The Zinc Finger-containing Transcription Factors GATA-4, -5, and -6 (2000)

myocyte enhancer factor-2 thyroid transcription factor-1 nuclear factor of activated T-cells-c4 friend of GATA-2 CREB-binding protein Six GATA transcription factors have been identified in vertebrates, each of which contains a highly conserved DNA binding domain consisting of two zinc fingers of the motif Cys-X2-Cys-X17-Cys-X2-Cys (1Evans T. Felsenfeld G. Cell. 1989; 58: 877-885Abstract Full Text PDF PubMed Scopus (450) Google Scholar, 2Tsai S.-F. Martin D.I. Zon L.I. D'Andrea A.D. Wong G.G. Orkin S.H. Nature. 1989; 339: 446-451Crossref PubMed Scopus (663) Google Scholar, 3Yamamoto M. Ko L.J. Leonard M.W. Beug H. Orkin S.H. Engel J.D. Genes Dev. 1990; 4: 1650-1662Crossref PubMed Scopus (451) Google Scholar, 4Arceci R.J. King A.A.J. Simon M.C. Orkin S.H. Wilson D.B. Mol. Cell. Biol. 1993; 13: 2235-2246Crossref PubMed Google Scholar, 5Kelley C. Blumberg H. Zon L.I. Evans T. Development. 1993; 118: 817-827Crossref PubMed Google Scholar, 6Laverriere A.C. MacNeill C. Mueller C. Poelmann R.E. Burch J.B.E. Evans T. J. Biol. Chem. 1994; 269: 23177-23184Abstract Full Text PDF PubMed Google Scholar, 7Morrisey E.E. Ip H.S. Lu M.M. Parmacek M.S. Dev. Biol. 1996; 177: 309-322Crossref PubMed Scopus (382) Google Scholar, 8Morrisey E.E. Ip H.S. Tang Z. Lu M.M. Parmacek M.S. Dev. Biol. 1997; 183: 21-36Crossref PubMed Scopus (213) Google Scholar, 9Suzuki E. Evans T. Lowry J. Truong L. Bell D.W. Testa J.R. Walsh K. Genomics. 1996; 38: 283-290Crossref PubMed Scopus (117) Google Scholar) that directs binding to the nucleotide sequence element (A/T)GATA(A/G) (10Ko J.L. Engel J.D. Mol. Cell. Biol. 1993; 13: 4011-4022Crossref PubMed Scopus (505) Google Scholar, 11Merika M. Orkin S.H. Mol. Cell. Biol. 1993; 13: 3999-4010Crossref PubMed Scopus (560) Google Scholar). Based on their expression patterns, the GATA proteins have been divided into two subfamilies, GATA-1, -2, and -3 and GATA-4, -5, and -6. GATA-1, -2, and -3 genes are prominently expressed in hematopoietic stem cells where they regulate differentiation-specific gene expression in T-lymphocytes, erythroid cells, and megakaryocytes (reviewed in Ref. 12Orkin S.H. Int. J. Dev. Biol. 1998; 42: 927-934PubMed Google Scholar). GATA-4, -5, and -6 genes are expressed in various mesoderm- and endoderm-derived tissues such as heart, liver, lung, gonad, and gut where they play critical roles in regulating tissue-specific gene expression (4Arceci R.J. King A.A.J. Simon M.C. Orkin S.H. Wilson D.B. Mol. Cell. Biol. 1993; 13: 2235-2246Crossref PubMed Google Scholar, 5Kelley C. Blumberg H. Zon L.I. Evans T. Development. 1993; 118: 817-827Crossref PubMed Google Scholar, 6Laverriere A.C. MacNeill C. Mueller C. Poelmann R.E. Burch J.B.E. Evans T. J. Biol. Chem. 1994; 269: 23177-23184Abstract Full Text PDF PubMed Google Scholar, 7Morrisey E.E. Ip H.S. Lu M.M. Parmacek M.S. Dev. Biol. 1996; 177: 309-322Crossref PubMed Scopus (382) Google Scholar, 8Morrisey E.E. Ip H.S. Tang Z. Lu M.M. Parmacek M.S. Dev. Biol. 1997; 183: 21-36Crossref PubMed Scopus (213) Google Scholar, 9Suzuki E. Evans T. Lowry J. Truong L. Bell D.W. Testa J.R. Walsh K. Genomics. 