GATA4

Transcription factor GATA-4 is a protein that in humans is encoded by the GATA4 gene.[5]

GATA4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2M9W
Identifiers
Aliases	GATA4, GATA binding protein 4, ASD2, TACHD, VSD1, TOF
External IDs	OMIM: 600576 MGI: 95664 HomoloGene: 1551 GeneCards: GATA4
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8p23.1 Start 11,676,959 bp[1] End 11,760,002 bp[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)[2] Band 14 D1|14 33.24 cM Start 63,198,922 bp[2] End 63,271,692 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • sequence-specific DNA binding • co-SMAD binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001105 transcription coactivator activity • zinc ion binding • transcription factor binding • chromatin binding • activating transcription factor binding • metal ion binding • GO:0001948 protein binding • GO:0001158 core promoter proximal region sequence-specific DNA binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • RNA polymerase II regulatory region sequence-specific DNA binding • RNA polymerase II transcription factor binding • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • protein kinase binding • NFAT protein binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding Cellular component • nucleoplasm • RNA polymerase II transcription factor complex • cell nucleus • nuclear body Biological process • endoderm development • male gonad development • regulation of transcription, DNA-templated • ventricular septum development • cell growth involved in cardiac muscle cell development • embryonic foregut morphogenesis • endocardial cushion development • cardiac muscle cell differentiation • cell-cell signaling • response to mechanical stimulus • blood coagulation • transcription from RNA polymerase II promoter • transcription, DNA-templated • positive regulation of angiogenesis • positive regulation of transcription, DNA-templated • heart looping • atrial septum morphogenesis • response to vitamin A • regulation of cardiac muscle cell contraction • atrial septum secundum morphogenesis • atrial septum primum morphogenesis • intestinal epithelial cell differentiation • embryonic heart tube anterior/posterior pattern specification • positive regulation of BMP signaling pathway • positive regulation of cardioblast differentiation • positive regulation of vascular endothelial growth factor production • negative regulation of autophagy • cardiac ventricle morphogenesis • cardiac right ventricle morphogenesis • response to drug • cellular response to glucose stimulus • positive regulation of transcription from RNA polymerase II promoter • transdifferentiation • aortic valve morphogenesis • heart development • animal organ morphogenesis • histogenesis • cell development • anatomical structure formation involved in morphogenesis • digestive tract development • cardiac muscle tissue development • atrioventricular valve formation • negative regulation of cardiac muscle cell apoptotic process • regulation of protein kinase B signaling • cardiac muscle tissue regeneration • positive regulation of ERK1 and ERK2 cascade • negative regulation of oxidative stress-induced cell death • negative regulation of apoptotic signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2626	14463
Ensembl	ENSG00000136574 ENSG00000285109	ENSMUSG00000021944
UniProt	P43694	Q08369
RefSeq (mRNA)	NM_001308093 NM_001308094 NM_002052 NM_001374273 NM_001374274	NM_008092 NM_001310610
RefSeq (protein)	NP_001295022 NP_001295023 NP_002043 NP_001361202 NP_001361203	NP_001297539 NP_032118
Location (UCSC)	Chr 8: 11.68 – 11.76 Mb	Chr 14: 63.2 – 63.27 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

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. Mutations in this gene have been associated with cardiac septal defects as well as reproductive defects.[6][7]

GATA4 is a critical transcription factor for proper mammalian cardiac development and essential for survival of the embryo. GATA4 works in combination with other essential cardiac transcription factors as well, such as Nkx2-5 and Tbx5. GATA4 is expressed in both embryo and adult cardiomyocytes where it functions as a transcriptional regulator for many cardiac genes, and also regulates hypertrophic growth of the heart.[8] GATA4 promotes cardiac morphogenesis, cardiomyocytes survival, and maintains cardiac function in the adult heart.[8] Mutations or defects in the GATA4 gene can lead to a variety of cardiac problems including congenital heart disease, abnormal ventral folding, and defects in the cardiac septum separating the atria and ventricles, and hypoplasia of the ventricular myocardium.[9] As seen from the abnormalities from deletion of GATA4, it is essential for cardiac formation and the survival of the embryo during fetal development.[10] GATA4 is not only important for cardiac development, but also development and function of the mammalian fetal ovary and contributes to fetal male gonadal development and mutations may lead to defects in reproductive development. GATA4 has also been discovered to have an integral role in controlling the early stages of pancreatic and hepatic development.[11]

