GATA-binding factor 1 orGATA-1 (also termedErythroid transcription factor) is the founding member of theGATA family of transcription factors. Thisprotein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by theGATA1 andGata1 genes, respectively. These genes are located on theX chromosome in both species.[5][6]
GATA1 regulates theexpression (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 thematuration of precursor cells, e.g.erythroblasts, to red blood cells and stimulating these cells to erect theircytoskeleton andbiosynthesize their oxygen-carrying components viz.,hemoglobin andheme. GATA1 plays a similarly critical role in the maturation of bloodplatelets frommegakaryoblasts,promegakaryocytes, andmegakaryocytes; the latter cells then shed membrane-enclosed fragments of their cytoplasm, i.e. platelets, into the blood.[5][7]
In consequence of the vital role that GATA1 has in the proper maturation of red blood cells and platelets,inactivating mutations in theGATA1 gene (i.e. mutations that result in the production of no, reduced levels of, or a less active GATA1) causeX chromosome-linkedanemic and/orbleeding 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 includetransient myeloproliferative disorder occurring in Down syndrome,acute megakaryoblastic leukemia occurring inDown syndrome,Diamond–Blackfan anemia, and various combinedanemia-thrombocytopenia syndromes including agray platelet syndrome-type disorder.[8][9][10]
Reduced levels of GATA1 due to reductions in the translation of GATA1mRNA into its transcription factor product are associated with promoting the progression ofmyelofibrosis, i.e. a malignant disease that involves the replacement of bone marrow cells by fibrous tissue andextramedullary hematopoiesis, i.e. the extension of blood cell-forming cells to sites outside of thebone marrow.[11][12]
The humanGATA1 gene is located on the short (i.e. "p") arm of theX chromosome at position 11.23. It is 7.74kilobases in length, consists of 6exons, and codes for a full-length protein, GATA1, of 414amino 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.[13][14][15]GATA1 codes for twozinc fingerstructural 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.[8][15]
Studies inGata1-knockout mice, i.e. mice lacking theGata1 gene, indicate that this gene is essential for the development and maintenance of blood-based and/or tissue-based hematological cells, particularlyred blood cells andplatelets but alsoeosinophils,basophils,mast cells, anddendritic cells. The knock-out mice die by day 11.5 of theirembryonic 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 ofplatelets. These defects reflect the essential role of Gata-1 in stimulating the development, self-renewal, and/or maturation of red blood cell and plateletprecursor cells. Studies using mice depleted of theirGata1 gene during adulthood show that:1) Gata1 is required for the stimulation oferythropoiesis (i.e. increase in red blood cell formation) in response to stress and2)Gata1-deficient adult mice invariably develop a form ofmyelofibrosis.[16][17]
In both GATA1 and GATA1-S, C-ZnF (i.e.C-terminus zinc finger) binds to DNA-specificnucleic 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 ofGata1, 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 (achromatin remodeler) andCTBP1 (ahistone deacetylase) and three gene expression-regulating proteins,SET8 (a GATA1-inhibitinghistone methyltransferase),BRG1 (atranscription activator), andMediator (atranscription co-activator). Other interactions include those with:BRD3 (remodels DNAnucleosomes),[18][19][20]BRD4 (binds acetylated lysine residues in DNA-associated histone to regulate gene accessibility),[18]FLI1 (a transcription factor that blocks erythroid differentiation),[21][22]HDAC1 (ahistone deacetylase),[23]LMO2 (regulator of erythrocyte development),[24]ZBTB16 (transcription factor regulatingcell cycle progression),[25]TAL1 (a transcription factor),[26]FOG2 (a transcription factor regulator),[27] andGATA2 (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).[17][28][29] GATA1-FOG1 and GATA2-FOG1 interactions are critical for platelet formation in mice and may similarly be critical for this in humans.[17]
Other types ofGATA2 mutations cause the over-expression of the GATA2 transcription factor. This overexpression is associated with the development of non-familial AML. Apparently, theGATA2 gene's expression level must be delicately balanced between deficiency and excess in order to avoid life-threatening disease.[30]
GATA1 was first described as a transcription factor that activates thehemoglobin B gene in the red blood cell precursors of chickens.[31] 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 toself-renew.[32][33] GATA1 stimulates this maturation by, for example, inducing the expression of genes in erythroid cells that contribute to the formation of theircytoskeleton and that make enzymes necessary for thebiosynthesis ofhemoglobins andheme, 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.[5] 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. Thismaturation involves the stimulation ofmegakaryoblasts to mature ultimately tomegakaryocytes 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.[5][7]
Reduced levels of GATA1 due to defectivetranslation of GATA1mRNA in human megakaryocytes is associated withmyelofibrosis, 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 marrowstromal cells to become fiber-secretingfibroblasts andosteoblasts. Based on mouse studies, low GATA1 levels are also thought to promote the development of splenicenlargement andextramedullary hematopoiesis in human myelofibrosis disease. These effects appear to result directly from the over-proliferation of abnormal platelet precursor cells.[11][12][34][35]
