses lysosomal prosaposin, and limiting prosaposin restores cardiolipin production, mitochondrial function, and longevity in nfyb-1 mutants.","method":"RNAi screens, multi-omics (transcriptomics + metabolomics), genetic epistasis (prosaposin limitation rescues nfyb-1), cardiolipin supplementation rescue","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RNAi, multi-omics, epistasis, metabolite rescue) demonstrating mechanistic pathway","pmids":["32694663"],"is_preprint":false},{"year":2021,"finding":"NFYB binds the STK33 promoter and activates STK33 transcription; STK33 promotes cisplatin resistance in DLBCL by activating the Hedgehog signaling pathway downstream of NFYB.","method":"ChIP, luciferase reporter, knockdown/overexpression with drug sensitivity assays","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, ChIP and reporter with functional drug resistance readout","pmids":["34536775"],"is_preprint":false},{"year":2021,"finding":"IER5 upregulation after irradiation induces release of co-activator p300 from the Cdc25B promoter through interaction with NF-YB, leading to transcriptional repression of Cdc25B via the NF-YB binding site; both Sp1/Sp3 and NF-YB binding sites are required for irradiation-mediated Cdc25B regulation.","method":"ChIP assay, dual-luciferase reporter, site-directed mutagenesis of promoter elements","journal":"Toxicology research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP, mutagenesis, and reporter assays providing mechanistic detail, single lab","pmids":["34484679"],"is_preprint":false},{"year":2022,"finding":"NFYB binds the MBTD1 promoter to activate MBTD1 transcription; lncRNA H19 recruits NFYB to increase MBTD1 expression without altering NFYB levels, promoting doxorubicin resistance in lymphoma cells.","method":"Luciferase reporter assay, ChIP-qPCR, H19 knockdown/overexpression with drug resistance readout","journal":"Molecular biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assays with functional readout, single lab","pmids":["36434485"],"is_preprint":false},{"year":2023,"finding":"NFYB activates HDAC5 transcription by binding the HDAC5 promoter; HDAC5 in turn inhibits SHMT2 expression, and the NFYB→HDAC5→SHMT2 axis reduces glycolysis and temozolomide resistance in GBM cells.","method":"ChIP, dual-luciferase reporter, overexpression/knockdown with metabolic and cell viability assays","journal":"Journal of neuropathology and experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assays with functional rescue experiment, single lab","pmids":["37742129"],"is_preprint":false},{"year":2024,"finding":"E2F4, NF-YA, and NF-YB act together as transcription factors at the E2F7 promoter; coptisine inhibits HCC by downregulating these transcription factors, reducing E2F7 expression and inducing G2/M arrest.","method":"Promoter fragmentation experiments, ChIP, RNA-seq, overexpression/inhibition with cell cycle assays","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and promoter assays combined with functional cell cycle readout, single lab","pmids":["38795876"],"is_preprint":false},{"year":2025,"finding":"NFYB (as part of the NF-Y pioneer transcription factor complex) cooperates with the menin-MLL1 chromatin complex to regulate oncogenic gene transcription in HCC; NFYB knockout combined with menin inhibition causes significantly increased HCC cell death, placing NF-Y as a compensatory transcriptional activator at sites of menin-MLL1 dissociation.","method":"CRISPR/Cas9 epigenome-focused screens, chromatin accessibility (ATAC-seq), ChIP-seq, genetic epistasis (NFYB KO + menin inhibitor)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR screens with chromatin accessibility and epistasis analysis, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.04.05.647381"],"is_preprint":true}],"current_model":"NFYB (NF-YB/CBF-A) is the histone fold domain-containing subunit of the heterotrimeric NF-Y transcription factor complex: it forms an obligate heterodimer with NF-YC via histone fold motifs (structurally resolved by X-ray crystallography), this dimer then recruits NF-YA to assemble the trimer that binds CCAAT promoter elements with high specificity; beyond canonical CCAAT-driven transcription, NF-YB also interacts with TBP/TFIID to couple CCAAT-bound complexes to the basal transcription machinery, and in vertebrates it transactivates target genes (E2F1, STK33, HDAC5, MBTD1, Cdc25B) in contexts including cell cycle control, drug resistance, and mitochondrial/metabolic regulation, while in C. elegans NFYB-1 represses lysosomal prosaposin to coordinate lysosome-to-mitochondria lipid signaling and organismal longevity."