GATA2

GATA2
Identifiers
Aliases	GATA2 , DCML, IMD21, MONOMAC, NFE1B, GATA binding protein 2
External IDs	OMIM: 137295; MGI: 95662; HomoloGene: 32030; GeneCards: GATA2; OMA:GATA2 - orthologs
Gene location (Human) Chr. Chromosome 3 (human) [1] Band 3q21.3 Start 128,479,427 bp [1] End 128,493,201 bp [1]
Gene location (Mouse) Chr. Chromosome 6 (mouse) [2] Band 6 D1|6 39.2 cM Start 88,170,873 bp [2] End 88,184,014 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in seminal vesicula right lung left uterine tube renal medulla prostate body of uterus urethra canal of the cervix upper lobe of left lung placenta Top expressed in seminal vesicula gastrula medullary collecting duct placenta transitional epithelium of urinary bladder vestibular membrane of cochlear duct vas deferens vestibular sensory epithelium primary trophoblast giant cell inner renal medulla More reference expression data BioGPS n/a
Gene ontology Molecular function RNA polymerase II cis-regulatory region sequence-specific DNA binding DNA binding sequence-specific DNA binding RNA polymerase II transcription regulatory region sequence-specific DNA binding DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific zinc ion binding transcription factor binding chromatin binding C2H2 zinc finger domain binding metal ion binding protein binding cis-regulatory region sequence-specific DNA binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component transcription regulator complex nucleoplasm nucleus cytoplasm protein-containing complex Biological process commitment of neuronal cell to specific neuron type in forebrain positive regulation of phagocytosis cell differentiation negative regulation of fat cell differentiation pituitary gland development positive regulation of phagocytosis, engulfment regulation of transcription, DNA-templated positive regulation of erythrocyte differentiation somatic stem cell population maintenance negative regulation of macrophage differentiation GABAergic neuron differentiation positive regulation of cytosolic calcium ion concentration negative regulation of fat cell proliferation negative regulation of neural precursor cell proliferation embryonic placenta development neuron migration blood coagulation negative regulation of transcription by RNA polymerase II cell maturation semicircular canal development transcription, DNA-templated regulation of primitive erythrocyte differentiation ventral spinal cord interneuron differentiation response to lipid cell differentiation in hindbrain central nervous system neuron development inner ear morphogenesis positive regulation of neuron differentiation regulation of histone acetylation neuron differentiation regulation of forebrain neuron differentiation phagocytosis urogenital system development cell fate determination homeostasis of number of cells within a tissue definitive hemopoiesis neuron fate commitment negative regulation of myeloid cell differentiation positive regulation of megakaryocyte differentiation positive regulation of transcription by RNA polymerase II negative regulation of Notch signaling pathway eosinophil fate commitment positive regulation of mast cell degranulation cochlea development regulation of hematopoietic stem cell differentiation positive regulation of angiogenesis negative regulation of endothelial cell apoptotic process positive regulation of gene expression negative regulation of gene expression hemopoiesis pri-miRNA transcription by RNA polymerase II positive regulation of cell migration involved in sprouting angiogenesis positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis heart development animal organ morphogenesis tissue development cell development anatomical structure formation involved in morphogenesis positive regulation of pri-miRNA transcription by RNA polymerase II digestive tract development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2624 14461 Ensembl ENSG00000179348 ENSMUSG00000015053 UniProt P23769 O09100 RefSeq (mRNA) NM_032638 NM_001145661 NM_001145662 NM_008090 NM_001355253 RefSeq (protein) NP_001139133 NP_001139134 NP_116027 NP_032116 NP_001342182 Location (UCSC) Chr 3: 128.48 – 128.49 Mb Chr 6: 88.17 – 88.18 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

GATA2 or GATA-binding factor 2 is a transcription factor, i.e. a nuclear protein which regulates the expression of genes. ^[5] It regulates many genes that are critical for the embryonic development, self-renewal, maintenance, and functionality of blood-forming, lympathic system-forming, and other tissue-forming stem cells. GATA2 is encoded by the GATA2 gene, a gene which often suffers germline and somatic mutations which lead to a wide range of familial and sporadic diseases, respectively. The gene and its product are targets for the treatment of these diseases. ^{[6] [7]}

