| GATA binding protein 4 | OKDB#: 1033 |
| Symbols: | GATA4 | Species: | human | ||
| Synonyms: | TOF, ASD2, VSD1, TACHD | Locus: | 8p23.1 in Homo sapiens |
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| General Comment |
The GATA-binding proteins are a group of structurally related transcription factors that control gene expression and
differentiation in a variety of cell types. Members of this family of DNA-binding proteins recognize a consensus
sequence known as the 'GATA' motif, which is an important cis-element in the promoters of many genes. All
GATA-binding proteins contain 1 or 2 zinc finger motifs of the distinctive form CXNCX(17)CNXC.A fourth member of the GATA-binding family, GATA4, is
expressed in adult vertebrate heart, gut epithelium, and gonads. During fetal development, GATA4 is expressed in yolk
sac endoderm and cells involved in heart formation. Promoter and enhancer studies suggested that this factor may
regulate genes critical for myocardial differentiation and function.
NCBI Summary: This gene encodes a member of the GATA family of zinc-finger transcription factors. Members of this family recognize the GATA motif which is present in the promoters of many genes. This protein is thought to regulate genes involved in embryogenesis and in myocardial differentiation and function, and is necessary for normal testicular development. Mutations in this gene have been associated with cardiac septal defects. Additionally, alterations in gene expression have been associated with several cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015] |
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| General function | Nucleic acid binding, DNA binding, Transcription factor | ||||
| Comment | |||||
| Cellular localization | Nuclear | ||||
| Comment | GWAS123 | ||||
| Ovarian function | Follicle endowment, Follicle development, Steroid metabolism, Luteinization | ||||
| Comment | GATA4 and GATA6 Knockdown During Luteinization Inhibits Progesterone Production and Gonadotropin Responsiveness in the Corpus Luteum of Female Mice. Convissar SM et al. (2015) The surge of luteinizing hormone triggers the genomic reprogramming, cell differentiation, and tissue remodeling of the ovulated follicle, leading to the formation of the corpus luteum. During this process, called luteinization, follicular granulosa cells begin expressing a new set of genes that allow the resulting luteal cells to survive in a vastly different hormonal environment and to produce the extremely high amounts of progesterone (P4) needed to sustain pregnancy. To better understand the molecular mechanisms involved in the regulation of luteal P4 production in vivo, the transcription factors GATA4 and GATA6 were knocked down in the corpus luteum by crossing mice carrying Gata4 and Gata6 floxed genes with mice carrying Cre recombinase fused to the progesterone receptor. This receptor is expressed exclusively in granulosa cells after the luteinizing hormone surge, leading to recombination of floxed genes during follicle luteinization. The findings demonstrated that GATA4 and GATA6 are essential for female fertility, whereas targeting either factor alone causes subfertility. When compared to control mice, serum P4 levels and luteal expression of key steroidogenic genes were significantly lower in conditional knockdown mice. The results also showed that GATA4 and GATA6 are required for the expression of the receptors for prolactin and luteinizing hormone, the main luteotropic hormones in mice. The findings demonstrate that GATA4 and GATA6 are crucial regulators of luteal steroidogenesis and are required for the normal response of luteal cells to luteotropins.////////////////// The GATA-Keepers of Ovarian Development and Folliculogenesis. LaVoie HA 2014 et al. The transcription factors GATA4 and GATA6 are expressed in the embryonic and postnatal gonads and implicated as regulators of gonadal functions including steroidogenesis. The broad spatiotemporal expression and potentially overlapping functions of GATA factors complicates the task of defining all their roles. A role in embryonic development for both factors was indicated by early studies with genetically engineered mice lacking either Gata4 or Gata6, where homozygous deletion of either gene resulted in embryonic lethality. Gata4 null mice die between E8.5 and E10.5 with defects in ventral