1996; 38: 283-290Crossref PubMed Scopus (117) Google Scholar). Consistent with the observed expression patterns for GATA-4, -5, and -6, targeted disruption of each gene in the mouse has revealed important functions in heart, endoderm, lung epithelium, and genitourinary tract formation. Here we will discuss the biochemical characteristics and transcriptional regulatory roles of GATA-4, -5, and -6 transcription factors. The mouse GATA-4, -5, and -6 genes encode proteins of 48, 42, and 45 kDa, respectively (4Arceci R.J. King A.A.J. Simon M.C. Orkin S.H. Wilson D.B. Mol. Cell. Biol. 1993; 13: 2235-2246Crossref PubMed Google Scholar, 7Morrisey E.E. Ip H.S. Lu M.M. Parmacek M.S. Dev. Biol. 1996; 177: 309-322Crossref PubMed Scopus (382) Google Scholar, 8Morrisey E.E. Ip H.S. Tang Z. Lu M.M. Parmacek M.S. Dev. Biol. 1997; 183: 21-36Crossref PubMed Scopus (213) Google Scholar). Each protein contains a highly conserved DNA binding domain that consists of two zinc finger motifs and two adjacent stretches of basic amino acids (Fig. 1, A and B).GATA-4, -5, and -6 are ∼85% identical to one another at the amino acid level within the DNA binding region containing the zinc finger and basic regions (Fig. 1 B). Furthermore, mouse GATA-4 is ∼70% identical to mouseGATA-1 and Drosophila pannier within the DNA binding region, suggesting a high degree of sequence conservation between divergent GATA family members and across evolutionary disparate organisms (Fig. 1 A). Given the high degree of sequence identity between GATA protein family members, predictions can be drawn as to the residues that mediate DNA binding in GATA-4, -5, and -6 based on structural and mutagenesis studies performed in GATA-1. A number of reports have demonstrated that only the C-terminal zinc finger and adjacent basic domain are necessary for specific DNA binding in vitro (13Omichinski J.G. Trainor C. Evans T. Gronenborn A.M. Clore G.M. Felsenfeld G. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 1676-1680Crossref PubMed Scopus (119) Google Scholar, 14Visvader J.E. Crossley M. Hill J. Orkin S.H. Adams J.M. Mol. Cell. Biol. 1995; 15: 634-641Crossref PubMed Google Scholar, 15Yang H-Y. Evans T. Mol. Cell. Biol. 1992; 12: 4562-4570Crossref PubMed Scopus (136) Google Scholar). Using NMR, GATA-1 was shown to interact with 8 nucleotide base pairs when bound to DNA such that the N-terminal and central portion of the GATA-1 DNA binding domain made specific contacts within the major groove, whereas the C-terminal portion made site-specific interactions within the minor groove (13Omichinski J.G. Trainor C. Evans T. Gronenborn A.M. Clore G.M. Felsenfeld G. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 1676-1680Crossref PubMed Scopus (119) Google Scholar). Whereas just the C-terminal finger of GATA-1 is required for specific DNA binding, the N-terminal finger can interact with adjacent GATA DNA sequence elements or with protein cofactors (16Weiss M.J., Yu, C. Orkin S.H. Mol. Cell. Biol. 1997; 17: 1642-1651Crossref PubMed Scopus (292) Google Scholar, 17Trainor C.D. Omichinski J.G. Vandergon T.L. Gronenborn A.M. Clore G.M. Felsenfeld G. Mol. Cell. Biol. 1996; 16: 2238-2247Crossref PubMed Scopus (195) Google Scholar). Protein domain deletion analysis of GATA-4 confirms that the C-terminal zinc finger is necessary and sufficient for DNA binding, as with GATA-1 (18Morrisey E.E. Ip H.S. Tang Z. Parmacek M.S. J. Biol. Chem. 1997; 272: 8515-8524Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). The nuclear localization and transcriptional activation domains of GATA-4 have also been identified (18Morrisey E.E. Ip H.S. Tang Z. Parmacek M.S. J. Biol. Chem. 1997; 272: 8515-8524Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Deletion analysis suggests that a strong nuclear localization sequence is present within the basic domain adjacent to the C-terminal finger (amino acids 251–324), whereas two separate transcriptional activation domains are present within the N terminus of the protein (18Morrisey E.E. Ip H.S. Tang Z. Parmacek M.S. J. Biol. Chem. 1997; 272: 8515-8524Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar) (Fig. 1 A). Interestingly these transcriptional activation domains are partially conserved in GATA-5 and -6, suggesting a similar mechanism of transcriptional activation