},"narrative":{"teleology":[{"year":1987,"claim":"Establishing that CCAAT-box binding requires the cooperative, interdependent action of two protein subunits (HAP2 and HAP3, the NF-YA and NF-YB orthologs) resolved the composition question for the CCAAT-binding factor.","evidence":"Gel shift and methylation interference with tagged yeast HAP2/HAP3 on CYC1 UAS2","pmids":["2826015"],"confidence":"High","gaps":["Whether HAP2/HAP3 form a pre-assembled complex before DNA engagement was untested","Mammalian orthologs not yet identified"]},{"year":1988,"claim":"Demonstrating that HAP2 and HAP3 form a stable heteromeric complex in the absence of DNA established that subunit assembly precedes DNA binding, distinguishing this factor from cooperative DNA-nucleated assemblies.","evidence":"Affinity co-purification of LexA-HAP2/HAP3-β-gal fusions through four chromatographic steps","pmids":["2832951"],"confidence":"High","gaps":["Third subunit (HAP4/NF-YA) not yet incorporated","Structural basis of the interaction unknown"]},{"year":1989,"claim":"Identifying HAP4 as a third subunit required for DNA binding and as the principal activation domain carrier defined the heterotrimeric architecture and division of labor within the complex.","evidence":"Genetic epistasis, in vitro reconstitution, and GAL4 activation-domain swap in yeast","pmids":["2676721"],"confidence":"High","gaps":["Mammalian trimer not yet reconstituted","Whether the trimeric model applies across eukaryotes was unresolved"]},{"year":1990,"claim":"Cloning mammalian CBF-A (NF-YB) and revealing a 90-amino-acid domain conserved with yeast HAP3 established deep evolutionary conservation and enabled biochemical study in vertebrate systems.","evidence":"DNA affinity chromatography, cDNA cloning, and sequence alignment","pmids":["2266139"],"confidence":"High","gaps":["Mammalian NF-YC not yet cloned","No reconstituted mammalian trimer"]},{"year":1995,"claim":"Reconstituting the mammalian NF-Y trimer from recombinant subunits and demonstrating that NF-YA associates only with the preformed NF-YB/NF-YC dimer defined the obligate assembly order of the complex.","evidence":"Recombinant protein reconstitution, EMSA, co-IP, and cross-linking with rat subunits","pmids":["7878029"],"confidence":"High","gaps":["Structural basis of the NF-YB/NF-YC dimer unknown","NF-YA-binding surface on the dimer not mapped"]},{"year":1996,"claim":"Mapping the histone fold motif as the NF-YB/NF-YC dimerization interface and showing the dimer creates a tridentate surface for NF-YA identified the molecular logic of trimer assembly.","evidence":"Cross-linking, co-IP, yeast two-hybrid, and mutational analysis","pmids":["8754798"],"confidence":"High","gaps":["No atomic-resolution structure","How the histone fold contacts DNA remained speculative"]},{"year":1997,"claim":"Showing that NF-YB and NF-YC physically interact with TBP/TFIID via short sequences flanking the histone fold domain linked the CCAAT-bound complex to the basal transcription machinery, explaining how NF-Y activates transcription.","evidence":"TFIID immunopurification, sedimentation, mutagenesis of TBP basic residues","pmids":["9153318"],"confidence":"High","gaps":["Whether the NF-Y–TBP interaction is required in vivo at endogenous promoters was not tested","Contribution relative to other coactivators unknown"]},{"year":2002,"claim":"Solving the crystal structure of the NF-YB/NF-YC core confirmed an H2A/H2B-like histone fold dimer and revealed that the αC helix of NF-YC serves as an interaction platform for regulatory proteins (MYC, p53), providing the first structural framework for NF-Y regulation.","evidence":"X-ray crystallography with structural modeling of DNA-bound complex","pmids":["12401788"],"confidence":"High","gaps":["Full trimer–DNA co-crystal not obtained","Regulatory protein complexes not structurally resolved"]},{"year":2010,"claim":"Identifying Dysbindin as a physical partner that co-occupies CCAAT elements with NF-YB to repress MARCKS transcription in mouse brain expanded NF-YB function into neuronal gene regulation and showed the trimer can act as a repressor in specific contexts.","evidence":"Yeast two-hybrid, co-IP, ChIP, and reporter assay in mouse brain","pmids":["20098743"],"confidence":"Medium","gaps":["Single-lab study","Whether repression is direct or requires additional co-repressors is unclear","In vivo relevance in brain physiology not tested"]},{"year":2011,"claim":"Demonstrating that IER5 displaces co-activator p300 from the Cdc25B promoter through NF-YB, causing G2/M arrest, established NF-YB as a cell cycle checkpoint effector through cofactor exchange at CCAAT sites.","evidence":"ChIP, reporter assay, overexpression with flow cytometry in AML cells","pmids":["22132193","34484679"],"confidence":"Medium","gaps":["Mechanism by which IER5 displaces p300 is not fully resolved","Generality beyond Cdc25B promoter unknown"]},{"year":2017,"claim":"Establishing the NFYB→E2F1→CHK1 transcriptional axis in oxaliplatin-resistant colorectal cancer positioned NF-YB as a direct upstream driver of chemoresistance through checkpoint kinase signaling.","evidence":"Knockdown/overexpression cascade, transcriptome profiling, in vivo xenograft assays","pmids":["29203250"],"confidence":"Medium","gaps":["Direct NFYB binding to E2F1 promoter CCAAT box not demonstrated by ChIP in this study","Whether NFYB acts as part of the trimer or independently was not distinguished"]},{"year":2020,"claim":"Showing that C. elegans NFYB-1 represses lysosomal prosaposin to maintain cardiolipin levels and mitochondrial function revealed a conserved transcription factor