morphogenesis and cardiac development , and Gata6 null mice die between E6.5 and E7.5 with defects in endodermal differentiation . The early studies with Gata null mice revealed little about the role of GATA4 or GATA6 in gonadal development and nothing about postnatal roles for these factors. Forced overexpression of GATA4 and GATA6 in cultured cells indicated that some gonadal gene promoters, such as that for Star and CYP19a1, could be driven efficiently by either factor . In addition, RNAi-mediated depletion of GATA4, GATA6, and their combination in cultured ovarian granulosa cells revealed these GATA factors have both common and unique gene targets with combined GATA4 plus GATA6 depletion affecting a greater number of genes than with reduction of either factor alone . Yet, it was not clear if the data from cell culture studies actually translated to the intact gonad or was relevant to developmental changes that occur as germ cells mature, such as during follicle maturation in the ovary, and thus more refined gene targeting animal studies were needed.Since the original creation of the Gata4 and Gata6 null mice several additional genetic approaches have been utilized to study mainly GATA4 in the developing or postnatal gonad in mice. These genetic approaches have included analyses of heterozygous mice, use of inducible Cre vectors with floxed Gata4 or Gata6 genes, Amhr2Cre targeting Gata deletions to ovarian somatic cells, and knock-in studies disrupting the interaction of GATA4 with cofactor FOG2 (recently reviewed in . Each animal model had its limitations but each provided a piece of the puzzle regarding the role of GATA4 in gonadal development and function. GATA4 was found to be required for formation of the genital ridge of both sexes . For the ovary, the common finding in most of these studies was that depletion of GATA4 results in abnormal responses to exogenous gonadotropins and impaired fertility in adults. Fewer studies addressed GATA6 function in the ovary. Only recently have the combined functions of GATA4 and GATA6 in ovarian follicular development and function been investigated using Cre vectors targeting ovarian somatic cells. Combined requirement for GATA4 and GATA6 in postnatal follicle maturation was confirmed in a recent study by Bennett et al. who examined the individual and combined effects of GATA4 and GATA6 depletion in ovarian granulosa cells utilizing floxed Gata4 and Gata6 genes and Cre expression driven by the aromatase promoter (Cyp19Cre). Cyp19Cre is expressed in granulosa cells of all antral follicles with low or no expression in early follicles (primordial and primary) and no Cyp19Cre mediated recombination is observed before postnatal day 10 . ///////////////////////// GATA4 Reduction Enhances Cyclic AMP-stimulated Steroidogenic Acute Regulatory Protein mRNA and Progesterone Production in Luteinized Porcine Granulosa Cells. Hui YY et al. Previous studies with cultured granulosa cells implicated GATA4 in gonadotropin regulation of the steroidogenic acute regulatory protein (STAR) gene. Caveats to these prior studies exist. First, GATA4 levels are reduced in granulosa-luteal cells following the LH surge when GATA6 expression is relatively high. Second, STAR mRNA expression is negligible in granulosa cells until after the LH surge. Both exogenous GATA4 and GATA6 can transactivate STAR gene promoter constructs. We used an RNAi approach to determine the contributions of GATA4 and GATA6 to cyclic AMP analogue (cAMP) regulation of the endogenous STAR gene in luteinizing granulosa cells. STAR mRNA was stimulated by cAMP under control RNAi conditions. Surprisingly, GATA4 reduction by its respective RNAi approximately doubled the cAMP induction of STAR mRNA. At 24 h cAMP treatment, this augmentation was abolished by co-downregulation of GATA4+GATA6. GATA6 downregulation by itself did not alter STAR mRNA levels. GATA4+GATA6 co-downregulation elevated basal CYP11A mRNA at 24 h treatment but did not affect its induction by cAMP. Basal levels of HSD3B mRNA were reduced by GATA4 RNAi conditions leading to a greater fold-induction of its mRNA by cAMP. Fold cAMP-stimulated progesterone production was enhanced by GATA4 downregulation but not by GATA4+GATA6 co-downregulation. These data implicate GATA6 as the facilitator in cAMP-stimulated STAR mRNA and downstream progesterone accumulation under