within the GATA-4, -5, and -6 subfamily (18Morrisey E.E. Ip H.S. Tang Z. Parmacek M.S. J. Biol. Chem. 1997; 272: 8515-8524Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). However, a naturally occurring splice variant of GATA-5 lacking the N-terminal activation domain still promotes modest transcriptional activation suggesting the presence of a weak transcriptional activation domain in the C terminus of GATA-5 (19MacNeill C. Ayres B. Laverriere A.C. Burch J.B. J. Biol. Chem. 1997; 272: 8396-8401Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Using polymerase chain reaction site selection, GATA-1, -2, and -3 were each determined to bind the DNA consensus site (A/T)GATA(A/G), whereas GATA-2 and GATA-3 were also capable of binding the GATA-like site AGATCTT (10Ko J.L. Engel J.D. Mol. Cell. Biol. 1993; 13: 4011-4022Crossref PubMed Scopus (505) Google Scholar, 11Merika M. Orkin S.H. Mol. Cell. Biol. 1993; 13: 3999-4010Crossref PubMed Scopus (560) Google Scholar). Characterization of the 5′-regulatory regions of numerous genes has demonstrated that GATA-4, -5, and -6 factors also interact with a DNA sequence element containing a core GATA motif. More recently, polymerase chain reaction site selection with GATA-6 protein demonstrated an order of site preference to be GATA>GATT>GATC (20Sakai Y. Nakagawa R. Sato R. Maeda M. Biochem. Biophys. Res. Commun. 1998; 250: 682-688Crossref PubMed Scopus (41) Google Scholar). These analyses suggest that although GATA factors universally recognize a GATA DNA sequence element, subtle differences in the GATA core DNA motif might promote differential binding among coexpressed GATA family members within a specific tissue. Indeed, GATA-4, but not GATA-2 or GATA-3, specifically regulates expression of the interleukin-5 gene in a human T-cell line (21Yamagata T. Nishida J. Sakai R. Tanaka T. Honda H. Hirano N. Mano H. Yazaki Y. Hirai H. Mol. Cell. Biol. 1995; 15: 3830-3839Crossref PubMed Scopus (80) Google Scholar). In addition, activation of the α- and β-myosin heavy chain promoters preferentially utilized GATA-4 over GATA-6 in cardiac myocytes (22Charron F. Paradis P. Bronchain O. Nemer G. Nemer M. Mol. Cell. Biol. 1999; 19: 4355-4365Crossref PubMed Scopus (192) Google Scholar). Finally, the promoter of the novel phosphoprotein gene Dab2 was regulated by GATA-6, but not GATA-4, in visceral endoderm (23Morrisey E.E. Musco S. Chen M.Y. Lu M.M. Leiden J.M. Parmacek M.S. J. Biol. Chem. 2000; 275: 19949-19954Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Collectively, these studies indicate that although GATA-4, -5, and -6 each bind a GATA or GATA-like sequence element, their individual affinities for various promoters might depend on flanking nucleotide sequences or even on interactions with cofactors and other transcription factors. Such interactions might also provide a complex transcriptional code that allows programming of tissue-specific gene expression, despite a relatively broad expression pattern in multiple mesodermal and endodermal derived tissues. In the adult mouse, GATA-4 mRNA is detected in the heart, ovary, testis, lung, liver, and small intestine (4Arceci R.J. King A.A.J. Simon M.C. Orkin S.H. Wilson D.B. Mol. Cell. Biol. 1993; 13: 2235-2246Crossref PubMed Google Scholar). In embryonic and fetal mice, GATA-4 is expressed in the heart, proximal and distal gut, testis, ovary, liver, visceral endoderm, and parietal endoderm (4Arceci R.J. King A.A.J. Simon M.C. Orkin S.H. Wilson D.B. Mol. Cell. Biol. 1993; 13: 2235-2246Crossref PubMed Google Scholar, 7Morrisey E.E. Ip H.S. Lu M.M. Parmacek M.S. Dev. Biol. 1996; 177: 309-322Crossref PubMed Scopus (382) Google Scholar). GATA-5 gene is expressed in the adult small intestine, stomach, bladder, and