GATA3 is atranscription factor that in humans is encoded by theGATA3gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.[5][6][7]
The GATA3 transcription factor is critical for the embryonic development of various tissues as well as forinflammatory andhumoral immune responses and the proper functioning of theendothelium ofblood vessels. The GATA factors, GATA1 to GATA6 are a family of zinc finger transcription factors that bind to a consensus DNA sequence (A/T)-G-A-T-A-(A/G) in gene promoters and enhancers.[8]GATA3 plays central role in allergy and immunity against worm infections.[9][10]GATA3haploinsufficiency (i.e. loss of one or the two inheritedGATA3 genes) results in acongenital disorder termed theBarakat syndrome.[11][12][13]
Current clinical and laboratory research is focusing on determining the benefits of directly or indirectly blocking the action of GATA3 in inflammatory and allergic diseases such as asthma.[11] It is also proposed to be a clinically important marker for various types of cancer, particularly those of the breast. However, the role, if any, of GATA3 in the development of these cancers is under study and remains unclear.[14]
TheGATA3 gene is located close to the end of the short arm of chromosome 10 at position p14. It consists of 8exons, and codes for two variants viz., GATA3, variant 1, and GATA3, variant 2.[15] Expression ofGATA3 may be regulated in part or at times by theantisense RNA, GATA3-AS1, whose gene is located close to theGATA3 gene on the short arm of chromosome 10 at position p14.[16] Various types ofmutations includingpoint mutations as well as small- and large-scaledeletional mutations cause anautosomal dominantgenetic disorder, the Barakat syndrome (also termed hypoparathyroidism, deafness, and renal dysplasia syndrome). The location ofGATA3 borders that of other critical sites on chromosome 10, particularly a site located at 10p14-p13. Mutations in this site cause the congenital disorder DiGeorge syndrome/velocardiofacial syndrome complex 2 (or DiGeorge syndrome 2).[17] Large-scale deletions inGATA3 may span into the DiGeorge syndrome 2 area and thereby cause a complex syndrome with features of theBarakat syndrome combined with some of those of the DiGeorge syndrome 2.[13][18] Knockout of bothGATA3 genes in mice is fatal: these animals die at embryonic days 11 and 12 due to internal bleeding. They also exhibit gross deformities in the brain and spine as well as aberrations in fetal liver hematopoiesis.[19]
GATA3 variant 1 is alinear protein consisting of 444amino acids. GATA3 variant 2 protein is an identically structuredisoform of, but 1 amino acid shorter than, GATA3 variant 1. Differences, if any, in the functions of these two variants have not been reported.[20] With respect to the best studied variant, variant 1, but presumably also variant 2, one of thezinc fingerstructural motifs, ZNF2, is located at the protein'sC-terminus and binds to specificgene promoter DNA sequences to regulate the expression of the genes controlled by these promoters. The other zinc finger, ZNF1, is at the protein'sN-terminus and interacts with various nuclear factors, includingZinc finger protein 1 (i.e. ZFPM1, also termed Friends of GATA1 [i.e. FOG-1]) andZFPM2 (i.e. FOG-2), that modulate GATA3's gene-stimulating actions.[21]
The GATA3 transcription factor regulates the expression of genes involved in the development of various tissues as well as genes involved inphysiological as well aspathologicalhumoral inflammatory and allergic responses.[13][11]
GATA3 belongs to theGATA family oftranscription factors.Gene-deletion studies in mice indicate thatGata3 (mouse gene equivalent to GATA3) is critical for the embryonic development and/or function of various cell types (e.g.fat cells,neural crest cells,lymphocytes) and tissues (e.g. kidney, liver, brain, spinal cord, mammary gland).[12] Studies in humans implicate GATA3 in the following:
1) GATA3 is required for the development of theparathyroid gland, sensory components of the auditory system, and the kidney in animals and humans.[13] It may also contribute to the development of the vagina and uterus in humans.[12]
2) In humans, GATA3 is required for the development and/or function ofinnate lymphoid cells (ILCs), particularlyGroup 2 ILCs as well as for the development ofT helper cells,(Th cells), particularlyTh2 cells. Group 2 ILCs and Th2 cells, and thereby GATA3, are critical for the development of allergic andhumoral immune responses in humans. Comparable studies in animals implicate GATA3 in the development of lymphocytes that mediate allergic and humoral immunity as well as allergic and humoral immune responses.[22][12]
3) GATA3 promotes the secretion ofIL-4,IL-5, andIL-13 from Th2 cells in humans and has similar actions on comparable mouse lymphocytes. All three of these interleukins serve to promote allergic responses,[23]
4) GATA3 induces thematuration of precursor cells intobreastepithelial cells and maintains these cells in their mature state in mice and possibly humans.[24][25]
5) In mice, GATA3 is responsible for the normal development of various tissues including the skin, fat cells, thethymus, and the nervous system.[26][12]