Inactivating mutations of the GATA2 gene cause a reduction in the cellular levels of GATA2 and the development of a wide range of familial hematological, immunological, lymphatic, and/or other disorders that are grouped together into a common disease termed GATA2 deficiency. Less commonly, these disorders are associated with non-familial (i.e. sporadic or acquired) GATA inactivating mutations. GATA2 deficiency often begins with seemingly benign abnormalities but if untreated progresses to life-threatening opportunistic infections, virus-induced cancers, lung failure, the myelodysplastic syndrome (i.e. MDS), and/or acute myeloid leukemia, principally acute myeloid leukemia (AML), less commonly chronic myelomonocytic leukemia (CMML), and rarely a lymphoid leukemia. ^{[6] [7]}

Overexpression of the GATA2 transcription factor that is not due to mutations in the GATA2 gene appears to be a secondary factor that promotes the aggressiveness of non-familial EVI1 positive AML as well as the progression of prostate cancer. ^{[8] [9] [10] [11]}

GATA2 gene

The GATA2 gene is a member of the evolutionarily conserved GATA transcription factor gene family. All vertebrate species tested so far, including humans and mice, express 6 GATA genes, GATA1 through GATA6. ^[12] The human GATA2 gene is located on the long (or "q") arm of chromosome 3 at position 21.3 (i.e. the 3q21.3 locus) and consists of 8 exons. ^[13] Two sites, termed C-ZnF and N-ZnF, of the gene code for two Zinc finger structural motifs of the GATA2 transcription factor. These sites are critical for regulating the ability of the transcription factor to stimulate its target genes. ^{[14] [15]}

The GATA2 gene has at least five separate sites which bind nuclear factors that regulate its expression. One particularly important such site is located in intron 4. This site, termed the 9.5 kb enhancer, is located 9.5 kilobases (i.e. kb) down-stream from the gene's transcript initiation site and is a critically important enhancer of the gene's expression. ^[14] Regulation of GATA2 expression is highly complex. For example, in hematological stem cells, GATA2 transcription factor itself binds to one of these sites and in doing so is part of functionally important positive feedback autoregulation circuit wherein the transcription factor acts to promote its own production; in a second example of a positive feed back circuit, GATA2 stimulates production of Interleukin 1 beta and CXCL2 which act indirectly to simulate GATA2 expression. In an example of a negative feedback circuit, the GATA2 transcription factor indirectly causes activation of the G protein coupled receptor, GPR65, which then acts, also indirectly, to repress GATA2 gene expression. ^{[14] [15]} In a second example of negative feed-back, GATA2 transcription factor stimulates the expression of the GATA1 transcription factor which in turn can displace GATA2 transcription factor from its gene-stimulating binding sites thereby limiting GATA2's actions. ^[16]

The human GATA2 gene is expressed in hematological bone marrow cells at the stem cell and later progenitor cell stages of their development. Increases and/or decreases in the gene's expression regulate the self-renewal, survival, and progression of these immature cells toward their final mature forms viz., erythrocytes, certain types of lymphocytes (i.e. B cells, NK cells, and T helper cells), monocytes, neutrophils, platelets, plasmacytoid dendritic cells, macrophages and mast cells. ^{[14] [17] [18]} The gene is likewise critical for the formation of the lymphatic system, particularly for the development of its valves. The human gene is also expressed in endothelium, some non-hematological stem cells, the central nervous system, and, to lesser extents, prostate, endometrium, and certain cancerous tissues. ^{[6] [12] [14]}

The Gata2 gene in mice has a structure similar to its human counterpart, Deletion of both parental Gata2 genes in mice is lethal by day 10 of embryogenesis due to a total failure in the formation of mature blood cells. Inactivation of one mouse Gata2 gene is neither lethal nor associated with most of the signs of human GATA2 deficiency; however, these animals do show a ~50% reduction in their hematopoietic stem cells along with a reduced ability to repopulate the bone marrow of mouse recipients. The latter findings, human clinical studies, and experiments on human tissues support the conclusion that in humans both parental GATA2 genes are required for sufficient numbers of hematopoietic stem cells to emerge from the hemogenic endothelium during embryogenesis and for these cells and subsequent progenitor cells to survive, self-renew, and differentiate into mature cells. ^{[14] [17] [19]} As GATA2 deficient individuals age, their deficiency in hematopoietic stem cells worsens, probably as a result of factors such as infections or other stresses. In consequence, the signs and symptoms of their disease appear and/or become progressively more severe. ^[9] The role of GATA2 deficiency in leading to any of the leukemia types is not understood. Likewise, the role of GATA2 overexpression in non-familial AML as well as development of the blast crisis in chronic myelogenous leukemia and progression of prostate cancer is not understood. ^{[9] [15]}