GATA4 is regulated through the autophagy-lysosome pathway in eukaryotic cells. In cellular senescence, ATM and ATR inhibit p62, an autophagy adaptor responsible for selective autophagy of GATA4. Inhibition of p62 leads to increased GATA4 levels, resulting in NF-kB activation and subsequent SASP induction.[12][13]

Atrioventricular valve formation

GATA4 expression during cardiac development has been shown to be essential to proper atrioventricular (AV) formation and function.[14] Endocardial cells undergo epithelial to mesenchymal transitions (EMT) into the AV cushions during development. Their proliferation and fusion leads to division of the ventricular inlet into two different passageways with two AV valves, and they are thought to be under the influence of the GATA4 transcription factor.[14] GATA4 inactivation, with GATA4-null mice, leads to down regulation of Erbb3 and altered Erk expression, two other important molecules in EMT and ventricular inlet separation.[14] This has been shown to lead to pericardial effusion and peripheral hemorrhage in E12.5 mice, which succumb due to heart failure before weaning age.[14] This data could have important implications for human medicine by suggesting that mutations with the GATA4 transcription factor could be responsible for AV cushion defects in humans with improper septal formation leading to congenital heart disease.[14]

Interactions

GATA4 has been shown to interact with NKX2-5,[15][16][17] TBX5,[18] Serum response factor[19][20] HAND2,[21] and HDAC2.[22]

GATA4 has also been shown to interact with Erbb3, FOG-1, and FOG-2.[14]

Clinical relevance

Mutations in this gene have been associated to cases of congenital diaphragmatic hernia.[23] Atrial septal defects, tetralogy of Fallot, and ventricular septal defects associated with GATA4 mutation were also seen in South Indian patients.[24]