lungs whereas developmentally expression is detected in the allantois, heart, outflow tract, lung bud, urogenital ridge, bladder, and gut epithelium (8Morrisey E.E. Ip H.S. Tang Z. Lu M.M. Parmacek M.S. Dev. Biol. 1997; 183: 21-36Crossref PubMed Scopus (213) Google Scholar). Finally, mouseGATA-6 is expressed in the adult heart, aorta, stomach, small intestine, and bladder and weakly in the liver and lung (7Morrisey E.E. Ip H.S. Lu M.M. Parmacek M.S. Dev. Biol. 1996; 177: 309-322Crossref PubMed Scopus (382) Google Scholar). During embryonic and fetal development, GATA-6 mRNA is detected in the primitive streak, allantois, visceral endoderm, heart, lung buds, urogenital ridge, vascular smooth muscle cells, and the epithelial layer of the stomach, small intestine, and large intestine (7Morrisey E.E. Ip H.S. Lu M.M. Parmacek M.S. Dev. Biol. 1996; 177: 309-322Crossref PubMed Scopus (382) Google Scholar, 9Suzuki E. Evans T. Lowry J. Truong L. Bell D.W. Testa J.R. Walsh K. Genomics. 1996; 38: 283-290Crossref PubMed Scopus (117) Google Scholar, 24Narita N. Heikinheimo M. Bielinska M. White R.A. Wilson D.B. Genomics. 1996; 36: 345-348Crossref PubMed Scopus (45) Google Scholar, 25Huggon I.C. Davies A. Gove C. Moscoso G. Moniz C. Foss Y. Farzaneh F. Towner P. Biochim. Biophys. Acta. 1997; 1353: 98-102Crossref PubMed Scopus (25) Google Scholar). Collectively, these studies indicate that most tissues of either mesodermal or endodermal origin express one or more GATA-4, -5, or -6 factors at some point during development. Given these characteristic broad fields of expression one might predict that GATA-4, -5, and -6 factors are unlikely to act as master regulators of cell type specificity or determination. For example, the MyoD family of basic helix-loop-helix transcription factors is exclusively expressed in skeletal muscle, where they act as master regulators of myoblast cell identity and differentiation. However, it remains possible that GATA-4, -5, and -6 might still serve a function in regulating cell type specification or determination through unique interactions with other semi-restricted transcription factors. Such a notion is also consistent with the observed role of GATA-1, -2, and -3 as master regulators of erythroid and lymphoid cell identity, despite the observation that each factor is expressed outside hematopoietic cell lineages (12Orkin S.H. Int. J. Dev. Biol. 1998; 42: 927-934PubMed Google Scholar). Targeted disruption of the GATA-4, -5, and -6genes in the mouse has revealed phenotypes consistent with their individual expression patterns. Mice null for GATA-4 die between embryonic day 8 and 9 because of defects in heart morphogenesis and ventral closure of the foregut (26Molkentin J.D. Lin Q. Duncan S.A. Olson E.N. Genes Dev. 1997; 11: 1061-1072Crossref PubMed Scopus (947) Google Scholar, 27Kuo C.T. Morrisey E.E. Anandappa R. Sigrist K. Lu M.M. Parmacek M.S. Soudais C. Leiden J.M. Genes Dev. 1997; 11: 1048-1060Crossref PubMed Scopus (860) Google Scholar). Specifically,GATA-4 null mice present with cardia bifida because of ineffective ventral fusion of the lateral aspects of the embryo and the subsequent formation of the foregut. Aberrant heart formation inGATA-4 null mice is likely a secondary effect associated with an intrinsic defect in the definitive endoderm that underlies the splanchnic mesoderm containing the cardiac field (28Narita N. Bielinska M. Wilson D.B. Dev. Biol. 1997; 189: 270-274Crossref PubMed Scopus (172) Google Scholar). This interpretation is further supported by the observation thatGATA-4 null embryonic stem cells can generate cardiac myocytes but are partially defective in their ability to generate visceral endoderm and definitive endoderm of the foregut (27Kuo C.T. Morrisey E.E. Anandappa R. Sigrist K. Lu M.M. Parmacek M.S. Soudais C. Leiden J.M. Genes Dev. 1997; 11: 1048-1060Crossref PubMed Scopus (860) Google Scholar, 29Narita N. Bielinska M. Wilson D.B. Development. 