GATA3 (GATA binding protein 3)

2011-12-01   Mathieu Tremblay , Maxime Bouchard 

Goodman Cancer Research Centre, Department of Biochemistry, McGill University, Montreal, Canada

Identity

HGNC
LOCATION
10p14
LOCUSID
ALIAS
HDR,HDRS
FUSION GENES

DNA/RNA

Description

The GATA3 locus spans 20,51 kb and contains 6 exons.

Transcription

Two alternative exons 1 (1a and 1b) of the Gata3 locus are spliced to a common second exon, which contains the translation start site. All transcripts share exons 2 to 5 but transcript 1a and 1b splice to two variant exons 6 (6a and 6b respectively) giving rise to isoform a (1a-2-5-6a) and isoform b (1b-2-5-6b) (see figure 1) (Asnagli et al., 2002). The functional significance of these isoforms is unclear.

Proteins

Atlas Image
Figure 1. White boxes indicate a non-coding exonic sequence, and black boxes indicate coding sequences. Gata3 encodes a protein containing 2 transactivation domains (TA1 and TA2) and 2 Zn Finger domains (Zn1 and Zn2).

Description

The full length GATA3 protein contain either 443 AA (isoform a) or 444 AA (isoform b), corresponding to molecular weights of 47,9 kDa and 48,0 kDa respectively. The GATA3 protein contains two zinc finger motifs of a distinctive form CXNCX (17) and CNXC as well as two transactivation domains (TA1 and TA2). The N-terminal Zn finger (Zn1) is known to stabilize DNA binding and interact with other zinc finger proteins, whereas the C-terminal Zn finger (Zn2) binds DNA.

Expression

Hematopoietic system (blood, bone marrow, thymus, B, T, erythroid and myeloid lineages), blood vessels (endothelial cells), adipocytes, adrenal gland, ear, eye, bladder, mammary gland, prostate, seminal vesicle, kidney, CNS, hair follicle.

Localisation

Mostly nuclear.

Function

GATA3 acts as a transcription factor which binds to the consensus DNA sequence 5-(A/T)GATA(A/G)-3.

Gata3 gene inactivation in the mouse is embryonic lethal at mid-gestation (between embryonic days E11 and E12) (Tsai et al., 1994; Pandolfi et al., 1995). These mice display massive internal bleeding, marked growth retardation, severe deformities of the brain and spinal cord, and gross aberrations in fetal liver hematopoiesis. Lethality of Gata3 mutant embryos can be rescued by administration of catechol intermediates during pregnancy as it corrects the reduction in noradrenalin synthesis in the sympathetic nervous system (SNS) caused by reduced expression of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH). Pharmacologically rescued mutant embryos present developmental defects in structures derived from cephalic neural crest cells (Lim et al., 2000).
In the kidney, Gata3 is important for nephric (Wolffian) duct elongation and metanephric kidney induction (Grote et al., 2006; Grote et al., 2008). Conditional inactivation of Gata3 in the nephric duct leads to hydronephrosis and defective ureter maturation, partly due to the downregulation of the receptor tyrosine kinase gene Ret (Song et al., 2009; Chia et al., 2011).

Gata3 plays an important role in mammary gland maturation and cancer. The conditional deletion of Gata3 in the mouse mammary epithelium is associated with a failure in terminal end bud formation at puberty causing severe defects in mammary development. Moreover, Gata3 loss in adult mice leads to an expansion of undifferentiated luminal cells and basement-membrane detachment, which promotes tumor dissemination (Kouros-Mehr et al., 2006; Asselin-Labat et al., 2007; Kouros-Mehr et al., 2008; Kouros-Mehr et al., 2008; Dydensborg et al., 2009).
Reexpression of Gata3 drives invasive breast cancer cells to undergo the reversal of epithelial-mesenchymal transition, reducing both the tumorigenicity and metastatic potential through reduction of lysyl oxidase (LOX) expression, a metastasis-promoting, matrix-remodeling protein (Chu et al., 2011; Yan et al., 2010). Moreover, Gata3 interact with BRCA1 to repress the expression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including Foxc1, Foxc2, Cxcl1 and P-cadherin. Loss of GATA3 expression also contributes to drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs (Tkocz et al., 2011).