operating in a lysosome-to-mitochondria lipid-signaling axis that controls longevity.","evidence":"RNAi screen, transcriptomics + metabolomics, genetic epistasis with prosaposin, cardiolipin supplementation rescue","pmids":["32694663"],"confidence":"High","gaps":["Whether the prosaposin-cardiolipin axis is conserved in mammals is unknown","Direct promoter binding at prosaposin locus not shown by ChIP"]},{"year":2022,"claim":"Multiple studies showed NFYB directly transactivates diverse target promoters (STK33, MBTD1, HDAC5) to drive chemoresistance in lymphoma and glioblastoma, broadening the cancer-relevant transcriptional program of NF-YB beyond E2F1.","evidence":"ChIP-qPCR, luciferase reporters, knockdown/overexpression with drug sensitivity assays across multiple cancer types","pmids":["34536775","36434485","37742129"],"confidence":"Medium","gaps":["Each axis characterized in single-lab studies in distinct cancer types","Whether these targets are NF-Y trimer-dependent versus NFYB-autonomous is not addressed","In vivo validation limited"]},{"year":2024,"claim":"Identifying NF-YA/NF-YB cooperation with E2F4 at the E2F7 promoter linked NF-Y to G2/M control in hepatocellular carcinoma and expanded the repertoire of E2F-family genes regulated by NF-Y.","evidence":"Promoter fragmentation, ChIP, RNA-seq, cell cycle assays in HCC cells","pmids":["38795876"],"confidence":"Medium","gaps":["Single-lab study","Functional contribution of NF-YB versus NF-YA at this promoter not dissected"]},{"year":null,"claim":"It remains unknown how NF-YB discriminates between activating and repressing roles at different promoters, whether NFYB can function outside the canonical NF-Y trimer in mammalian cells, and whether the lysosome-to-mitochondria lipid axis controlled by NFYB is conserved in vertebrates.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full trimer–DNA co-crystal structure at atomic resolution","Genome-wide ChIP-seq of NFYB alone (versus trimer) not reported in the timeline","Mammalian in vivo knockout phenotype not characterized in the timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[7,12,13,14,16,18,19,20]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,7,11]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,11,12,14,16,18,19,20]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5,7,8,11,12,14,16,18,19,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12,17,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,14]}],"complexes":["NF-Y (CBF) heterotrimer"],"partners":["NFYA","NFYC","TBP","DTNBP1","IER5","EP300"],"other_free_text":[]},"mechanistic_narrative":"NFYB is the histone fold domain-containing subunit of the heterotrimeric NF-Y (CBF) transcription factor, a sequence-specific activator of CCAAT-box promoters that functions broadly in gene regulation, cell cycle control, drug resistance, and mitochondrial metabolism. NFYB heterodimerizes with NF-YC through reciprocal histone fold motifs structurally homologous to H2A/H2B, generating a platform that recruits NF-YA to complete the DNA-binding trimer [PMID:7878029, PMID:12401788]. Beyond CCAAT-dependent transcription, NFYB contacts TBP/TFIID to couple promoter-bound NF-Y to the basal machinery [PMID:9153318], and directly transactivates genes including E2F1, STK33, HDAC5, and MBTD1, linking NF-Y to chemoresistance and cell cycle checkpoint pathways [PMID:29203250, PMID:34536775, PMID:37742129]. In C. elegans, NFYB-1 represses lysosomal prosaposin to coordinate a lysosome-to-mitochondria lipid-signaling axis that controls cardiolipin levels, mitochondrial function, and organismal longevity [PMID:32694663]."},"prefetch_data":{"uniprot":{"accession":"P25208","full_name":"Nuclear transcription factor Y subunit beta","aliases":["CAAT box DNA-binding protein subunit B","Nuclear transcription factor Y subunit B","NF-YB"],"length_aa":207,"mass_kda":22.8,"function":"Component of the sequence-specific heterotrimeric transcription factor (NF-Y) which specifically recognizes a 5'-CCAAT-3' box motif found in the promoters of its target genes. NF-Y can function as both an activator and a repressor, depending on its interacting cofactors","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P25208/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NFYB","classification":"Common Essential","n_dependent_lines":1007,"n_total_lines":1208,"dependency_fraction":0.8336092715231788},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NFYB","total_profiled":1310},"omim":[{"mim_id":"621274","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 152; CCDC152","url":"https://www.omim.org/entry/621274"},{"mim_id":"616674","title":"SPINDLE- AND KINETOCHORE-ASSOCIATED COMPLEX, SUBUNIT 2; SKA2","url":"https://www.omim.org/entry/616674"},{"mim_id":"615920","title":"PROLINE-RICH PROTEIN 11; PRR11","url":"https://www.omim.org/entry/615920"},{"mim_id":"615385","title":"MICRO RNA 485; MIR485","url":"https://www.omim.org/entry/615385"},{"mim_id":"607267","title":"POLYMERASE, DNA, EPSILON-3; POLE3","url":"https://www.omim.org/entry/607267"}],"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/NFYB"},"hgnc":{"alias_symbol":["CBF-A","HAP3","NF-YB"],"prev_symbol":[]},"alphafold":{"accession":"P25208","domains":[{"cath_id":"1.10.20.10","chopping":"53-146","consensus_level":"medium","plddt":95.7766,"start":53,"end":146}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25208","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25208-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25208-F1-predicted_aligned_error_v6.png","plddt_mean":69.