Inactivating mutations in one of the two parental GATA3 genes cause thecongenital disorder ofhypoparathyroidism withsensorineural deafness andkidney malformations, i.e. theBarakat syndrome. This rare syndrome may occur in families or as a new mutation in an individual from a family with no history of the disorder. Mutations in GATA3 cause variable degrees of hypoparathyroidism, deafness, and kidney diseasebirth defects because of1) individual differences in thepenetrance of the mutation,2) a sporadic, and as yet unexplained, association with malformation of uterus and vagina, and3) mutations which extend beyond theGATA3 gene into chromosomal areas where mutations are responsible for developing other types of abnormalities which are characteristics of the DeGeorge syndrome 2. The Barakat syndrome is due to ahaploinsufficiency in GATA3 levels, i.e. levels of the transcription factor that are insufficient for the normal development of the cited tissues duringembryogenesis.[12][13][18]
Mouse studies indicate that inhibiting the expression of GATA3 usingantisense RNA methods suppresses allergic inflammation. The protein is overexpressed in the afflicted tissues of individuals with various forms of allergy including asthma, rhinitis, nasal polyps, and atopic eczema. This suggests that it may have a role in promoting these disorders.[27] In aphase IIA clinical study of individuals suffering allergen-induced asthma, inhalation ofDeoxyribozyme ST010, which specifically inactivates GATA3messenger RNA, for 28 days reduced early and late immune lung responses to inhaled allergen. The clinical benefit of inhibiting GATA3 in this disorder is thought to be due to interfering with the function of Group 2 ILCs and Th2 cells by, for example, reducing their production of IL-4, IL-13, and especially IL-5. Reduction in theseeosinophil-stimulating interleukins, it is postulated, reduces this cells ability to promote allergic reactivity and responses.[11][28] For similar reasons, this treatment might also prove to be clinical useful for treating other allergic disorders.[27]
GATA3 is one of the three genes mutated in >10% ofbreast cancers (Cancer Genome Atlas).[29] Studies in mice indicate that the gene is critical for the normal development of breast tissue and directly regulates luminal cell (i.e. cells lining mammary ducts) differentiation in experimentally induced breast cancer.[19][30] Analytic studies of human breast cancer tissues suggest thatGATA3 is required for specific type of low risk breast cancer (i.e. luminal A), is integral to the expression ofestrogen receptor alpha, and (in estrogen receptor negative/androgen receptor positive cancers)androgen receptor signaling.[31][32][33] These studies suggest thatGATA3 is involved in the development of at least certain types of breast cancer in humans. However, there is disagreement on this, with some studies suggesting that the expression of theGATA3 acts to inhibit and other studies suggesting that it acts to promote the development, growth, and/or spread of this cancer. Further studies are needed to elucidate the role, if any, of GATA3 in the development of breast cancer.[19]
Immuocytochemical analysis of GATA3 protein in breast cells is a valuable marker for diagnosing primary breast cancer, being tested as positive in up to 94% of cases. It is especially valuable for estrogen receptor positive breast cancers but is less sensitive (435-66% elevated), although still more valuable than many other markers, for diagnosingtriple-negative breast cancers. This analysis is widely used as a clinically valuable marker for breast cancer.[34][35]
GATA3 has been shown tointeract with the following transcription factor regulators:ZFPM1 andZFPM2;[21]LMO1;[37][38] andFOXA1.[39] These regulators may promote or inhibit GATA3 in stimulating the expression of its target genes.
^"GATA3 GATA binding protein 3".Entrez Gene. National Center for Biotechnology Information (NCBI), U.S. National Institutes of Health.
^Tremblay JJ, Viger RS (2003). "Novel roles for GATA transcription factors in the regulation of steroidogenesis".The Journal of Steroid Biochemistry and Molecular Biology.85 (2–5):291–298.doi:10.1016/S0960-0760(03)00211-5.
^Zheng WP, Flavell RA (June 2016). "Pillars Article: The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells. Cell. 1997. 89: 587-596".Journal of Immunology.196 (11):4426–4435.doi:10.1093/jimmunol/196.11.4426.PMID27207805.
^"Homo sapiens GATA binding protein 3 (GATA3)".RefSeqGene on Chromosome - Nucleotide. National Center for Biotechnology Information (NCBI), U.S. National Institutes of Health. 2019-05-21.
^abLindstrand A, Malmgren H, Verri A, Benetti E, Eriksson M, Nordgren A, et al. (May 2010). "Molecular and clinical characterization of patients with overlapping 10p deletions".American Journal of Medical Genetics. Part A.152A (5):1233–43.doi:10.1002/ajmg.a.33366.PMID20425828.S2CID22213304.
^abcDu F, Yuan P, Wang T, Zhao J, Zhao Z, Luo Y, et al. (November 2015). "The Significance and Therapeutic Potential of GATA3 Expression and Mutation in Breast Cancer: A Systematic Review".Medicinal Research Reviews.35 (6):1300–15.doi:10.1002/med.21362.PMID26313026.S2CID11668034.
^Ho IC, Pai SY (February 2007). "GATA-3 - not just for Th2 cells anymore".Cellular & Molecular Immunology.4 (1):15–29.PMID17349208.
^abBachert C, Zhang L, Gevaert P (December 2015). "Current and future treatment options for adult chronic rhinosinusitis: Focus on nasal polyposis".The Journal of Allergy and Clinical Immunology.136 (6):1431–1440.doi:10.1016/j.jaci.2015.10.010.PMID26654192.
^Dydensborg AB, Rose AA, Wilson BJ, Grote D, Paquet M, Giguère V, et al. (Jul 2009). "GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis".Oncogene.28 (29):2634–42.doi:10.1038/onc.2009.126.PMID19483726.S2CID2923763.