1997; 124: 3755-3764PubMed Google Scholar, 30Soudais C. Bielinska M. Heikinheimo M. MacArthur C.A. Narita N. Saffitz J.E. Simon M.C. Leiden J.M. Wilson D.B. Development. 1995; 121: 3877-3888PubMed Google Scholar). Finally, a role for GATA-4 in heart development is further suggested by the identification of a deletion in human chromosome 8p23.1 that contains the GATA-4 gene and is associated with congenital heart disease (31Pehlivan T. Pober B.R. Brueckner M. Garrett S. Slaugh R. Van Rheeden R. Wilson D.B. Watson M.S. Hing A.V. Am. J. Med. Genet. 1999; 83: 201-206Crossref PubMed Scopus (151) Google Scholar, 32Bhatia S.N. Suri V. Bundy A. Krauss C.M. Prenat. Diagn. 1999; 19: 863-867Crossref PubMed Scopus (24) Google Scholar). Taken together, it is likely that GATA-4 regulates cardiac development by both direct and indirect mechanisms. Targeted disruption of the GATA-5 gene in the mouse did not result in developmental lethality but instead females displayed defects in genitourinary tract development (33Molkentin J.D. Tymitz K.M. Richardson J.A. Olson E.N. Mol. Cell. Biol. 2000; 20: 5256-5260Crossref PubMed Scopus (108) Google Scholar), consistent with the observed pattern of GATA-5 expression in the urogenital ridge during embryogenesis (8Morrisey E.E. Ip H.S. Tang Z. Lu M.M. Parmacek M.S. Dev. Biol. 1997; 183: 21-36Crossref PubMed Scopus (213) Google Scholar). Interestingly, a GATA-5 null mutation in zebrafish resulted in embryonic lethality with an identical phenotype to that observed in GATA-4 null mice, suggesting a reversal in the roles of GATA-4 and GATA-5 between the mouse and fish (34Reiter J.F. Alexander J. Rodaway A. Yelon D. Patient R. Holder N. Stainier D.Y. Genes Dev. 1999; 13: 2983-2995Crossref PubMed Scopus (354) Google Scholar). GATA-6 null mice die during early embryonic development (embryonic day 5.5–7.5) because of defects in visceral endoderm function and subsequent extraembryonic development (35Koutsourakis M. Langeveld A. Patient R. Beddington R. Grosveld F. Development. 1999; 126: 723-732Crossref Google Scholar, 36Morrisey E.E. Tang Z. Sigrist K. Lu M.M. Jiang F. Ip H.S. Parmacek M.S. Genes Dev. 1998; 12: 3579-3590Crossref PubMed Scopus (540) Google Scholar), a phenotype that is consistent with the expression pattern ofGATA-6 in the embryonic primitive endoderm (7Morrisey E.E. Ip H.S. Lu M.M. Parmacek M.S. Dev. Biol. 1996; 177: 309-322Crossref PubMed Scopus (382) Google Scholar). In the future, it will be interesting to generate tissue-specific disruptions of GATA-4 and -6 in the mouse using cre-lox technology to permit a more careful evaluation of the role that each factor plays in regulating of tissue-specific gene expression in the heart, gut, lung, and liver. Expression of GATA-4 and -6 is dependent on one another given the observation that GATA-6 is up-regulated inGATA-4 null mice and that GATA-6 null embryos show down-regulation of GATA-4 (26Molkentin J.D. Lin Q. Duncan S.A. Olson E.N. Genes Dev. 1997; 11: 1061-1072Crossref PubMed Scopus (947) Google Scholar, 27Kuo C.T. Morrisey E.E. Anandappa R. Sigrist K. Lu M.M. Parmacek M.S. Soudais C. Leiden J.M. Genes Dev. 1997; 11: 1048-1060Crossref PubMed Scopus (860) Google Scholar, 36Morrisey E.E. Tang Z. Sigrist K. Lu M.M. Jiang F. Ip H.S. Parmacek M.S. Genes Dev. 1998; 12: 3579-3590Crossref PubMed Scopus (540) Google Scholar). Although the mechanism underlying this regulation has not been elucidated, it is tempting to speculate that GATA-4 negatively regulates GATA-6 gene expression whereas