See also

• GATA transcription factor

References

1. ENSG00000285109 GRCh38: Ensembl release 89: ENSG00000136574, ENSG00000285109 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000021944 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. White RA, Dowler LL, Pasztor LM, Gatson LL, Adkison LR, Angeloni SV, Wilson DB (October 1995). "Assignment of the transcription factor GATA4 gene to human chromosome 8 and mouse chromosome 14: Gata4 is a candidate gene for Ds (disorganization)". Genomics. 27 (1): 20–6. doi:10.1006/geno.1995.1003. PMID 7665171.
6. "Entrez Gene: GATA4 GATA binding protein 4".
7. Köhler B, Lin L, Ferraz-de-Souza B, Wieacker P, Heidemann P, Schröder V, Biebermann H, Schnabel D, Grüters A, Achermann JC (January 2008). "Five novel mutations in steroidogenic factor 1 (SF1, NR5A1) in 46,XY patients with severe underandrogenization but without adrenal insufficiency". Hum. Mutat. 29 (1): 59–64. doi:10.1002/humu.20588. PMC 2359628. PMID 17694559.
8. [Perrino, Cinzia and Rockman, Howard A. GATA4 and the two sides of gene expression reprogramming. 2006. Circulation Research, 98: 837-845.]
9. Black BL, McCulley DJ. "Transcription factor pathways and congenital heart disease. 2012". Current Topics in Developmental Biology. 100: 253–277.
10. Zhou P, et al. "Regulation of GATA4 transcriptional activity in cardiovascular development and disease. 2012". Current Topics in Developmental Biology. 100: 143–169.
11. [Perrino, Cinzia and Rockman, Howard A. GATA4 and the two sides of gene expression reprogramming. 2006. Circulation Research, 98: 837-845]
12. Cao X, Li M (2015). "A New Pathway for Senescence Regulation". Genomics, Proteomics & Bioinformatics. 13 (6): 333–335. doi:10.1016/j.gpb.2015.11.002. PMC 4747646. PMID 26777575.
13. Kang C, Xu O, Martin TD, Li MZ, Demaria M, Aron L, Lu T, Yankner BA, Campisi J, Elledge SJ (2015). "The DNA Damage Response Induces Inflammation and Senescence by Inhibiting Autophagy of GATA4". Science. 349 (6255): aaa5612. doi:10.1126/science.aaa5612. PMC 4942138. PMID 26404840.
14. Rivera-Feliciano, Jose; Kyu-Ho Lee; Sek Won Kong; Satish Rajagopal; Qing Ma; Zhangli Springer; Seigo Izumo; Clifford J. Tabin; William T. Pu (September 15, 2006). "Development of heart valves requires GATA4 expression in endothelial-derived cells". Development. 133: 3607–3618. doi:10.1242/dev.02519. PMC 2735081. PMID 16914500. Retrieved 13 April 2015.
15. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (July 2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature. 424 (6947): 443–7. doi:10.1038/nature01827. PMID 12845333.
16. Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M (September 1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". EMBO J. 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. PMC 1170200. PMID 9312027.
17. Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I (November 2000). "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease". J. Biol. Chem. 275 (45): 35291–6. doi:10.1074/jbc.M000525200. PMID 10948187.
18. Svensson EC, Tufts RL, Polk CE, Leiden JM (February 1999). "Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes". Proc. Natl. Acad. Sci. U.S.A. 96 (3): 956–61. doi:10.1073/pnas.96.3.956. PMC 15332. PMID 9927675.
19. Belaguli NS, Sepulveda JL, Nigam V, Charron F, Nemer M, Schwartz RJ (October 2000). "Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators". Mol. Cell. Biol. 20 (20): 7550–8. doi:10.1128/MCB.20.20.7550-7558.2000. PMC 86307. PMID 11003651.
20. Morin S, Paradis P, Aries A, Nemer M (February 2001). "Serum response factor-GATA ternary complex required for nuclear signaling by a G-protein-coupled receptor". Mol. Cell. Biol. 21 (4): 1036–44. doi:10.1128/MCB.21.4.1036-1044.2001. PMC 99558. PMID 11158291.
21. Dai YS, Cserjesi P, Markham BE, Molkentin JD (July 2002). "The transcription factors GATA4 and dHAND physically interact to synergistically activate cardiac gene expression through a p300-dependent mechanism". J. Biol. Chem. 277 (27): 24390–8. doi:10.1074/jbc.M202490200. PMID 11994297.
22. Trivedi CM, Zhu W, Wang Q, Jia C, Kee HJ, Li L, Hannenhalli S, Epstein JA (September 2010). "Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation". Dev. Cell. 19 (3): 450–9. doi:10.1016/j.devcel.2010.08.012. PMC 2947937. PMID 20833366. Lay summary – Phys.Org.
23. Yu L, Wynn J, Cheung YH, Shen Y, Mychaliska GB, Crombleholme TM, Azarow KS, Lim FY, Chung DH, Potoka D, Warner BW, Bucher B, Stolar C, Aspelund G, Arkovitz MS, Chung WK (November 2012). "Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia". Hum. Genet. 132 (3): 285–92. doi:10.1007/s00439-012-1249-0. PMC 3570587. PMID 23138528.
24. Mattapally S, Nizamuddin S, Murthy KS, Thangaraj K, Banerjee SK (December 2015). "c.620C>T mutation in GATA4 is associated with congenital heart disease in South India". BMC Med. Genet. 16 (1): 7. doi:10.1186/s12881-015-0152-7. PMC 4422155. PMID 25928801.