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NFYB","jax_strain_url":"https://www.jax.org/strain/search?query=NFYB"},"sequence":{"accession":"P25208","fasta_url":"https://rest.uniprot.org/uniprotkb/P25208.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25208/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25208"}},"corpus_meta":[{"pmid":"2676721","id":"PMC_2676721","title":"Identification and characterization of HAP4: a third component of the CCAAT-bound HAP2/HAP3 heteromer.","date":"1989","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/2676721","citation_count":349,"is_preprint":false},{"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 HAP2 and HAP3.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7878029","citation_count":253,"is_preprint":false},{"pmid":"12401788","id":"PMC_12401788","title":"The NF-YB/NF-YC structure gives insight into DNA binding and transcription regulation by CCAAT factor NF-Y.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12401788","citation_count":233,"is_preprint":false},{"pmid":"2826015","id":"PMC_2826015","title":"Yeast HAP2 and HAP3 activators both bind to the CYC1 upstream activation site, UAS2, in an interdependent manner.","date":"1987","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/2826015","citation_count":211,"is_preprint":false},{"pmid":"19207209","id":"PMC_19207209","title":"Arabidopsis NF-YB subunits LEC1 and LEC1-LIKE activate transcription by interacting with seed-specific ABRE-binding factors.","date":"2009","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19207209","citation_count":169,"is_preprint":false},{"pmid":"8223474","id":"PMC_8223474","title":"Mutations in yeast HAP2/HAP3 define a hybrid CCAAT box binding domain.","date":"1993","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8223474","citation_count":136,"is_preprint":false},{"pmid":"8754798","id":"PMC_8754798","title":"Determination of functional domains in the C subunit of the CCAAT-binding factor (CBF) necessary for formation of a CBF-DNA complex: CBF-B interacts simultaneously 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\"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro DNA binding assay with tagged proteins, replicated across multiple labs\",\n      \"pmids\": [\"2826015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"HAP2 and HAP3 (yeast orthologs) form a stable heteromeric complex in the absence of DNA, co-purifying through four chromatographic steps, establishing that complex assembly precedes DNA binding.\",\n      \"method\": \"Affinity co-purification (LexA-HAP2 / HAP3-beta-galactosidase fusions), multi-step chromatography\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of complex from purified tagged subunits with rigorous controls\",\n      \"pmids\": [\"2832951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"HAP4 (yeast NF-YA-like activator) is a third subunit required for DNA binding by the HAP2/HAP3 heteromer at UAS2; HAP4 provides the principal transcriptional activation domain (acidic region replaceable by GAL4 activation domain).\",\n      \"method\": \"Genetic analysis, in vitro DNA binding assay, deletion mutagenesis, GAL4 activation domain swap\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — genetic epistasis combined with in vitro reconstitution and mutagenesis, highly cited foundational study\",\n      \"pmids\": [\"2676721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Mammalian CBF-A (NF-YB) shares a conserved 90-amino-acid domain with yeast HAP3, establishing evolutionary conservation of the CCAAT-binding subunit.\",\n      \"method\": \"Protein purification by DNA affinity chromatography, cDNA cloning, sequence alignment, in vitro transcription/translation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein purification and sequence identification, foundational cloning paper\",\n      \"pmids\": [\"2266139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The DNA-binding domain of HAP2 (21 residues with critical histidines and arginines) and a 7-residue region of HAP3 (NF-YB ortholog) form a hybrid CCAAT-binding domain; mutations in HAP3 suppress DNA-binding mutations in HAP2, indicating direct inter-subunit contacts at the DNA interface.\",\n      \"method\": \"Site-directed mutagenesis, genetic suppressor analysis, in vitro DNA binding assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with inter-subunit suppression demonstrating direct contacts\",\n      \"pmids\": [\"8223474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Recombinant rat CBF-C (NF-YC) is required together with CBF-A (NF-YB) and CBF-B (NF-YA) to form a CBF-DNA complex; CBF-A and CBF-C interact directly to form a heterodimer, and CBF-B associates only with the CBF-A/CBF-C complex, not with either subunit alone.