reduced GATA4 conditions. Data also demonstrate that basal levels of GATA4/6 are not required for cAMP-induction of the STAR gene. The altered ratio of GATA4 to GATA6 following ovulation may allow GATA6 to enhance STAR mRNA accumulation. Concerted regulation of the porcine StAR gene promoter activity by FSH and IGF-I in granulosa cells involves GATA-4 and C/EBP{beta} LaVoie HA, et al 2004 previously demonstrated that FSH alone or in combination with insulin-like growth factor I (IGF-I) activated the porcine steroidogenic acute regulatory protein (StAR) gene promoter in a concerted manner in primary cultures of granulosa cells. Studies were undertaken to further delineate cis- and trans-acting elements of the porcine promoter and mechanisms mediating FSH-stimulation and its augmentation by IGF-I. Mutation of several putative regulatory elements localized hormone-stimulated activity to the highly conserved GATA site and identified novel nucleotides downstream as a functional C/EBPbeta site. In granulosa cell nuclear extracts GATA-4 and C/EBPbeta formed a high molecular weight complex with an oligonucleotide spanning -76 to -32 bp of the porcine promoter. The intensity of this high molecular weight complex was increased in granulosa cell nuclear extracts by treatment with FSH alone and was enhanced with the combination of FSH and IGF-I at 2 to 3 h of treatment. GATA-4 and C/EBPbeta proteins were uniformly expressed with all treatments at time points associated with increased DNA binding. Treatment (2 h) with FSH alone or FSH + IGF-I increased phosphorylation of GATA-4 on a PKA-consensus site. The 38 kDa isoform of C/EBPbeta exhibited greater phosphorylation with FSH + IGF-I treatment. Porcine luteal cell nuclear extracts also demonstrated GATA-4 and C/EBPbeta binding to the -76 to -32 bp region of the promoter providing evidence for their cooperation in vivo. These data indicate that GATA-4 and C/EBPbeta are both required for FSH +/- IGF-I stimulation of the porcine StAR promoter in homologous granulosa cell cultures. Follicle Stimulating Hormone-Induced Activation of Gata4 Contributes in the Upregulation of Cyp19 Expression in Rat Granulosa Cells. Kwintkiewicz J et al. Several studies have suggested that the transcription factor GATA4 plays an important role in ovarian function. This study evaluated the effects of GATA4 on the regulation of the Cyp19 gene in primary rat granulosa cells under basal conditions and in response to stimulation by follicle-stimulating hormone (FSH). A significant increase in GATA4 mRNA, protein, and DNA binding activity was observed in rats treated with pregnant mare serum gonadotropin, a hormone that binds to the FSH receptors, and in granulosa cells incubated with FSH. Enrichment of the Cyp19 promoter was observed in granulosa cells treated with FSH after chromatin precipitation with an anti-GATA4 antibody. Mutation of the GATA binding site on the Cyp19 promoter and inhibition of GATA4 expression with specific small interference RNA significantly reduced FSH-enhanced Cyp19 expression, whereas overexpression of GATA4 increased Cyp19 promoter activity. A synergistic effect observed between GATA4 overexpression and FSH treatment in Cyp19 expression was abolished by mutating Ser105 in the GATA4 protein or by pretreating granulosa cells with a protein kinase A inhibitor. Inhibition of PI3-K/CK2 or ERK1/2 attenuated GATA4/FSH synergism, whereas the simultaneous blockade of PI3-K/CK2 and ERK1/2 activity eliminated Cyp19 stimulation. Finally, we demonstrated that FSH increases GATA4 phosphorylation and that GATA4 activation requires the activation of multiple kinases, including ERK1/2, PI3-K, and PKA. These findings demonstrate that GATA4 contributes in the regulation of Cyp19 expression in the rat ovary and provide the first evidence that FSH regulates GATA4 activity. | ||||
| Expression regulated by | FSH, Growth Factors/ cytokines, Eicosanoids, notch | ||||