Further reading

• Evans T, Reitman M, Felsenfeld G (1988). "An erythrocyte-specific DNA-binding factor recognizes a regulatory sequence common to all chicken globin genes". Proc. Natl. Acad. Sci. U.S.A. 85 (16): 5976–80. doi:10.1073/pnas.85.16.5976. PMC 281888. PMID 3413070.
• Huang WY, Cukerman E, Liew CC (1995). "Identification of a GATA motif in the cardiac alpha-myosin heavy-chain-encoding gene and isolation of a human GATA-4 cDNA". Gene. 155 (2): 219–23. doi:10.1016/0378-1119(94)00893-W. PMID 7721094.
• Yamagata T, Nishida J, Sakai R, et al. (1995). "Of the GATA-binding proteins, only GATA-4 selectively regulates the human interleukin-5 gene promoter in interleukin-5-producing cells which express multiple GATA-binding proteins". Mol. Cell. Biol. 15 (7): 3830–9. PMC 230622. PMID 7791790.
• Molkentin JD, Kalvakolanu DV, Markham BE (1994). "Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene". Mol. Cell. Biol. 14 (7): 4947–57. PMC 358867. PMID 8007990.
• Arceci RJ, King AA, Simon MC, et al. (1993). "Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart". Mol. Cell. Biol. 13 (4): 2235–46. PMC 359544. PMID 8455608.
• Huang WY, Heng HH, Liew CC (1997). "Assignment of the human GATA4 gene to 8p23.1→p22 using fluorescence in situ hybridization analysis". Cytogenet. Cell Genet. 72 (2–3): 217–8. doi:10.1159/000134194. PMID 8978781.
• Herzig TC, Jobe SM, Aoki H, et al. (1997). "Angiotensin II type1a receptor gene expression in the heart: AP-1 and GATA-4 participate in the response to pressure overload". Proc. Natl. Acad. Sci. U.S.A. 94 (14): 7543–8. doi:10.1073/pnas.94.14.7543. PMC 23858. PMID 9207128.
• Durocher D, Charron F, Warren R, et al. (1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". EMBO J. 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. PMC 1170200. PMID 9312027.
• Molkentin JD, Lu JR, Antos CL, et al. (1998). "A calcineurin-dependent transcriptional pathway for cardiac hypertrophy". Cell. 93 (2): 215–28. doi:10.1016/S0092-8674(00)81573-1. PMC 4459646. PMID 9568714.
• Svensson EC, Tufts RL, Polk CE, Leiden JM (1999). "Molecular cloning of FOG-2: a modulator of transcription factor GATA-4 in cardiomyocytes". Proc. Natl. Acad. Sci. U.S.A. 96 (3): 956–61. doi:10.1073/pnas.96.3.956. PMC 15332. PMID 9927675.
• Tremblay JJ, Viger RS (1999). "Transcription factor GATA-4 enhances Müllerian inhibiting substance gene transcription through a direct interaction with the nuclear receptor SF-1". Mol. Endocrinol. 13 (8): 1388–401. doi:10.1210/me.13.8.1388. PMID 10446911.
• Lin L, Aggarwal S, Glover TW, et al. (2000). "A minimal critical region of the 8p22-23 amplicon in esophageal adenocarcinomas defined using sequence tagged site-amplification mapping and quantitative polymerase chain reaction includes the GATA-4 gene". Cancer Res. 60 (5): 1341–7. PMID 10728696.
• Morin S, Charron F, Robitaille L, Nemer M (2000). "GATA-dependent recruitment of MEF2 proteins to target promoters". EMBO J. 19 (9): 2046–55. doi:10.1093/emboj/19.9.2046. PMC 305697. PMID 10790371.
• Zhu W, Shiojima I, Hiroi Y, et al. (2001). "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease". J. Biol. Chem. 275 (45): 35291–6. doi:10.1074/jbc.M000525200. PMID 10948187.
• Belaguli NS, Sepulveda JL, Nigam V, et al. (2000). "Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators". Mol. Cell. Biol. 20 (20): 7550–8. doi:10.1128/MCB.20.20.7550-7558.2000. PMC 86307. PMID 11003651.
• Morin S, Paradis P, Aries A, Nemer M (2001). "Serum response factor-GATA ternary complex required for nuclear signaling by a G-protein-coupled receptor". Mol. Cell. Biol. 21 (4): 1036–44. doi:10.1128/MCB.21.4.1036-1044.2001. PMC 99558. PMID 11158291.
• Crispino JD, Lodish MB, Thurberg BL, et al. (2001). "Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors". Genes Dev. 15 (7): 839–44. doi:10.1101/gad.875201. PMC 312667. PMID 11297508.
• Dai YS, Markham BE (2001). "p300 Functions as a coactivator of transcription factor GATA-4". J. Biol. Chem. 276 (40): 37178–85. doi:10.1074/jbc.M103731200. PMID 11481322.
• Liang Q, Wiese RJ, Bueno OF, et al. (2001). "The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes". Mol. Cell. Biol. 21 (21): 7460–9. doi:10.1128/MCB.21.21.7460-7469.2001. PMC 99918. PMID 11585926.

External links

• GATA4+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
• Overview of all the structural information available in the PDB for UniProt: P43694 (Transcription factor GATA-4) at the PDBe-KB.

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