\",\n      \"method\": \"Recombinant protein reconstitution, EMSA, co-immunoprecipitation, cross-linking\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — full in vitro reconstitution of trimeric complex with recombinant subunits, multiple orthogonal assays\",\n      \"pmids\": [\"7878029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The histone fold motif of CBF-C (NF-YC) mediates interaction with CBF-A (NF-YB); the CBF-A/CBF-C heterodimer generates a tridentate interaction surface for CBF-B (NF-YA), defining the assembly order of the heterotrimeric NF-Y complex.\",\n      \"method\": \"Cross-linking, co-immunoprecipitation, yeast two-hybrid, mutational analysis, in vitro binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis combined with multiple interaction assays, clear domain mapping\",\n      \"pmids\": [\"8754798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NF-YA and NF-YB together (but not separately) bind the CCAAT Y-box of MHC class II gene I-Aβ promoter; antisense constructs against NF-YA or NF-YB each reduce reporter gene expression from the I-Aβ promoter.\",\n      \"method\": \"EMSA, supershift assay, antisense knockdown with reporter assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional evidence with EMSA and reporter, single lab\",\n      \"pmids\": [\"8760361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"NF-YB and NF-YC interact with TBP in solution and associate with TFIID; short conserved stretches adjacent to their histone fold motifs are necessary for TBP binding; TBP basic-residue mutants defective in NC2 binding also fail to bind NF-YB and NF-YC.\",\n      \"method\": \"Immunopurification of holo-TFIID, sedimentation velocity centrifugation, in vitro interaction assays, mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods with domain mapping and mutagenesis\",\n      \"pmids\": [\"9153318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of the NF-YC/NF-YB subcomplex reveals that the core domains interact via histone fold motifs closely related to H2A/H2B; the αC helix of NF-YC is essential for NF-Y trimerization and serves as a binding surface for regulatory proteins such as MYC and p53.\",\n      \"method\": \"X-ray crystallography, structural modeling of NF-YB/NF-YC/DNA and full NF-Y/CCAAT complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation by modeling; highly cited\",\n      \"pmids\": [\"12401788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"MADS-box protein OsMADS18 forms a ternary complex with rice NF-YB1 (and mouse NF-YB as NF-YB/NF-YC dimer) through MADS and I regions; NF-YB's histone fold motif mediates this interaction; a D99S mutation in the HFM α2-helix of OsNF-YB1 restores NF-YA interaction but not DNA binding, separating these functions.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in vivo and in vitro, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro and in vivo interaction assays combined with mutagenesis separating distinct functions\",\n      \"pmids\": [\"11971906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Dysbindin physically interacts with NF-YB in mouse brain; the Dysbindin-NF-YB complex binds the MARCKS promoter via NF-YB's CCAAT-binding activity and represses MARCKS transcription; knockdown of either protein increases MARCKS expression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, chromatin immunoprecipitation, DNA chip/reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays (Y2H, IP, ChIP, reporter) in single lab\",\n      \"pmids\": [\"20098743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IER5 binds the Cdc25B promoter and represses Cdc25B transcription through NF-YB and the co-activator p300 in AML cells; IER5 overexpression causes G2/M arrest via reduction of Cdc25B expression dependent on NF-YB and p300 displacement.\",\n      \"method\": \"ChIP, reporter assay, knockdown/overexpression with flow cytometry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay with functional phenotypic readout in single lab\",\n      \"pmids\": [\"22132193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NFYB is a direct transcriptional target of E2F1; NFYB knockdown enhances E2F1-induced apoptosis, indicating NFYB mediates a pro-survival joint transcriptional program downstream of E2F1.\",\n      \"method\": \"Genome-wide expression analysis, NFYB knockdown, apoptosis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — expression profiling combined with functional knockdown and apoptosis readout, single lab\",\n      \"pmids\": [\"26039627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NFYB transactivates the E2F1 gene promoter in oxaliplatin-resistant colorectal cancer cells; the NFYB→E2F1→CHK1 axis suppresses oxaliplatin-induced apoptosis and maintains tumorigenicity in vitro and in vivo.