The clinical features associated with inactivatingGATA1 mutations or other causes of reduced GATA1 levels vary greatly with respect not only to the types of disease exhibited but also to disease severity. This variation depends on at least four factors.First, inactivating mutations inGATA1 causeX-linked recessive diseases. Males, with only oneGATA1 gene, experience the diseases of these mutations while women, with two GATA1 genes, experience no or extremely mild evidence of these diseases unless they have inactivating mutations in both genes or their mutation isdominant negative, i.e. inhibiting the good gene's function.Second, the extent to which a mutation reduces the cellular levels of fully functional GATA1 correlates with disease severity.Third, inactivatingGATA1 mutations can cause different disease manifestations. For example, mutations in GATA1's N-ZnF that interfere with its interaction with FOG1 result in reduced red blood cell and platelet levels whereas mutations in N-ZnF that reduce its binding affinity to target genes cause a reduction in red blood cells plusthalassemia-type andporphyria-type symptoms.Fourth, the genetic background of individuals can impact the type and severity of symptoms. For example,GATA1-inactivating mutations in individuals with the extrachromosome 21 of Down syndrome exhibit a proliferation of megakaryoblasts that infiltrate and consequentially directly damage liver, heart, marrow, pancreas, and skin plus secondarily life-threatening damage to the lungs and kidneys. These same individuals can develop secondary mutations in other genes that results inacute megakaryoblastic leukemia.[15][36]
GATA1 genemutations are associated with the development of variousgenetic disorders which may be familial (i.e. inherited) or newly acquired. In consequence of its X chromosome location, GATA1 mutations generally have a far greater physiological and clinical impact in men, who have only one X chromosome along with itsGATA1 gene, than woman, who have two of these chromosomes and genes: GATA1 mutations lead toX-linked diseases occurring predominantly in males.[15] Mutations in the activation domain of GATA1 (GATA1-S lacks this domain) are associated with the transient myeloproliferative disorder and acute megakaryoblastic leukemia of Down syndrome while mutations in the N-ZnF motif of GATA1 and GATA1-S are associated with diseases similar to congenital dyserythropoietic anemia, congenital thrombocytopenia, and certain features that occur inthalassemia,gray platelet syndrome,congenital erythropoietic porphyria, andmyelofibrosis.[8]
Acquired inactivating mutations in the activation domain of GATA1 are the apparent cause of the transient myeloproliferative disorder that occurs in individuals with Down syndrome. These mutations areframeshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and therefore a greatly reduced ability to regulate GATA1-targeted genes. The presence of these mutations is restricted to cells bearing the trisomy 21karyotype (i.e. extrachromosome 21) of Down syndrome: GATA1 inactivating mutations and trisomy 21 are necessary and sufficient for development of the disorder.[36] Transient myeloproliferative disorder consists of a relatively mild but pathological proliferation of platelet-precursor cells, primarilymegakaryoblasts, which often show an abnormal morphology that resembles immaturemyeloblasts (i.e.unipotent stem cells which differentiate intogranulocytes and are the malignant proliferating cell inacute myeloid leukemia).Phenotype analyses indicate that these blasts belong to the megakaryoblast series. Abnormal findings include the frequent presence of excessiveblast cell numbers, reduced platelet and red blood cell levels, increased circulatingwhite blood cell levels, and infiltration of platelet-precursor cells into the bone marrow, liver, heart, pancreas, and skin.[36] The disorder is thought to developin utero and is detected at birth in about 10% of individuals with Down syndrome. It resolves totally within ~3 months but in the following 1–3 years progresses to acute megakaryoblastic leukemia in 20% to 30% of these individuals: transient myeloprolierative disorder is aclonal (abnormal cells derived from single parent cells), pre-leukemic condition and is classified as amyelodysplastic syndrome disease.[7][8][16][36]
Acute megakaryoblastic leukemia is a subtype of acute myeloid leukemia that is extremely rare in adults and, although still rare, more common in children. The childhood disease is classified into two major subgroups based on its occurrence in individuals with or withoutDown syndrome. The disease in Down syndrome occurs in 20% to 30% of individuals who previously had transient myeloproliferative disorder. TheirGATA1 mutations areframeshifts in exon 2 that result in the failure to make GATA1 protein, continued formation of GATA1-S, and thus a greatly reduced ability to regulate GATA1-targeted genes. Transient myeloproliferative disorder is detected at or soon after birth and generally resolves during the next months but is followed within 1–3 years by acute megakaryoblastic leukemia.[7] During this 1-3 year interval, individuals accumulate multiplesomatic mutations in cells bearing inactivating GATA1 mutations plus trisomy 21. These mutations are thought to result from the uncontrolled proliferation of blast cells caused by theGATAT1 mutation in the presence of the extra chromosome 21 and to be responsible for progression of the transient disorder to leukemia. The mutations occur in one or, more commonly, multiple genes including:TP53,RUNX1,FLT3,ERG,DYRK1A,CHAF1B,HLCS,CTCF,STAG2,RAD21,SMC3,SMC1A,NIPBL,SUZ12,PRC2,JAK1,JAK2,JAK3,MPL,KRAS,NRAS,SH2B3, andMIR125B2 which is the gene formicroRNA MiR125B2.[7][37]