In T cells, Gata3 acts at multiple stages of thymocyte differentiation. It is indispensable for early thymic progenitor differentiation (Hosoya et al., 2009) and for thymocytes to pass through beta selection and T cell commitment. Gata3 is also necessary for single-positive CD4 thymocyte development as well as for Th1-Th2 lineage commitment (Ting et al., 1996; Zhang et al., 1997; Zheng and Flavell, 1997; Zhang et al., 1998; Pai et al., 2003). As master regulator of Th2 lineage commitment, GATA3 acts either as a transcriptional activator or repressor through direct action at many critical loci encoding cytokines, cytokine receptors, signaling molecules as well as transcription factors that are involved in the regulation of T(h)1 and T(h)2 differentiation (Jenner et al., 2009). For example, it regulates the expression of Th2 lineage specific cytokine gene such as IL5 and repress the Th1 lineage specific genes IL-12 receptor β2 and STAT4 as well as neutralizing RUNX3 function through protein-protein interaction. Mice lacking Gata3 produce IFN-gamma rather than Th2 cytokines (IL5 and IL13) in response to infection (Zhu et al., 2004). It acts in mutual opposition to the transcription factor T-bet, as T-bet promotes whereas GATA3 represses Fut7 transcription (Hwang et al., 2005). It also acts with Tbx21 to regulate cell lineage-specific expression of lymphocyte homing receptors and cytokine in both Th1 and Th2 lymphocyte subsets (Chen et al., 2006). Enforced expression of Gata3 during T cell development induced CD4(+)CD8(+) double-positive (DP) T cell lymphoma (Nawijn et al., 2001a; Nawijn et al., 2001b).

Gata3 is essential for the expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation. Gata3 overexpression causes enhanced allergen-induced airway inflammation and airway remodeling, including subepithelial fibrosis, and smooth muscle cell hyperplasia (Kiwamoto et al., 2006). It additionally has a critical function in regulatory T cells and immune tolerance since deletion of Gata3 specifically in regulatory T cells led to a spontaneous inflammatory disorder in mice (Wang et al., 2011).

Gata3 is critical for the differentiation and survival of parathyroid progenitor cells through regulation of GCM2/B (Grigorieva et al., 2010). Gata3 is essential for the survival but not the differentiation of sympathetic neurons and adrenal chromaffin cells (Tsarovina et al., 2010) and acts with Hand2 to induce noradrenergic genes during development (Pellegrino et al., 2011).

Gata3 drives trophoblast differentiation and has been shown to induce a trophoblast cell fate in embryonic stem cells (Ralston et al., 2010). Gata3 and its close paralog Gata2 are important for trophectoderm lineage specification (Ray et al., 2009).

During adipogenesis, Gata3 is a negative regulator of differentiation which needs to be downregulated to permit expression of the peroxisome proliferator-activated receptor-gamma and preadipocyte to adipocyte transition (Tong et al., 2000).

In keratinocytes, Gata3 is a key regulator of KLK1 expression and is involved in growth control and the maintenance of a differentiated state in epithelial cells (Son do et al., 2009).
In hair follicle morphogenesis Gata3 controls cell fate decision between the inner root sheath and hair shaft cell (Kaufman et al., 2003; Kurek et al., 2007).

Gata3 is essential for lens cells differentiation and proper cell cycle control (Maeda et al., 2009) as well as in the morphogenesis of the mouse inner ear (Karis et al., 2001; Lilleväli et al., 2004).
It plays an essential role during angiogenesis through ANGPT1-TEK and Ang-1-Tie2-mediated signaling in large vessel endothelial cells.
A role for Gata3 in the developing heart was revealed by pharmacological rescue of Gata3-null embryos, which survive until birth and harbor ventricular septal defect (VSD), double-outlet of right ventricle (DORV), anomalies of the aortic arch (AAA) and persistent truncus arteriosus (PTA) (Raid et al., 2009).

Homology

GATA3 is a member of the GATA family of proteins comprising 6 paralogs. GATA1, GATA2 and GATA3 are mainly expressed in hematopoiesis, whereas GATA4, GATA5 and GATA6 are expressed in mesoderm and endoderm-derived tissue. All six GATA family members share a highly conserved double zinc-finger DNA-binding domain. GATA3 Zn fingers are most closely conserved with those of GATA1.

Mutations

Germinal

Deletion of chromosome 10 (del10p) and GATA3 gene mutations leading to haploinsufficiency associated with HDR syndrome (Van Esch et al., 2000; Nesbit et al., 2004; Ali et al., 2007; Lindstrand et al., 2010).

Somatic

Heterozygous frameshift mutations close to the second Zn finger domain of GATA3 are associated with familial and sporadic breast tumors (Ciocca et al., 2009; Arnold et al., 2010).