Mutations

Scores of different types of inactivating GATA mutations have been associated with GATA2 deficiency; these include frameshift, point, insertion, splice site and deletion mutations scattered throughout the gene but concentrated in the region encoding the GATA2 transcription factor's C-ZnF, N-ZnF, and 9.5 kb sites. Rare cases of GATA2 deficiency involve large mutational deletions that include the 3q21.3 locus plus contiguous adjacent genes; these mutations seem more likely than other types of GATA mutations to cause increased susceptibilities to viral infections, developmental lymphatic disorders, and neurological disturbances. ^{[6] [17]}

One GATA2 mutation is a gain of function type, i.e. it is associated with an increase in the activity rather than levels of GATA2. This mutation substitutes valine for leucine in the 359 amino acid position (i.e. within the N-ZnF site) of the transcription factor and has been detected in individuals undergoing the blast crisis of chronic myelogenous leukemia. ^{[9] [20]}

Pathological inhibition

Analyses of individuals with AML have discovered many cases of GATA2 deficiency in which one parental GATA2 gene was not mutated but silenced by hypermethylation of its gene promoter. Further studies are required to integrate this hypermethylation-induced form of GATA2 deficiency into the diagnostic category of GATA2 deficiency. ^[19]

Pathological stimulation

Non-mutational stimulation of GATA2 expression and consequential aggressiveness in EVI1-positive AML appears due to the ability of EVI1, a transcription factor, to directly stimulate the expression of the GATA2 gene. ^{[10] [11]} The reason for the overexpression of GATA2 that begins in the early stages of prostate cancer is unclear but may involve the ability of FOXA1 to act indirect to stimulate the expression of the GATA2 gene. ^[11]

GATA2

The full length GATA2 transcription factor is a moderately sized protein consisting of 480 amino acids. Of its two zinc fingers, C-ZnF (located toward the protein's C-terminus) is responsible for binding to specific DNA sites while its N-ZnF (located toward the proteins N-terminus) is responsible for interacting with various other nuclear proteins that regulate its activity. The transcription factor also contains two transactivation domains and one negative regulatory domain which interact with other nuclear proteins to up-regulate and down-regulate, respectively, its activity. ^{[14] [21]} In promoting embryonic and/or adult-type haematopoiesis (i.e. maturation of hematological and immunological cells), GATA2 interacts with other transcription factors (viz., RUNX1, SCL/TAL1, GFI1, GFI1b, MYB, IKZF1, Transcription factor PU.1, LYL1) and cellular receptors (viz., MPL, GPR56). ^[15] In a wide range of tissues, GATA2 similarly interacts with HDAC3, ^[22] LMO2, ^[23] POU1F1, ^[24] POU5F1, ^[25] PML ^[26] SPI1, ^[27] and ZBTB16. ^[28]

GATA2 binds to a specific nucleic acid sequence viz., (T/A(GATA)A/G), on the promoter and enhancer sites of its target genes and in doing so either stimulates or suppresses the expression of these target genes. However, there are thousands of sites in human DNA with this nucleotide sequence but for unknown reasons GATA2 binds to <1% of these. Furthermore, all members of the GATA transcription factor family bind to this same nucleotide sequence and in doing so may in certain instances serve to interfere with GATA2 binding or even displace the GATA2 that is already bound to these sites. For example, displacement of GATA2 bond to this sequence by the GATA1 transcription factor appears important for the normal development of some types of hematological stem cells. This displacement phenomenon is termed the "GATA switch". In all events, the actions of GATA2, particularly with referenced to its interactions with many other gene-regulating factors, in controlling its target genes is extremely complex and not fully understood. ^{[6] [14] [15] [16]}

GATA2-related disorders

Inactivating GATA2 mutations

Main article: GATA2 deficiency

Familial and sporadic inactivating mutations in one of the two parental GATA2 genes causes a reduction, i.e. a haploinsufficiency, in the cellular levels of the GATA2 transcription factor. In consequence, individuals commonly develop a disease termed GATA2 deficiency. GATA2 deficiency is a grouping of various clinical presentations in which GATA2 haploinsufficiency results in the development over time of hematological, immunological, lymphatic, and/or other presentations that may begin as apparently benign abnormalities but commonly progress to life-threatening opportunistic infections, virus infection-induced cancers, the myelodysplastic syndrome, and/or leukemias, particularly AML. ^{[6] [7]} The various presentations of GATA2 deficiency include all cases of Monocytopenia and Mycobacterium Avium Complex/Dendritic Cell Monocyte, B and NK Lymphocyte deficiency (i.e. MonoMAC) and the Emberger syndrome as well as a significant percentage of cases of familial myelodysplastic syndrome/acute myeloid leukemia, congenital neutropenia, chronic myelomonocytic leukemia, aplastic anemia, and several other presentations. ^{[6] [7] [29] [30]}

