Biology:GATA4

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Transcription factor GATA-4 is a protein that in humans is encoded by the GATA4 gene.[1]

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.[2][3]

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.[4] GATA4 promotes cardiac morphogenesis, cardiomyocytes survival, and maintains cardiac function in the adult heart.[4] 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.[5] As seen from the abnormalities from deletion of GATA4, it is essential for cardiac formation and the survival of the embryo during fetal development.[6] 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.[4]

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.[7][8]

Atrioventricular valve formation

GATA4 expression during cardiac development has been shown to be essential to proper atrioventricular (AV) formation and function.[9] 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.[9] 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.[9] 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.[9] 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.[9]

Interactions

GATA4 has been shown to interact with NKX2-5,[10][11][12] TBX5,[13] Serum response factor[14][15] HAND2,[16] and HDAC2.[17]

GATA4 has also been shown to interact with Erbb3, FOG-1, and FOG-2.[9]

Clinical relevance

Mutations in this gene have been associated to cases of congenital diaphragmatic hernia.[18] Atrial septal defects, tetralogy of Fallot, and ventricular septal defects associated with GATA4 mutation were also seen in South Indian patients.[19]

See also

References

  1. ↑ "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. October 1995. doi:10.1006/geno.1995.1003. PMID 7665171. 
  2. ↑ "Entrez Gene: GATA4 GATA binding protein 4". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2626. 
  3. ↑ "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. January 2008. doi:10.1002/humu.20588. PMID 17694559. 
  4. ↑ 4.0 4.1 4.2 "GATA4 and the two sides of gene expression reprogramming". Circ Res 98 (6): 715–6. March 2006. doi:10.1161/01.RES.0000217593.07196.af. PMID 16574910. 
  5. ↑ "Transcription factor pathways and congenital heart disease". Curr Top Dev Biol. Current Topics in Developmental Biology 100: 253–77. 2012. doi:10.1016/B978-0-12-387786-4.00008-7. ISBN 9780123877864. PMID 22449847. 
  6. ↑ "Regulation of GATA4 transcriptional activity in cardiovascular development and disease". Curr Top Dev Biol. Current Topics in Developmental Biology 100: 143–69. 2012. doi:10.1016/B978-0-12-387786-4.00005-1. ISBN 9780123877864. PMID 22449843. 
  7. ↑ "A New Pathway for Senescence Regulation". Genomics, Proteomics & Bioinformatics 13 (6): 333–335. 2015. doi:10.1016/j.gpb.2015.11.002. PMID 26777575. 
  8. ↑ "The DNA Damage Response Induces Inflammation and Senescence by Inhibiting Autophagy of GATA4". Science 349 (6255): aaa5612. 2015. doi:10.1126/science.aaa5612. PMID 26404840. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 "Development of heart valves requires Gata4 expression in endothelial-derived cells". Development 133 (18): 3607–18. September 2006. doi:10.1242/dev.02519. PMID 16914500. 
  10. ↑ "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature 424 (6947): 443–7. July 2003. doi:10.1038/nature01827. PMID 12845333. Bibcode: 2003Natur.424..443G. 
  11. ↑ "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". EMBO J. 16 (18): 5687–96. September 1997. doi:10.1093/emboj/16.18.5687. PMID 9312027. 
  12. ↑ "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease". J. Biol. Chem. 275 (45): 35291–6. November 2000. doi:10.1074/jbc.M000525200. PMID 10948187. 
  13. ↑ "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. February 1999. doi:10.1073/pnas.96.3.956. PMID 9927675. Bibcode: 1999PNAS...96..956S. 
  14. ↑ "Cardiac tissue enriched factors serum response factor and GATA-4 are mutual coregulators". Mol. Cell. Biol. 20 (20): 7550–8. October 2000. doi:10.1128/MCB.20.20.7550-7558.2000. PMID 11003651. 
  15. ↑ "Serum response factor-GATA ternary complex required for nuclear signaling by a G-protein-coupled receptor". Mol. Cell. Biol. 21 (4): 1036–44. February 2001. doi:10.1128/MCB.21.4.1036-1044.2001. PMID 11158291. 
  16. ↑ "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. July 2002. doi:10.1074/jbc.M202490200. PMID 11994297. 
  17. ↑ "Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation". Dev. Cell 19 (3): 450–9. September 2010. doi:10.1016/j.devcel.2010.08.012. PMID 20833366. 
  18. ↑ "Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia". Hum. Genet. 132 (3): 285–92. November 2012. doi:10.1007/s00439-012-1249-0. PMID 23138528. 
  19. ↑ "c.620C>T mutation in GATA4 is associated with congenital heart disease in South India". BMC Med. Genet. 16 (1): 7. December 2015. doi:10.1186/s12881-015-0152-7. PMID 25928801. 

Further reading

External links

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



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