GATA-6 regulates GATA-4 gene Such a transcriptional between GATA-4 and GATA-6 is also consistent with the that GATA-4 mice are and die during embryonic development. D. and E. N. it is also possible that the of GATA-4 and -6 proteins is critical for development. between these two transcription factors is also supported by the observation that GATA-4 and -6 proteins with one another in the of cardiac myocytes and (22Charron F. Paradis P. Bronchain O. Nemer G. Nemer M. Mol. Cell. Biol. 1999; 19: 4355-4365Crossref PubMed Scopus (192) Google Scholar). GATA-4, -5, and -6 have been as important regulators of gene expression in heart, liver, gonad, gut epithelium, and GATA-4 regulates expression of a number of cardiac structural genes such as heavy cardiac factor and cardiac and the chain GATA factors also regulate developmental expression of the cardiac transcription factor suggesting the of a transcriptional regulatory between and GATA factors in the heart C. B. R. Richardson J.A. Olson E.N. Development. 1999; 126: PubMed Google Scholar, C.M. Development. 1998; PubMed Google Scholar). Furthermore, the regulates expression of the myocyte enhancer factor-2 gene in the role of GATA factors as regulators of heart gene expression to K. N. J.D. R.A. Development. 1998; 126: Scholar). Collectively, the studies indicate that GATA factors are important regulators of both structural and regulatory genes in the GATA-6 has been in the transcriptional regulation of genes within the epithelium of the GATA-6 regulates expression of the protein A and thyroid transcription factor-1 promoters C. Morrisey E.E. J.A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, J.R. J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, GATA-5 was to regulate promoter suggesting a specific role for GATA-6 in the lung J.R. J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). 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GATA-4 and -6 have also been in the regulation of gene expression through analysis of the and the gene P. Development. 1998; Scholar, Burch J.B. Mol. 1996; Google Scholar, 2000; PubMed Scopus Google Scholar). GATA-4, -5, and -6 factors are also important regulators of gene expression within the Expression of the promoter is regulated by GATA-4 in cells and Mol. 1999; 13: PubMed Scopus Google Scholar, C. J.M. Nemer M. Development. 1998; PubMed Google Scholar, K. Proc. Natl. Acad. Sci. U. S. A. 2000; PubMed Scopus Google Scholar), and GATA-4 regulates expression of the regulatory protein promoter in the E. S. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Collectively, these various studies indicate that GATA-4, -5, and -6 factors are important regulators of tissue-specific gene expression in multiple and tissues. However, it is likely that GATA-4, -5, and -6 factors regulate tissue-specific gene expression across these divergent cell through specific interactions with other semi-restricted transcription factors or cofactors GATA-4 has been as a of gene expression in cardiac myocytes in to analysis of the β-myosin heavy chain promoter in revealed a proximal GATA binding site that gene expression K. 1997; PubMed Scopus Google Scholar). In a similar GATA-4 was as a of promoter in to in the adult heart H. J.D. S. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). In was associated with a in GATA-4 suggesting a mechanism of regulation GATA-4 is up-regulated during Y. J.B. A. M. R.E. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). GATA-4 transcriptional might also be regulated by by in to T. K. S. T. H. T. S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). 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Cell. Biol. 1998; PubMed Scopus Google Scholar, Y. T. H. R.J. S. