GATA1

1GNF, 1Y0J, 2L5E, 2L6Y, 2L6Z, 3VD6, 3VEK262314460ENSG00000102145ENSMUSG00000031162P15976P17679NM_002049NM_008089NP_002040NP_032115GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.1gnf: SOLUTION STRUCTURE OF THE N-TERMINAL ZINC FINGER OF MURINE GATA-1, NMR, 25 STRUCTURES1y0j: Zinc fingers as protein recognition motifs: structural basis for the GATA-1/Friend of GATA interaction GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species. GATA1 regulates the expression (i.e. formation of the genes' products) of an ensemble of genes that mediate the development of red blood cells and platelets. Its critical roles in red blood cell formation include promoting the maturation of precursor cells, e.g. erythroblasts, to red blood cells and stimulating these cells to erect their cytoskeleton and biosynthesize their oxygen-carrying components viz., hemoglobin and heme. GATA1 plays a similarly critical role in the maturation of blood platelets from megakaryoblasts, promegakaryocytes, and megakaryocytes; the latter cells then shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood. In consequence of the vital role that GATA1 has in the proper maturation of red blood cells and platelets, inactivating mutations in the GATA1 gene (i.e. mutations that result in the production of no, reduced levels of, or a less active GATA1) cause X chromosome-linked anemic and/or bleeding diseases due to the reduced formation and functionality of red blood cells and/or platelets, respectively, or, under certain circumstances, the pathological proliferation of megakaryoblasts. These diseases include transient myeloproliferative disorder occurring in Down syndrome, acute megakaryoblastic leukemia occurring in Down syndrome, Diamond-Blackfan anemia, and various combined anemia-thrombocytopenia syndromes including a gray platelet syndrome-type disorder. Reduced levels of GATA1 due to reductions in the translation of GATA1 mRNA into its transcription factor product are associated with promoting the progression of myelofibrosis, i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue and extramedullary hematopoiesis, i.e. the extension of blood cell-forming cells to sites outside of the bone marrow. The human GATA1 gene is located on the short (i.e. 'p') arm of the X chromosome at position 11.23. It is 7.74 kilobases in length, consists of 6 exons, and codes for a full length protein, GATA1, of 414 amino acids as well as a shorter one, GATA1-S. GATA1-S lacks the first 83 amino acids of GATA1 and therefore consists of only 331 amino acids. GATA1 codes for two zinc finger structural motifs, C-ZnF and N-ZnF, that are present in both GATA1 and GATA1-S proteins. These motifs are critical for both transcription factors' gene-regulating actions. N-ZnF is a frequent site of disease-causing mutations. Lacking the first 83 amino acids and therefore one of the two activation domains of GATA1, GATA1-S has significantly less gene-regulating activity than GATA1. Studies in Gata1-knockout mice, i.e. mice lacking the Gata1 gene, indicate that this gene is essential for the development and maintenance of blood-based and/or tissue-based hematological cells, particularly red blood cells and platelets but also eosinophils, basophils, mast cells, and dendritic cells. The knock-out mice die by day 11.5 of their embryonic development due to severe anemia that is associated with absence of cells of the red blood cell lineage, excessive numbers of malformed platelet-precursor cells, and an absence of platelets. These defects reflect the essential role of Gata-1 in stimulating the development, self-renewal, and/or maturation of red blood cell and platelet precursor cells. Studies using mice depleted of their Gata1 gene during adulthood show that: 1) Gata1 is required for the stimulation of erythropoiesis (i.e. increase in red blood cell formation) in response to stress and 2) Gata1-deficient adult mice invariably develop a form of myelofibrosis. In both GATA1 and GATA1-S, C-ZnF (i.e. C-terminus zinc finger) binds to DNA-specific nucleic acid sequences sites viz., (T/A(GATA)A/G), on the expression-regulating sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. Their N-ZnF (i.e. N-terminus zinc fingers) interacts with an essential transcription factor-regulating nuclear protein, FOG1. FOG1 powerfully promotes or suppresses the actions that the two transcription factors have on most of their target genes. Similar to the knockout of Gata1, knockout of the mouse gene for FOG1, Zfpm1, causes total failure of red blood cell development and embryonic lethality by day 11.5. Based primarily on mouse studies, it is proposed that the GATA1-FOG1 complex promotes human erythropoiesis by recruiting and binding with at least two gene expression-regulating complexes, Mi-2/NuRD complex (a chromatin remodeler) and CTBP1 (a histone deacetylase) and three gene expression-regulating proteins, SET8 (a GATA1-inhibiting histone methyltransferase), BRG1 (a transcription activator), and Mediator (a transcription co-activator). Other interactions include those with: BRD3 (remodels DNA nucleosomes), BRD4 (binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility), FLI1 (a transcription factor that blocks erythroid differentiation), HDAC1 (a histone deacetylase), LMO2 (regulator of erythrocyte development), ZBTB16 (transcription factor regulating cell cycle progression), TAL1 (a transcription factor), FOG2 (a transcription factor regulator), and GATA2 (Displacement of GATA2 by GATA1, i.e. the 'GATA switch', at certain gene-regulating sites is critical for red blood development in mice and, presumably, humans). GATA1-FOG1 and GATA2-FOG1 interactions are critical for platelet formation in mice and may similarly be critical for this in humans. GATA1 was first described as a transcription factor that activates the hemoglobin B gene in the red blood cell precursors of chickens. Subsequent studies in mice and isolated human cells found that GATA1 stimulates the expression of genes that promote the maturation of precursor cells (e.g. erythroblasts) to red blood cells while silencing genes that cause these precursors to proliferate and thereby to self-renew. GATA1 stimulates this maturation by, for example, inducing the expression of genes in erythroid cells that contribute to the formation of their cytoskeleton and that make enzymes necessary for the biosynthesis of hemoglobins and heme, the oxygen-carrying components of red blood cells. GATA1-inactivating mutations may thereby result in a failure to produce sufficient numbers of and/or fully functional red blood cells. Also based on mouse and isolated human cell studies, GATA1 appears to play a similarly critical role in the maturation of platelets from their precursor cells. This maturation involves the stimulation of megakaryoblasts to mature ultimately to megakaryocytes which cells shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood. GATA1-inactivating mutations may thereby result in reduced levels of and/or dysfunctional blood platelets. Reduced levels of GATA1 due to defective translation of GATA1 mRNA in human megakaryocytes is associated with myelofibrosis, i.e. the replacement of bone marrow cells by fibrous tissue. Based primarily on mouse and isolated human cell studies, this myelofibrosis is thought to result from the accumulation of platelet precursor cells in the bone marrow and their release of excessive amounts of cytokines that stimulate bone marrow stromal cells to become fiber-secreting fibroblasts and osteoblasts. Based on mouse studies, low GATA1 levels are also thought to promote the development of splenic enlargement and extramedullary hematopoiesis in human myelofibrosis disease. These effects appear to result directly from the over-proliferation of abnormal platelet precursor cells.