GATA1

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GATA1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000102145

ENSMUSG00000031162

UniProt

P15976

P17679

RefSeq (mRNA)

NM_002049

NM_008089

RefSeq (protein)

NP_002040

NP_032115

Location (UCSC)Chr X: 48.79 – 48.79 MbChr X: 7.83 – 7.84 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6]

GATA1 regulates the

platelets from megakaryoblasts, promegakaryocytes, and megakaryocytes; 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,

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.[8][9][10]

Reduced levels of GATA1 due to reductions in the translation of GATA1

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.[11][12]

Gene

The human GATA1 gene is located on the short (i.e. "p") arm of the

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.[13][14][15] 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.[8][15]

Studies in Gata1-

myelofibrosis.[16][17]

GATA1 proteins

In both GATA1 and GATA1-S, C-ZnF (i.e.

BRD3 (remodels DNA nucleosomes),[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 (a histone deacetylase),[23] LMO2 (regulator of erythrocyte development),[24] ZBTB16 (transcription factor regulating cell cycle progression),[25] TAL1 (a transcription factor),[26] FOG2 (a transcription factor regulator),[27] 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).[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]

Physiology and Pathology

GATA1 was first described as a transcription factor that activates the

erythroblasts) to red blood cells while silencing genes that cause these precursors to proliferate and thereby to self-renew.[31][32] 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.[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. 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.[5][7]

Reduced levels of GATA1 due to defective

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.[11][12][33][34]

The clinical features associated with inactivating GATA1 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 in GATA1 cause X-linked recessive diseases. Males, with only one GATA1 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 is dominant 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, inactivating GATA1 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 plus thalassemia-type and porphyria-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 extra chromosome 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 in acute megakaryoblastic leukemia.[15][35]

Genetic disorders

GATA1 gene

myelofibrosis.[8]

Down syndrome-related disorders

Main article: Down syndrome § Cancer

Transient myeloproliferative disorder

Main article: Transient myeloproliferative disease

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 are

blast cell numbers, reduced platelet and red blood cell levels, increased circulating white blood cell levels, and infiltration of platelet-precursor cells into the bone marrow, liver, heart, pancreas, and skin.[35] The disorder is thought to develop in 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 a clonal (abnormal cells derived from single parent cells), pre-leukemic condition and is classified as a myelodysplastic syndrome disease.[7][8][16][35]

Acute megakaryoblastic leukemia

Main article: Acute megakaryoblastic leukemia

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 without

JAK3, MPL, KRAS, NRAS, SH2B3, and MIR125B2 which is the gene for microRNA MiR125B2.[7][36]

Diamond–Blackfan anemia

Main article: Diamond–Blackfan anemia

Diamond–Blackfan anemia is a familial (i.e. inherited) (45% of cases) or acquired (55% of cases) genetic disease that presents in

RPS24.[8][10] However, several cases of familial Diamond–Blackfan anemia have been associated with GATA1 gene mutations in the apparent absence of a mutation in ribosomal protein genes. These GATA1 mutations occur in an exon 2 splice site or the start 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 these GATA1 mutations are a cause for Diamond Blackfan anemia.[8][15][16]

Combined anemia-thrombocytopenia syndromes

Main article: congenital dyserythropoietic anemia

Certain GATA1-inactivatng 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. These GATA1 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][37][38]

  • V205M: familial disease characterized by severe anemia in fetuses and newborns; bone marrow has increased numbers of malformed platelet and red blood cell precursors.
  • G208S and D218G: familial disease characterized by severe bleeding, reduced number of circulating platelets which are malformed (i.e. enlarged), and mild anemia.
  • D218Y: familial disease similar to but more severe that the disease cause by G209S and D218G mutations.
  • R216W: characterized by a
    congenital erythropoietic porphyria
    ; mild to moderately severe thrombocytopenia with features of the gray platelet syndrome.
  • R216Q: familial disease characterized by mild anemia with features of heterozygous rather than homozygous (i.e. overt) beta thalassemia; mild thrombocytopenia with features of the gray platelet syndrome.
  • G208R: disease characterized by mild anemia and severe thrombocytopenia with malformed erythroblasts and megakaryoblasts in the bone marrow. Structural features of these cells were similar to those observed in congenital dyserythropoietic anemia.
  • -183G>A: rare Single-nucleotide polymorphism (rs113966884[39]) in which the nucleotide adenine replaces guanine in DNA at the position 183 nucleotides upstream of the start of GATA1; disorder characterized as mild anemia with structural features in bone marrow red cell precursors similar to those observed in congenital dyserythropoietic anemia.

The

autosomal dominant disease of GFI1B-related syndrome caused by mutations in GFI1B (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 by NBEAL2 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 the NBEAL2-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, a thalassemia-like disorder due to unbalanced hemoglobin production, and/or a porphyria-like disorder.[40][37] A recent study found that GATA1 is a strong enhancer of NBEAL2 expression and that the R216W and R216Q inactivating mutations in GATA1 may cause the development of alpha granule-deficient platelets by failing to stimulate the expression of NBDAL2 protein.[41] Given these differences, the GATA1 mutation-related disorder appears better classified as clinically and pathologically different than the gray platelet syndrome.[40]

GATA1 in myelofibrosis

Main article:
Myelofibrosis

Myelofibrosis is a rare hematological malignancy characterized by progressive fibrosis of the bone marrow,

leukemic transformation.[12][33][34]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000102145 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031162 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Further reading

External links

Other types of GATA2 mutations cause the over-expression of the GATA2 transcription factor. This overexpression is associated with the development of non-familial AML. Apparently, the GATA2 gene's expression level must be delicately balanced between deficiency and excess in order to avoid life-threatening disease.[1][2]

  1. PMID 25619630
    .
  2. PMID 28179282
    .
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