Diamond–Blackfan anemia is a familial (i.e. inherited) (45% of cases) or acquired (55% of cases) genetic disease that presents ininfancy or, less commonly, later childhood asaplastic anemia and the circulation of abnormally enlargedred blood cells. Other types of blood cell and platelets circulate at normal levels and appear normal in structure. About half of affected individuals have variousbirth defects.[10] The disease is regarded as a uniformly genetic disease although the genes causing it have not been identified in ~30% of cases. In virtually all the remaining cases,autosomal recessive inactivating mutations occur in any one of 20 of the 80 genes encodingribosomal proteins. About 90% of the latter mutations occur in 6 ribosomal protein genes viz.,RPS19,RPL5,RPS26,RPL11,RPL35A, andRPS24.[8][10] However, several cases of familial Diamond–Blackfan anemia have been associated withGATA1 gene mutations in the apparent absence of a mutation in ribosomal protein genes. TheseGATA1 mutations occur in an exon 2 splice site or thestart codon of GATA1, cause the production of the GATA1-S in the absence of the GATA1 transcription factor, and therefore are gene-inactivating in nature. It is proposed that theseGATA1 mutations are a cause for Diamond Blackfan anemia.[8][15][16]
CertainGATA1-inactivating mutations are associated with familial or, less commonly, sporadic X-linked disorders that consist of anemia and thrombocytopenia due to a failure in the maturation of red blood cell and platelet precursors plus other hematological abnormalities. TheseGATA1 mutations are identified by an initial letter identifying the normal amino acid followed by a number giving the position of this amino acid in GATA1, followed by a final letter identifying the amino acid substituted for the normal one. The amino acids are identified as V=valine; M=methionine; G=glycine; S=serine, D=aspartic acid; Y=tyrosine, R=arginine; W=tryptophan, Q=glutamine). These mutations and some key abnormalities they cause are:[8][16][38][39]
TheGray platelet syndrome is a rare congenital bleeding disorder caused by reductions or absence ofalpha-granules in platelets. Alpha-granules contain various factors which contribute to blood clotting and other functions. In their absence, platelets are defective. The syndrome is commonly considered to result solely from mutations in theNBEAL2 gene located on humanchromosome 3 at position p21. In these cases, the syndrome followsautosomal recessive inheritance, causes a mild to moderate bleeding tendency, and may be accompanied by a defect in the secretion of the granule contents inneutrophils. There are other causes for a congenital platelet alpha-granule-deficient bleeding disorder viz., the autosomal recessive disease ofArc syndrome caused by mutations in either theVPS33B (on human chromosome 15 at q26) orVIPAS39 (on chromosome 14 at q34); theautosomal dominant disease of GFI1B-related syndrome caused by mutations inGFI1B (located on human chromosome 9 at q34); and the disease caused by R216W and R216Q mutations in GATA1. The GATA1 mutation-related disease resembles the one caused byNBEAL2 mutations in that it is associated with the circulation of a reduced number (i.e.thrombocytopenia) of abnormally enlarged (i.e. macrothrombocytes), alpha-granule deficient platelets. It differs from theNBEAL2-induced disease in that it is X chromosome-linked, accompanied by a moderately severe bleeding tendency, and associated with abnormalities in red blood cells (e.g. anemia, athalassemia-like disorder due to unbalanced hemoglobin production, and/or aporphyria-like disorder.[41][38] A recent study found that GATA1 is a strong enhancer ofNBEAL2 expression and that the R216W and R216Q inactivating mutations inGATA1 may cause the development of alpha granule-deficient platelets by failing to stimulate the expression of NBDAL2 protein.[42] Given these differences, theGATA1 mutation-related disorder appears better classified as clinically and pathologically different than the gray platelet syndrome.[41]
Myelofibrosis is a rare hematological malignancy characterized by progressive fibrosis of the bone marrow,extramedullary hematopoiesis (i.e. formation of blood cells outside of their normal site in the bone marrow), variable reductions in the levels of circulating blood cells, increases in the circulating levels of the precursors to the latter cells, abnormalities in platelet precursor cell maturation, and the clustering of grossly malformedmegakaryocytes in the bone marrow. Ultimately, the disease may progress toleukemia. Recent studies indicate that the megakaryocytes but not other cell types in rare cases of myelofibrosis have greatly reduced levels of GATA1 as a result of a ribosomal deficiency intranslating GATA1mRNA into GATA1 transcription factor. The studies suggest that these reduced levels of GATA1 contribute to the progression of myelofibrosis by leading to an impairment in platelet precursor cell maturation, by promoting extramedullary hematopoiesis, and, possibly, by contributing to itsleukemic transformation.[12][34][35]