\",\n      \"method\": \"Knockdown/overexpression, transcriptome profiling, in vitro and in vivo phenotype assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement confirmed by gene knockdown cascade with functional in vitro/in vivo readouts\",\n      \"pmids\": [\"29203250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"C. elegans NFYB-1 (NF-Y beta subunit) regulates mitochondrial gene expression, oxygen consumption, mitochondrial morphology, and cardiolipin levels; NFYB-1 represses lysosomal prosaposin, and limiting prosaposin restores cardiolipin production, mitochondrial function, and longevity in nfyb-1 mutants.\",\n      \"method\": \"RNAi screens, multi-omics (transcriptomics + metabolomics), genetic epistasis (prosaposin limitation rescues nfyb-1), cardiolipin supplementation rescue\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNAi, multi-omics, epistasis, metabolite rescue) demonstrating mechanistic pathway\",\n      \"pmids\": [\"32694663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NFYB binds the STK33 promoter and activates STK33 transcription; STK33 promotes cisplatin resistance in DLBCL by activating the Hedgehog signaling pathway downstream of NFYB.\",\n      \"method\": \"ChIP, luciferase reporter, knockdown/overexpression with drug sensitivity assays\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, ChIP and reporter with functional drug resistance readout\",\n      \"pmids\": [\"34536775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IER5 upregulation after irradiation induces release of co-activator p300 from the Cdc25B promoter through interaction with NF-YB, leading to transcriptional repression of Cdc25B via the NF-YB binding site; both Sp1/Sp3 and NF-YB binding sites are required for irradiation-mediated Cdc25B regulation.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter, site-directed mutagenesis of promoter elements\",\n      \"journal\": \"Toxicology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP, mutagenesis, and reporter assays providing mechanistic detail, single lab\",\n      \"pmids\": [\"34484679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NFYB binds the MBTD1 promoter to activate MBTD1 transcription; lncRNA H19 recruits NFYB to increase MBTD1 expression without altering NFYB levels, promoting doxorubicin resistance in lymphoma cells.\",\n      \"method\": \"Luciferase reporter assay, ChIP-qPCR, H19 knockdown/overexpression with drug resistance readout\",\n      \"journal\": \"Molecular biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays with functional readout, single lab\",\n      \"pmids\": [\"36434485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NFYB activates HDAC5 transcription by binding the HDAC5 promoter; HDAC5 in turn inhibits SHMT2 expression, and the NFYB→HDAC5→SHMT2 axis reduces glycolysis and temozolomide resistance in GBM cells.\",\n      \"method\": \"ChIP, dual-luciferase reporter, overexpression/knockdown with metabolic and cell viability assays\",\n      \"journal\": \"Journal of neuropathology and experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assays with functional rescue experiment, single lab\",\n      \"pmids\": [\"37742129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"E2F4, NF-YA, and NF-YB act together as transcription factors at the E2F7 promoter; coptisine inhibits HCC by downregulating these transcription factors, reducing E2F7 expression and inducing G2/M arrest.\",\n      \"method\": \"Promoter fragmentation experiments, ChIP, RNA-seq, overexpression/inhibition with cell cycle assays\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and promoter assays combined with functional cell cycle readout, single lab\",\n      \"pmids\": [\"38795876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NFYB (as part of the NF-Y pioneer transcription factor complex) cooperates with the menin-MLL1 chromatin complex to regulate oncogenic gene transcription in HCC; NFYB knockout combined with menin inhibition causes significantly increased HCC cell death, placing NF-Y as a compensatory transcriptional activator at sites of menin-MLL1 dissociation.\",\n      \"method\": \"CRISPR/Cas9 epigenome-focused screens, chromatin accessibility (ATAC-seq), ChIP-seq, genetic epistasis (NFYB KO + menin inhibitor)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screens with chromatin accessibility and epistasis analysis, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.04.05.647381\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NFYB (NF-YB/CBF-A) is the histone fold domain-containing subunit of the heterotrimeric NF-Y transcription factor complex: it forms an obligate heterodimer with NF-YC via histone fold motifs (structurally resolved by X-ray crystallography), this dimer then recruits NF-YA to assemble the trimer that binds CCAAT promoter elements with high specificity; beyond canonical CCAAT-driven transcription, NF-YB also interacts with TBP/TFIID to couple CCAAT-bound complexes to the basal transcription machinery, and in vertebrates it transactivates target genes (E2F1, STK33, HDAC5, MBTD1, Cdc25B) in contexts including cell cycle control, drug resistance, and mitochondrial/metabolic regulation, while in C. elegans NFYB-1 represses lysosomal prosaposin to coordinate lysosome-to-mitochondria lipid signaling and organismal