Activating GATA2 mutation

The L359V gain of function mutation (see above section on mutation) increases the activity of the GATA2 transcription factor. The mutation occurs during the blast crisis of chronic myelogenous leukemia and is proposed to play a role in the transformation of the chronic and/or accelerated phases of this disease to its blast crisis phase. ^{[9] [20]}

Repression of GATA2

The repression of GATA2 expression due to methylation of promoter sites in the GATA2 gene rather than a mutation in this gene has been suggested to be an alternate cause for the GATA2 deficiency syndrome. ^[19] This epigenetic gene silencing also occurs in certain types of non-small-cell lung carcinoma and is suggested to have a protective effect on progression of the disease. ^{[21] [31]}

Overexpression of GATA2

Elevated levels of GATA2 transcription factor due to overexpression of its gene GATA2 is a common finding in AML. It is associated with a poor prognosis, appears to promote progression of the disease, and therefore proposed to be a target for therapeutic intervention. This overexpression is not due to mutation but rather caused at least in part by the overexpression of EVI1, a transcription factor that stimulates GATA2 expression. ^[8] GATA2 overexpression also occurs in prostate cancer where it appears to increase metastasis in the early stages of androgen-dependent disease and to stimulate prostate cancer cell survival and proliferation through activating by an unknown mechanism the androgen pathway in androgen-independent (i.e. castration-resistant) disease). ^{[10] [11]}

See also

• GATA transcription factor
• GATA2 deficiency
• MonoMAC
• Emberger syndrome

References

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23. Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH (October 1995). "Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1". Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9585–9. Bibcode:1995PNAS...92.9585O. doi: 10.1073/pnas.92.21.9585 . PMC   40846 . PMID   7568177.
24. Dasen JS, O'Connell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, Hooshmand F, Aggarwal AK, Rosenfeld MG (May 1999). "Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types". Cell. 97 (5): 587–98. doi: 10.1016/s0092-8674(00)80770-9 . PMID   10367888. S2CID   15737684.
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26. Tsuzuki S, Towatari M, Saito H, Enver T (September 2000). "Potentiation of GATA-2 activity through interactions with the promyelocytic leukemia protein (PML) and the t(15;17)-generated PML-retinoic acid receptor alpha oncoprotein". Mol. Cell. Biol. 20 (17): 6276–86. doi:10.1128/mcb.20.17.6276-6286.2000. PMC   86102 . PMID   10938104.
27. Zhang P, Behre G, Pan J, Iwama A, Wara-Aswapati N, Radomska HS, Auron PE, Tenen DG, Sun Z (July 1999). "Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1". Proc. Natl. Acad. Sci. U.S.A. 96 (15): 8705–10. Bibcode:1999PNAS...96.8705Z. doi: 10.1073/pnas.96.15.8705 . PMC   17580 . PMID   10411939.
28. Tsuzuki S, Enver T (May 2002). "Interactions of GATA-2 with the promyelocytic leukemia zinc finger (PLZF) protein, its homologue FAZF, and the t(11;17)-generated PLZF-retinoic acid receptor alpha oncoprotein". Blood. 99 (9): 3404–10. doi: 10.1182/blood.v99.9.3404 . PMID   11964310. S2CID   35192406.
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31. Tessema M, Yingling CM, Snider AM, Do K, Juri DE, Picchi MA, Zhang X, Liu Y, Leng S, Tellez CS, Belinsky SA (June 2014). "GATA2 is epigenetically repressed in human and mouse lung tumors and is not requisite for survival of KRAS mutant lung cancer". Journal of Thoracic Oncology. 9 (6): 784–93. doi:10.1097/JTO.0000000000000165. PMC   4132640 . PMID   24807155.