Implicated in

Entity name
Sporadic breast cancer and familial breast cancer
Cytogenetics
Somatic mutations in GATA3: familial breast tumors harbored heterozygous frameshift somatic mutations close to the second Zn finger domain.
Oncogenesis
GATA3 is mutated in ~5% of sporadic and ~13% of familial breast tumors (Usary et al., 2004; Mehra et al., 2005; Arnold et al., 2010).
GATA3 is an important predictor of disease outcome in breast cancer patients whereby low GATA3 expression was a significant predictor of disease-related death (Yoon et al., 2010).
Entity name
HDR (Barakat) syndrome
Disease
Familial hypoparathyroidism - deafness - renal defects syndrome.
- Hypoparathyroidism.
- Sensorineural deafness, bilateral, symmetric, deficit affecting all frequencies but slightly more marked at the higher end of the frequency range.
- Renal defects such as aplasia, dysplasia and vesicoureteral reflux, associated or not to genital tract malformation.
Prognosis
Depends on the penetrance of renal defects.
Cytogenetics
- Deletion of chromosome 10 (del10p).
- GATA3 gene mutations leading to functional haploinsufficiency.
Atlas Image
Figure 2. Both chromosome deletion and point mutations of the GATA3 locus have been associated with HDR syndrome.

Bibliography

Pubmed IDLast YearTitleAuthors
172106742007Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor.Ali A et al
191892132010Frequent somatic mutations of GATA3 in non-BRCA1/BRCA2 familial breast tumors, but not in BRCA1-, BRCA2- or sporadic breast tumors.Arnold JM et al
119709652002Cutting edge: Identification of an alternative GATA-3 promoter directing tissue-specific gene expression in mouse and human.Asnagli H et al
171870622007Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation.Asselin-Labat ML et al
170750442006Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes.Chen GY et al
215217372011Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice.Chia I et al
218922082012GATA3 inhibits lysyl oxidase-mediated metastases of human basal triple-negative breast cancer cells.Chu IM et al
190842672009The significance of GATA3 expression in breast cancer: a 10-year follow-up study.Ciocca V et al
194837262009GATA3 inhibits breast cancer growth and pulmonary breast cancer metastasis.Dydensborg AB et al
204848212010Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2.Grigorieva IV et al
191124892008Gata3 acts downstream of beta-catenin signaling to prevent ectopic metanephric kidney induction.Grote D et al
163191122006Pax 2/8-regulated Gata 3 expression is necessary for morphogenesis and guidance of the nephric duct in the developing kidney.Grote D et al
199340222009GATA-3 is required for early T lineage progenitor development.Hosoya T et al
156620162005T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3.Hwang ES et al
198050382009The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes.Jenner RG et al
111352392001Transcription factor GATA-3 alters pathway selection of olivocochlear neurons and affects morphogenesis of the ear.Karis A et al
129230592003GATA-3: an unexpected regulator of cell lineage determination in skin.Kaufman CK et al
166143502006Transcription factors T-bet and GATA-3 regulate development of airway remodeling.Kiwamoto T et al
183587092008GATA-3 and the regulation of the mammary luminal cell fate.Kouros-Mehr H et al
171510172007Transcriptome and phenotypic analysis reveals Gata3-dependent signalling pathways in murine hair follicles.Kurek D et al
154995602004Partially overlapping expression of Gata2 and Gata3 during inner ear development.Lilleväli K et al
108356392000Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system.Lim KC et al
204258282010Molecular and clinical characterization of patients with overlapping 10p deletions.Lindstrand A et al
196236122009Transcription factor GATA-3 is essential for lens development.Maeda A et al
163571292005Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis.Mehra R et al
114410762001Enforced expression of GATA-3 in transgenic mice inhibits Th1 differentiation and induces the formation of a T1/ST2-expressing Th2-committed T cell compartment in vivo.Nawijn MC et al
114410752001Enforced expression of GATA-3 during T cell development inhibits maturation of CD8 single-positive cells and induces thymic lymphoma in transgenic mice.Nawijn MC et al
149853652004Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome.Nesbit MA et al
146703032003Critical roles for transcription factor GATA-3 in thymocyte development.Pai SY et al
75503121995Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis.Pandolfi PP et al
212418052011Cytokines inhibit norepinephrine transporter expression by decreasing Hand2.Pellegrino MJ et al
189551342009Lack of Gata3 results in conotruncal heart anomalies in mouse.Raid R et al
200811882010Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2.Ralston A et al
191060992009Context-dependent function of regulatory elements and a switch in chromatin occupancy between GATA3 and GATA2 regulate Gata2 transcription during trophoblast differentiation.Ray S et al
192323842009Abundant expression of Kallikrein 1 gene in human keratinocytes was mediated by GATA3.Son DN et al
196749702009Critical role for GATA3 in mediating Tie2 expression and function in large vessel endothelial cells.Song H et al
89454761996Transcription factor GATA-3 is required for development of the T-cell lineage.Ting CN et al
221207232012BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers.Tkocz D et al
110217982000Function of GATA transcription factors in preadipocyte-adipocyte transition.Tong Q et al
80785821994An early haematopoietic defect in mice lacking the transcription factor GATA-2.Tsai FY et al
207027122010The Gata3 transcription factor is required for the survival of embryonic and adult sympathetic neurons.Tsarovina K et al
153618402004Mutation of GATA3 in human breast tumors.Usary J et al
109356392000GATA3 haplo-insufficiency causes human HDR syndrome.Van Esch H et al
219249282011An essential role of the transcription factor GATA-3 for the function of regulatory T cells.Wang Y et al
201899932010GATA3 inhibits breast cancer metastasis through the reversal of epithelial-mesenchymal transition.Yan W et al
210784392010Higher levels of GATA3 predict better survival in women with breast cancer.Yoon NK et al
92611811997Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene.Zhang DH et al
97801451998Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3.Zhang DH et al
91607501997The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.Zheng W et al
154759592004Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses.Zhu J et al