longevity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NFYB is the histone fold domain-containing subunit of the heterotrimeric NF-Y (CBF) transcription factor, a sequence-specific activator of CCAAT-box promoters that functions broadly in gene regulation, cell cycle control, drug resistance, and mitochondrial metabolism. NFYB heterodimerizes with NF-YC through reciprocal histone fold motifs structurally homologous to H2A/H2B, generating a platform that recruits NF-YA to complete the DNA-binding trimer [PMID:7878029, PMID:12401788]. Beyond CCAAT-dependent transcription, NFYB contacts TBP/TFIID to couple promoter-bound NF-Y to the basal machinery [PMID:9153318], and directly transactivates genes including E2F1, STK33, HDAC5, and MBTD1, linking NF-Y to chemoresistance and cell cycle checkpoint pathways [PMID:29203250, PMID:34536775, PMID:37742129]. In C. elegans, NFYB-1 represses lysosomal prosaposin to coordinate a lysosome-to-mitochondria lipid-signaling axis that controls cardiolipin levels, mitochondrial function, and organismal longevity [PMID:32694663].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Establishing that CCAAT-box binding requires the cooperative, interdependent action of two protein subunits (HAP2 and HAP3, the NF-YA and NF-YB orthologs) resolved the composition question for the CCAAT-binding factor.\",\n      \"evidence\": \"Gel shift and methylation interference with tagged yeast HAP2/HAP3 on CYC1 UAS2\",\n      \"pmids\": [\"2826015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HAP2/HAP3 form a pre-assembled complex before DNA engagement was untested\", \"Mammalian orthologs not yet identified\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Demonstrating that HAP2 and HAP3 form a stable heteromeric complex in the absence of DNA established that subunit assembly precedes DNA binding, distinguishing this factor from cooperative DNA-nucleated assemblies.\",\n      \"evidence\": \"Affinity co-purification of LexA-HAP2/HAP3-β-gal fusions through four chromatographic steps\",\n      \"pmids\": [\"2832951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Third subunit (HAP4/NF-YA) not yet incorporated\", \"Structural basis of the interaction unknown\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Identifying HAP4 as a third subunit required for DNA binding and as the principal activation domain carrier defined the heterotrimeric architecture and division of labor within the complex.\",\n      \"evidence\": \"Genetic epistasis, in vitro reconstitution, and GAL4 activation-domain swap in yeast\",\n      \"pmids\": [\"2676721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian trimer not yet reconstituted\", \"Whether the trimeric model applies across eukaryotes was unresolved\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Cloning mammalian CBF-A (NF-YB) and revealing a 90-amino-acid domain conserved with yeast HAP3 established deep evolutionary conservation and enabled biochemical study in vertebrate systems.\",\n      \"evidence\": \"DNA affinity chromatography, cDNA cloning, and sequence alignment\",\n      \"pmids\": [\"2266139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian NF-YC not yet cloned\", \"No reconstituted mammalian trimer\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Reconstituting the mammalian NF-Y trimer from recombinant subunits and demonstrating that NF-YA associates only with the preformed NF-YB/NF-YC dimer defined the obligate assembly order of the complex.\",\n      \"evidence\": \"Recombinant protein reconstitution, EMSA, co-IP, and cross-linking with rat subunits\",\n      \"pmids\": [\"7878029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the NF-YB/NF-YC dimer unknown\", \"NF-YA-binding surface on the dimer not mapped\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapping the histone fold motif as the NF-YB/NF-YC dimerization interface and showing the dimer creates a tridentate surface for NF-YA identified the molecular logic of trimer assembly.\",\n      \"evidence\": \"Cross-linking, co-IP, yeast two-hybrid, and mutational analysis\",\n      \"pmids\": [\"8754798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure\", \"How the histone fold contacts DNA remained speculative\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that NF-YB and NF-YC physically interact with TBP/TFIID via short sequences flanking the histone fold domain linked the CCAAT-bound complex to the basal transcription machinery, explaining how NF-Y activates transcription.\",\n      \"evidence\": \"TFIID immunopurification, sedimentation, mutagenesis of TBP basic residues\",\n      \"pmids\": [\"9153318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the NF-Y–TBP interaction is required in vivo at endogenous promoters was not tested\", \"Contribution relative to other coactivators unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Solving the crystal structure of the NF-YB/NF-YC core confirmed an H2A/H2B-like histone fold dimer and revealed that the αC helix of NF-YC serves as an interaction platform for regulatory proteins (MYC, p53), providing the first structural framework for NF-Y regulation.