Further reading

• Minegishi N (2002). "[Transcription factors regulating hematopoiesis: researches spanning from molecule to whole body]". Seikagaku. 74 (5): 398–402. PMID   12073612.
• Ohneda K, Yamamoto M (2003). "Roles of hematopoietic transcription factors GATA-1 and GATA-2 in the development of red blood cell lineage". Acta Haematol. 108 (4): 237–45. doi:10.1159/000065660. PMID   12432220. S2CID   29966039.
• Dorfman DM, Wilson DB, Bruns GA, Orkin SH (1992). "Human transcription factor GATA-2. Evidence for regulation of preproendothelin-1 gene expression in endothelial cells". J. Biol. Chem. 267 (2): 1279–85. doi: 10.1016/S0021-9258(18)48426-8 . PMID   1370462.
• Page RL, Wharton JM, Wilkinson WE, Friedman IM, Claypool WD, Karim A, Kowalski KG, McDonald SJ, Gardiner P, Pritchett EL (1992). "Bidisomide (SC-40230), a new antiarrhythmic agent: initial study of tolerability and pharmacokinetics". Clin. Pharmacol. Ther. 51 (4): 371–8. doi:10.1038/clpt.1992.36. PMID   1563207. S2CID   21141791.
• Lee ME, Temizer DH, Clifford JA, Quertermous T (1991). "Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells". J. Biol. Chem. 266 (24): 16188–92. doi: 10.1016/S0021-9258(18)98533-9 . PMID   1714909.
• Zhang R, Min W, Sessa WC (1995). "Functional analysis of the human endothelial nitric oxide synthase promoter. Sp1 and GATA factors are necessary for basal transcription in endothelial cells". J. Biol. Chem. 270 (25): 15320–6. doi: 10.1074/jbc.270.25.15320 . PMID   7541039.
• Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH (1995). "Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1". Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9585–9. Bibcode:1995PNAS...92.9585O. doi: 10.1073/pnas.92.21.9585 . PMC   40846 . PMID   7568177.
• Towatari M, May GE, Marais R, Perkins GR, Marshall CJ, Cowley S, Enver T (1995). "Regulation of GATA-2 phosphorylation by mitogen-activated protein kinase and interleukin-3". J. Biol. Chem. 270 (8): 4101–7. doi: 10.1074/jbc.270.8.4101 . PMID   7876160.
• Tsai FY, Keller G, Kuo FC, Weiss M, Chen J, Rosenblatt M, Alt FW, Orkin SH (1994). "An early haematopoietic defect in mice lacking the transcription factor GATA-2". Nature. 371 (6494): 221–6. Bibcode:1994Natur.371..221T. doi:10.1038/371221a0. PMID   8078582. S2CID   4235579.
• Briegel K, Lim KC, Plank C, Beug H, Engel JD, Zenke M (1993). "Ectopic expression of a conditional GATA-2/estrogen receptor chimera arrests erythroid differentiation in a hormone-dependent manner". Genes Dev. 7 (6): 1097–109. doi: 10.1101/gad.7.6.1097 . PMID   8504932.
• Towatari M, Kanei Y, Saito H, Hamaguchi M (1998). "Hematopoietic transcription factor GATA-2 activates transcription from HIV-1 long terminal repeat". AIDS. 12 (3): 253–9. doi: 10.1097/00002030-199803000-00002 . PMID   9517987. S2CID   45961447.
• Dasen JS, O'Connell SM, Flynn SE, Treier M, Gleiberman AS, Szeto DP, Hooshmand F, Aggarwal AK, Rosenfeld MG (1999). "Reciprocal interactions of Pit1 and GATA2 mediate signaling gradient-induced determination of pituitary cell types". Cell. 97 (5): 587–98. doi: 10.1016/S0092-8674(00)80770-9 . PMID   10367888. S2CID   15737684.
• Zhang P, Behre G, Pan J, Iwama A, Wara-Aswapati N, Radomska HS, Auron PE, Tenen DG, Sun Z (1999). "Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1". Proc. Natl. Acad. Sci. U.S.A. 96 (15): 8705–10. Bibcode:1999PNAS...96.8705Z. doi: 10.1073/pnas.96.15.8705 . PMC   17580 . PMID   10411939.
• Wieser R, Volz A, Vinatzer U, Gardiner K, Jäger U, Mitterbauer M, Ziegler A, Fonatsch C (2000). "Transcription factor GATA-2 gene is located near 3q21 breakpoints in myeloid leukemia". Biochem. Biophys. Res. Commun. 273 (1): 239–45. doi:10.1006/bbrc.2000.2947. PMID   10873593.
• Tsuzuki S, Towatari M, Saito H, Enver T (2000). "Potentiation of GATA-2 Activity through Interactions with the Promyelocytic Leukemia Protein (PML) and the t(15;17)-Generated PML-Retinoic Acid Receptor α Oncoprotein". Mol. Cell. Biol. 20 (17): 6276–86. doi:10.1128/MCB.20.17.6276-6286.2000. PMC   86102 . PMID   10938104.
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External links

• GATA2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook GATA2
• Overview of all the structural information available in the PDB for UniProt : P23769 (Endothelial transcription factor GATA-2) at the PDBe-KB .

This article incorporates text from the United States National Library of Medicine, which is in the public domain.