| Comment | Notch signaling represses GATA4-induced expression of genes involved in steroid biosynthesis. George RM et al. (2015) Notch2 and Notch3 and elements of the Notch signaling network are dynamically expressed in developing follicles, where they are essential for normal granulosa cell proliferation and meiotic maturation. Notch receptors, ligands, and downstream effector genes are also expressed in testicular Leydig cells, predicting a potential role in regulating steroidogenesis. In this study, we sought to determine if Notch signaling in small follicles regulates the proliferation response of granulosa cells to follicle stimulating hormone and represses the up-regulation steroidogenic gene expression that occurs in response to FSH as the follicle grows. Inhibition of Notch signaling in small preantral follicles led to the up-regulation of the expression of genes in the steroid biosynthetic pathway. Similarly, progesterone secretion by MA-10 Leydig cells was significantly inhibited by constitutively active Notch. Together, these data indicated that Notch signaling inhibits steroidogenesis. GATA4 has been shown to be a positive regulator of steroidogenic genes, including steroidogenic acute regulatory protein, P450 aromatase, and 3Β-hydroxysteroid dehydrogenase. We observed that Notch downstream effectors HEY1, HEY2, and HEYL are able to differentially regulate these GATA-dependent promoters. These data are supported by the presence of HEY/HES binding sites in these promoters. These studies indicate that Notch signaling has a role in the complex regulation of the steroidogenic pathway.////////////////// GATA-4 is a granulosa cell factor employed in inhibin-{alpha} activation by the TGF-{beta} pathway. Anttonen M et al. Part of heterodimeric inhibin, inhibin-alpha is crucial for mammalian ovarian function. Regulation of inhibin-alpha expression in granulosa cells is both endocrine, primarily by follicle-stimulating hormone (FSH), and paracrine, primarily by members of the transforming growth factor beta (TGF-beta) superfamily. Smad proteins transmit TGF-beta signals to the nucleus, but the cooperating transcription factors involved in inhibin-alpha promoter activation remain unknown. Transcription factor GATA-4 regulates inhibin-alpha in gonadal cells, and the FSH cascade activates GATA-4. We hypothesized that the TGF-beta signalling cascade and GATA-4 also cooperate to regulate inhibin-alpha expression. In KK-1 granulosa tumour cells, which resemble normal granulosa cells and express inhibin-alpha, we found that TGF-beta upregulated GATA-4 expression. Transient transfection experiments in KK-1 cells demonstrated that dominant negative GATA-4 variants or mutations of GATA-binding sites in the inhibin-alpha promoter attenuated TGF-beta-induced gene activation. In GATA-4-deficient COS-7 cells, TGF-beta enhanced the expression of the inhibin-alpha promoter only in the presence of exogenous GATA-4. Smad3, but not Smad2, cooperated with GATA-4 in the transcriptional activation of the inhibin-alpha promoter, and immunoprecipitation experiments in KK-1 cells revealed a physical Smad3:GATA-4 interaction. Our data suggest that GATA-4, interacting with Smad3, is a cofactor for TGF-beta signalling to activate inhibin-alpha in granulosa cells. Prostaglandin E2 increases cyp19 expression in rat granulosa cells: Implication of GATA-4. Cai Z et al. The expression of Cyp19, the key gene of estrogen biosynthesis, in granulosa cells (GC) is essential for follicular growth and coordination of the ovulatory process. The goal of this study was to examine the effect of PGE2 and PGF2alpha on Cyp19 expression in undifferentiated and luteinized GC (UGC and LGC). In UGC, PGE2 increased Cyp19 mRNA and Cyp19 protein levels whereas PGF2alpha had no effect. In LGC, PGF2alpha decreased Cyp19 expression whereas PGE2 had no effect. Gene-reporter experiments demonstrated that PGE2 increases Cyp19 transcription in UGC. A protein kinase A inhibitor blocked PGE2-induced increase in Cyp19 promoter activity. PGE2 increased GATA-4 binding to the Cyp19 promoter. Mutation of the GATA binding site resulted in the loss of PGE2 stimulation. This study demonstrates that PGE2 stimulates Cyp19 expression in rat GC and suggests that GATA-4 may mediate (at least in part) the stimulatory effect of PGE2. | ||||
| Ovarian localization | Granulosa, Theca, Luteal cells, Ovarian tumor | ||||