\",\n      \"evidence\": \"X-ray crystallography with structural modeling of DNA-bound complex\",\n      \"pmids\": [\"12401788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full trimer–DNA co-crystal not obtained\", \"Regulatory protein complexes not structurally resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identifying Dysbindin as a physical partner that co-occupies CCAAT elements with NF-YB to repress MARCKS transcription in mouse brain expanded NF-YB function into neuronal gene regulation and showed the trimer can act as a repressor in specific contexts.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, ChIP, and reporter assay in mouse brain\",\n      \"pmids\": [\"20098743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Whether repression is direct or requires additional co-repressors is unclear\", \"In vivo relevance in brain physiology not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that IER5 displaces co-activator p300 from the Cdc25B promoter through NF-YB, causing G2/M arrest, established NF-YB as a cell cycle checkpoint effector through cofactor exchange at CCAAT sites.\",\n      \"evidence\": \"ChIP, reporter assay, overexpression with flow cytometry in AML cells\",\n      \"pmids\": [\"22132193\", \"34484679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which IER5 displaces p300 is not fully resolved\", \"Generality beyond Cdc25B promoter unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing the NFYB→E2F1→CHK1 transcriptional axis in oxaliplatin-resistant colorectal cancer positioned NF-YB as a direct upstream driver of chemoresistance through checkpoint kinase signaling.\",\n      \"evidence\": \"Knockdown/overexpression cascade, transcriptome profiling, in vivo xenograft assays\",\n      \"pmids\": [\"29203250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NFYB binding to E2F1 promoter CCAAT box not demonstrated by ChIP in this study\", \"Whether NFYB acts as part of the trimer or independently was not distinguished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that C. elegans NFYB-1 represses lysosomal prosaposin to maintain cardiolipin levels and mitochondrial function revealed a conserved transcription factor operating in a lysosome-to-mitochondria lipid-signaling axis that controls longevity.\",\n      \"evidence\": \"RNAi screen, transcriptomics + metabolomics, genetic epistasis with prosaposin, cardiolipin supplementation rescue\",\n      \"pmids\": [\"32694663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the prosaposin-cardiolipin axis is conserved in mammals is unknown\", \"Direct promoter binding at prosaposin locus not shown by ChIP\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple studies showed NFYB directly transactivates diverse target promoters (STK33, MBTD1, HDAC5) to drive chemoresistance in lymphoma and glioblastoma, broadening the cancer-relevant transcriptional program of NF-YB beyond E2F1.\",\n      \"evidence\": \"ChIP-qPCR, luciferase reporters, knockdown/overexpression with drug sensitivity assays across multiple cancer types\",\n      \"pmids\": [\"34536775\", \"36434485\", \"37742129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each axis characterized in single-lab studies in distinct cancer types\", \"Whether these targets are NF-Y trimer-dependent versus NFYB-autonomous is not addressed\", \"In vivo validation limited\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying NF-YA/NF-YB cooperation with E2F4 at the E2F7 promoter linked NF-Y to G2/M control in hepatocellular carcinoma and expanded the repertoire of E2F-family genes regulated by NF-Y.\",\n      \"evidence\": \"Promoter fragmentation, ChIP, RNA-seq, cell cycle assays in HCC cells\",\n      \"pmids\": [\"38795876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Functional contribution of NF-YB versus NF-YA at this promoter not dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how NF-YB discriminates between activating and repressing roles at different promoters, whether NFYB can function outside the canonical NF-Y trimer in mammalian cells, and whether the lysosome-to-mitochondria lipid axis controlled by NFYB is conserved in vertebrates.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full trimer–DNA co-crystal structure at atomic resolution\", \"Genome-wide ChIP-seq of NFYB alone (versus trimer) not reported in the timeline\", \"Mammalian in vivo knockout phenotype not characterized in the timeline\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [7, 12, 13, 14, 16, 18, 19, 20]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 7, 11]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 11, 12, 14, 16, 18, 19, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5, 7, 8, 11, 12, 14, 16, 18, 19, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12, 17, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"complexes\": [\n      \"NF-Y (CBF) heterotrimer\"\n    ],\n    \"partners\": [\n      \"NFYA\",\n      \"NFYC\",\n      \"TBP\",\n      \"DTNBP1\",\n      \"IER5\",\n      \"EP300\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}