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). GATA-4 also by of the C-terminal zinc finger with nuclear factor of activated T-cells-c4 and in the regulation of cardiac gene expression J.D. Lu J.R. B. Richardson J. J. Olson E.N. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, S. F. L. Nemer M. J. 2000; 19: PubMed Scopus Google Scholar). Such suggest a GATA-4 regulates gene expression through with other transcription factors. In cells, GATA-4 was shown to interact with the nuclear to transcriptional on the gene promoter Mol. 1999; 13: PubMed Scopus Google Scholar). Finally, GATA-4 and -6 were shown to interact with one another in cardiac myocytes suggesting between GATA factors (22Charron F. Paradis P. Bronchain O. Nemer G. Nemer M. Mol. Cell. Biol. 1999; 19: 4355-4365Crossref PubMed Scopus (192) Google Scholar). is the C-terminal zinc finger domain of GATA-4 is capable of interactions with such a broad of disparate transcription because this protein domain direct nucleotide contacts within the major groove of this it is possible that GATA-4 with each of the transcription factors as of a cell complex (Fig. A). However, it is also possible that GATA-4 as a consisting of only one or a of these cofactors at one GATA-4 as a large complex with other transcription factors through an indirect with regulators of transcription such as (Fig. B). Consistent with this GATA-5 and -6 were each shown to interact with in transcriptional T. K. T. S. H. S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus (80) Google Scholar, H. K. T. T. T. S. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), and was to transcription dependent on GATA-4 T. R. M. Orkin S.H. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). More recently, GATA-4 was shown to interact with the transcriptional friend of GATA-2 through a the N-terminal zinc finger of GATA-4 J.R. H. Richardson J.A. Olson E.N. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar, Leiden J.M. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, Y. G. Orkin S.H. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). This is conserved in Drosophila where the a GATA M. Y. F. P. Y. P. P. Genes Dev. 1997; 11: PubMed Scopus Google Scholar). is likely that plays an important role in regulating GATA gene expression in the heart given the phenotype of mice that die during embryogenesis with cardiac Tanaka M. M. S.H. S. Y. Orkin S.H. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Lin H. C. Jiang F. R. Leiden J.M. Genet. 2000; PubMed Scopus Google Scholar). is as a transcriptional or of GATA-4, -5, and -6 factors or transcriptional cell type to cell However, also with the transcriptional as a transcriptional of GATA-4, -5, and -6 M. J. A. O. Crossley M. B. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Whereas the of studies to GATA-4, -5, and -6 transcription factors have on cardiac expressed that multiple tissues GATA-4, -5, or -6 factors in programming cell gene However, it is a family of expressed transcription factors might regulate differentiation-specific gene expression and identity in such cell as heart, lung, and liver. specificity by GATA-4, -5, or -6 transcription factors through cell interactions with other transcription factors that are expressed in semi-restricted patterns. For example, GATA-4 with the transcription factors and which are coexpressed in the In the lung, GATA-6 with the semi-restricted factor suggesting a unique transcriptional code that is specific to the In numerous studies have a the subfamily of GATA-4, -5, and -6 factors regulates tissue-specific gene expression in multiple cell through unique interactions with other semi-restricted transcription factors. for critical evaluation of this for studies because of