Other Information

Locus ID:

NCBI: 2625
MIM: 131320
HGNC: 4172
Ensembl: ENSG00000107485

Variants:

dbSNP: 2625
ClinVar: 2625
TCGA: ENSG00000107485
COSMIC: GATA3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000107485ENST00000346208P23771
ENSG00000107485ENST00000379328P23771
ENSG00000107485ENST00000481743A0A2R8Y2A9
ENSG00000107485ENST00000643001A0A2R8Y4T2

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

PathwaySourceExternal ID
Inflammatory bowel disease (IBD)KEGGhsa05321
Inflammatory bowel disease (IBD)KEGGko05321
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
HemostasisREACTOMER-HSA-109582
Factors involved in megakaryocyte development and platelet productionREACTOMER-HSA-983231
DeubiquitinationREACTOMER-HSA-5688426
Ub-specific processing proteasesREACTOMER-HSA-5689880
Th1 and Th2 cell differentiationKEGGko04658
Th1 and Th2 cell differentiationKEGGhsa04658
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164760860pegaspargaseChemicalClinicalAnnotationassociatedPD24141364
PA448492asparaginaseChemicalClinicalAnnotationassociatedPD24141364
PA449165cyclophosphamideChemicalClinicalAnnotationassociatedPD24141364
PA449177cytarabineChemicalClinicalAnnotationassociatedPD24141364
PA449212daunorubicinChemicalClinicalAnnotationassociatedPD24141364
PA449247dexamethasoneChemicalClinicalAnnotationassociatedPD24141364
PA449412doxorubicinChemicalClinicalAnnotationassociatedPD24141364
PA450198leucovorinChemicalClinicalAnnotationassociatedPD24141364
PA450379mercaptopurineChemicalClinicalAnnotationassociatedPD24141364
PA450428methotrexateChemicalClinicalAnnotationassociatedPD24141364
PA451100prednisoneChemicalClinicalAnnotationassociatedPD24141364
PA451663thioguanineChemicalClinicalAnnotationassociatedPD24141364
PA451879vincristineChemicalClinicalAnnotationassociatedPD24141364

References

Pubmed IDYearTitleCitations
230633302012The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells.214
176582792007Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch.171
176167092007Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer.152
231728722013GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility.126
163571292005Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis.101
177034122007Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes.100
153618402004Mutation of GATA3 in human breast tumors.98
198050382009The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes.97
241413642013Inherited GATA3 variants are associated with Ph-like childhood acute lymphoblastic leukemia and risk of relapse.85
197986942010GATA3 in development and cancer differentiation: cells GATA have it!83

Citation

Mathieu Tremblay ; Maxime Bouchard

GATA3 (GATA binding protein 3)

Atlas Genet Cytogenet Oncol Haematol. 2011-12-01

Online version: http://atlasgeneticsoncology.org/gene/107/gata3id107ch10p14