| Comment | GATA-4 regulates Bcl-2 expression in ovarian granulosa cell tumors. Kyr?hti A et al. Excessive cell proliferation and decreased apoptosis have been implicated in the pathogenesis of ovarian granulosa cell tumors (GCTs). We hypothesized that transcription factor GATA-4 controls expression of the anti-apoptotic factor Bcl-2 and the cell cycle regulator cyclin D2 in normal and neoplastic granulosa cells. To test this hypothesis, a tissue microarray based on 80 GCTs was subjected to immunohistochemistry for GATA-4, Bcl-2 and cyclin D2 and the data were correlated to clinical and histopathological parameters. In addition, quantitative RT-PCR for GATA-4, Bcl-2 and cyclin D2 was performed on 21 human GCTs. A mouse GCT model was used to complement these studies. The role of GATA-4 in the regulation of Bcl-2 and ccdn2 (coding for cyclin D2) was studied by transactivation assays and by disrupting GATA-4 function with dominant negative approaches in mouse and human GCT cell lines. We found that GATA-4 expression correlated with Bcl-2 and cyclin D2 expression in human and murine GCTs. Moreover, GATA-4 enhanced Bcl-2 and cyclin D2 promoter activity in murine GCT cells. Whereas GATA-4 overexpression upregulated and dominant negative GATA-4 suppressed Bcl-2 expression in human GCT cells, the effects on cyclin D2 were negligible. Our results reveal a previously unknown relationship between GATA-4 and Bcl-2 in mammalian granulosa cells and GCTs, and suggest that GATA-4 influences granulosa cell fate by transactivating Bcl-2. Laitinen MPE, et al 2000 reported that transcription factors GATA-4 and GATA-6 and a GATA family cofactor, FOG-2, are expressed in human ovary and sex cord-derived ovarian tumors. In rodents, GATA-4 is expressed in granulosa cells of primary and early antral follicles, whereas GATA-6 is expressed in granulosa cells of late antral follicles and luteal glands. Both transcription factors can be detected in lesser amounts in theca cells and interstitial cells. Based on in situ hybridization and immunohistochemistry that GATA-4 and GATA-6 messenger RNA (mRNA) and GATA-4 protein are present in granulosa and theca cells in both preantral and antral follicles. Both human ovarian tissue samples and freshly isolated granulosa luteal (GL) cells derived from preovulatory follicles of gonadotropin-treated women express GATA-4, GATA-6, and FOG-2 transcripts. The mRNA for FOG-2, a recently discovered regulator of GATA-4, is coexpressed with GATA-4 in human ovary samples, normal granulosa cells, and in sex cord-derived tumors. The results demonstrate that GATA-4, GATA-6, and FOG-2 are expressed in human ovary and in granulosa and theca cell tumors. Our findings support a role for GATA-binding proteins in human ovarian folliculogenesis. Moreover, these data suggest that GATA factors may contribute to the phenotypes of sex cord-derived ovarian tumors. | ||||
| Follicle stages | Secondary, Antral, Preovulatory, Corpus luteum | ||||
| Comment | Vaskivuo TE et al 2001 studied the survival of human ovarian follicles from fetal to adult life and the expression of apoptosis-related proteins, and transcription factor GATA-4. They investigated the extent and localization of apoptosis in human fetal (aged 13-40 weeks) and adult ovaries. Furthermore, the expression of apoptosis-regulating proteins, bcl-2 and bax, and the relationship of transcription factor GATA-4 were studied. Apoptosis was found in ovarian follicles throughout fetal and adult life. During fetal development, apoptosis was localized mainly to primary oocytes and was highest between weeks 14-28, decreasing thereafter toward term. Expression of bcl-2 was observed only in the youngest fetal ovaries (weeks 13-14), and bax was present in the ovaries throughout the entire fetal period. In adult ovaries, apoptosis was detected in granulosa cells of secondary and antral follicles, and Bcl-2 and bax were expressed from primary follicles onwards. During fetal ovarian development, GATA-4 messenger RNA and protein were localized to the granulosa cells, with expression being highest in the youngest ovaries and decreasing somewhat toward term. | ||||
| Phenotypes |
PCO (polycystic ovarian syndrome) |
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| Mutations |
7 mutations
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: mouse
Species: human
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| Genomic Region | show genomic region | ||||
| Phenotypes and GWAS | show phenotypes and GWAS | ||||
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| created: | Oct. 3, 2000, midnight | by: |
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| last update: | April 6, 2020, 11:32 a.m. | by: | hsueh email: |
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