GATA4

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

GATA4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGATA4, GATA binding protein 4, ASD2, TACHD, VSD1, TOF
External IDsOMIM: 600576 MGI: 95664 HomoloGene: 1551 GeneCards: GATA4
Orthologs
SpeciesHumanMouse
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 MbChr 14: 63.44 – 63.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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.[8]

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.[11][12]

Atrioventricular valve formation

GATA4 expression during cardiac development has been shown to be essential to proper atrioventricular (AV) formation and function.[13] 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.[13] 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.[13] 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.[13] 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.[13]

Interactions

GATA4 has been shown to interact with NKX2-5,[14][15][16] TBX5,[17] Serum response factor[18][19] HAND2,[20] and HDAC2.[21]

GATA4 has also been shown to interact with Erbb3, FOG-1, and FOG-2.[13]

Clinical relevance

Mutations in this gene have been associated to cases of congenital diaphragmatic hernia.[22] Atrial septal defects, tetralogy of Fallot, and ventricular septal defects associated with GATA4 mutation were also seen in South Indian patients.[23]

See also

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 C, Rockman HA (March 2006). "GATA4 and the two sides of gene expression reprogramming". Circ Res. 98 (6): 715–6. doi:10.1161/01.RES.0000217593.07196.af. PMID 16574910. S2CID 18985950.
  9. McCulley DJ, Black BL (2012). "Transcription factor pathways and congenital heart disease". Curr Top Dev Biol. Current Topics in Developmental Biology. 100: 253–77. doi:10.1016/B978-0-12-387786-4.00008-7. ISBN 9780123877864. PMC 3684448. PMID 22449847.
  10. Zhou P, He A, Pu WT (2012). "Regulation of GATA4 transcriptional activity in cardiovascular development and disease". Curr Top Dev Biol. Current Topics in Developmental Biology. 100: 143–69. doi:10.1016/B978-0-12-387786-4.00005-1. ISBN 9780123877864. PMID 22449843.
  11. 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.
  12. 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.
  13. Rivera-Feliciano J, Lee KH, Kong SW, Rajagopal S, Ma Q, Springer Z, Izumo S, Tabin CJ, Pu WT (September 2006). "Development of heart valves requires Gata4 expression in endothelial-derived cells". Development. 133 (18): 3607–18. doi:10.1242/dev.02519. PMC 2735081. PMID 16914500.
  14. 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. Bibcode:2003Natur.424..443G. doi:10.1038/nature01827. PMID 12845333. S2CID 4304709.
  15. 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.
  16. 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.
  17. 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. Bibcode:1999PNAS...96..956S. doi:10.1073/pnas.96.3.956. PMC 15332. PMID 9927675.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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

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