Alternative titles; symbols
HGNC Approved Gene Symbol: NFYA
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:41,072,974-41,102,403 (from NCBI)
NFYA and NFYB (189904) encode the 2 subunits, both necessary for DNA binding, of NF-Y, a transcription factor thought to be essential for expression of the class II genes of the major histocompatibility complex (MHC; see 142800). NF-Y recognizes a CCAAT motif upstream of gene promoters and is probably involved in the regulation of a variety of genes, including those for albumin (103600), alpha-globin (141800), collagen (see 120150), and beta-actin (102630) (summary by Li et al., 1991).
Becker et al. (1991) reported the isolation of a HeLa cDNA whose expression in S. cerevisiae corrected the respiratory defect in a strain bearing a Hap2 deletion. The cDNA encoding the human Hap2 homolog encodes a protein of 257 amino acids which has a 62-amino acid C-terminal region that shares 73% identity with the essential core region of Hap2. Hap2, Hap3, and Hap4 form the Hap complex, which is required for the expression of respiration in Saccharomyces cerevisiae--in particular, for expression of the principal isoform of cytochrome C (CYC1; 123980). In the yeast, 3 proteins are associated in a heteromeric complex that binds to an upstream activation sequence in the CYC1 promoter. Like Hap2/3/4, CYP in the human consists of a heteromeric association of at least 2 components, CP1A and CP1B, both of which are required for binding. Most strikingly, the subunits of CP1 and Hap2/3/4 can be interchanged in vitro. Thus, CP1 likely represents the human homolog of the yeast Hap complex, with the CP1B fraction containing the Hap2 homolog and the CP1A fraction containing a Hap3 equivalent.
By in situ hybridization and analysis of somatic cell hybrids, Li et al. (1991) assigned the NFYA gene to chromosome 6p21 (close to MHC) and the NFYB gene to human chromosome 12. After in situ hybridization, the maximum concentration of grains was in the region 12q22-q23. By Southern blot analysis of recombinant inbred lines and by in situ hybridization, the Nfya and Nfyb genes were assigned to mouse chromosome 17 and mouse chromosome 10, respectively.
Using CRISPR technology, Liu et al. (2021) identified an activator element at the gamma-globin (see 142200) promoters near the binding site for BCL11A, a gamma-globin repressor. They noted that the gamma-globin promoters contain duplicated BCL11A-binding sites that overlap CCAAT motifs. Knockdown, chromatin immunoprecipitation, and base-editing analyses revealed that NFY activated gamma-globin expression through direct binding to the proximal CCAAT box, whereas BCL11A functioned through the distal binding motif. BCL11A and NFY competed for binding at the gamma-globin promoters to regulate expression of gamma-globin, thereby controlling the switch from fetal to adult hemoglobin. Mutation or deletion of the distal BCL11A-binding motif promoted NFY complex occupancy at the proximal CCAAT motif and activated robust gamma-globin expression, and thus assembly of adult hemoglobin. In contrast, binding of BCL11A to the distal motif constituted a steric barrier to NFY binding at the proximal CCAAT motif, leading to repression of gamma-globin expression, and thus inhibiting the switch from fetal to adult hemoglobin.
Becker, D. M., Fikes, J. D., Guarente, L. A cDNA encoding a human CCAAT-binding protein cloned by functional complementation in yeast. Proc. Nat. Acad. Sci. 88: 1968-1972, 1991. [PubMed: 2000400] [Full Text: https://doi.org/10.1073/pnas.88.5.1968]
Li, X.-Y., Mattei, M. G., Zaleska-Rutczynska, Z., Hooft van Huijsduijnen, R., Figueroa, F., Nadeau, J., Benoist, C., Mathis, D. One subunit of the transcription factor NF-Y maps close to the major histocompatibility complex in murine and human chromosomes. Genomics 11: 630-634, 1991. [PubMed: 1774067] [Full Text: https://doi.org/10.1016/0888-7543(91)90070-u]
Liu, N., Xu, S., Yao, Q., Zhu, Q., Kai, Y., Hsu, J., Sakon, P., Pinello, L., Yuan, G.-C., Bauer, D. E., Orkin, S. H. Transcription factor competition at the gamma-globin promoters controls hemoglobin switching. Nature Genet. 53: 511-520, 2021. Note: Erratum: Nature Genet. 53: 586 only, 2021. [PubMed: 33649594] [Full Text: https://doi.org/10.1038/s41588-021-00798-y]