Abstract OBJECTIVE: Gata4 is an important transcription factor in heart development. Gata4 post-transcriptional protein modification regulates transcriptional activity and DNA binding, which in turn affects expression of downstream genes and transcription factors, differentiation of embryonic stem cells and cardiogenesis. This article summarizes the effect of post-transcriptional protein modification on transcriptional activity of Gata4 and the relationship between this effect and congenital heart disease. It was shown that acetylation, phosphorylation and SUMOylation upregulate transcriptional activity, DNA binding, downstream gene expression and embryonic stem cell differentiation. On the other hand, methylation and deacetylation downregulate Gata4 transcriptional activity. Post-transcriptional protein modification of Gata4 is very important in clinical research on congenital and other heart diseases.
［2］Molkentin JD. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression［J］. J Biol Chem, 2000, 275(50): 38949-38952.
［3］Pu WT, Ishiwata T, Juraszek AL, Ma Q, Izumo S. GATA4 is a dosage-sensitive regulator of cardiac morphogenesis［J］. Dev Biol, 2004, 275(1): 235-244.
［4］Takaya T, Kawamura T, Morimoto T, Ono K, Kita T, Shimatsu A, et al. Identification of p300-targeted acetylated residues in GATA4 during hypertrophic responses in cardiac myocytes［J］. J Biol Chem, 2008, 283(15): 9828-9835.
［5］Kawamura T, Ono K, Morimoto T, Wada H, Hirai M, Hidaka K, et al. Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes［J］. J Biol Chem, 2005, 280(20): 19682-19688.
［6］Kaichi S, Takaya T, Morimoto T, Sunagawa Y, Kawamura T, Ono K, et al. Cyclin-dependent kinase 9 forms a complex with GATA4 and is involved in the differentiation of mouse ES cells into cardiomyocytes［J］. J Cell Physiol, 2011, 226(1): 248-254.
［7］Sun H, Yang X, Zhu J, Lv T, Chen Y, Chen G, et al. Inhibition of p300-HAT results in a reduced histone acetylation and down-regulation of gene expression in cardiac myocytes［J］. Life Sci, 2010, 87(23-26): 707-714.
［8］Trivedi CM, Zhu W, Wang Q, Jia C, Kee HJ, Li L, et al. Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation［J］. Dev Cell, 2010, 19(3): 450-459.
［9］Li T, Liu Z, Hu X, Ma K, Zhou C. Involvement of ERK-RSK cascade in phenylephrine-induced phosphorylation of GATA4［J］. Biochim Biophys Acta, 2011, 1823(2): 582-592.
［10］Hu X, Li T, Zhang C, Liu Y, Xu M, Wang W, et al. GATA4 regulates ANF expression synergistically with Sp1 in a cardiac hypertrophy model ［J］. J Cell Mol Med, 2011, 15(9):1865-1877.
［11］Gallagher JM, Komati H, Roy E, Nemer M, Latinkic BV. Dissociation of cardiogenic and postnatal myocardial activities of GATA4［J］. Mol Cell Biol, 2012, 32(12): 2214-2223.
［12］Kitta K, Day RM, Kim Y, Torregroza I, Evans T, Suzuki YJ. Hepatocyte growth factor induces GATA-4 phosphorylation and cell survival in cardiac muscle cells［J］. J Biol Chem, 2003, 278(7): 4705-4712.
［13］Kehat I, Molkentin JD. Extracellular signalregulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy［J］. Ann N Y Acad Sci, 2010, 1188: 96-102.
［14］Muslin AJ. MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets［J］. Clin Sci (Lond), 2008, 115(7): 203-218.
［15］Shan X, Xu X, Cao B, Wang Y, Guo L, Zhu Q, et al, Transcription factor GATA-4 is involved in erythropoietin-induced cardioprotection against myocardial ischemia/reperfusion injury［J］. Int J Cardiol, 2009, 134(3): 384-392.
［16］Belaguli NS, Zhang M, Garcia AH, Berger DH. PIAS1 is a GATA4 SUMO ligase that regulates GATA4-dependent intestinal promoters independent of SUMO ligase activity and GATA4 sumoylation［J］. PLoS One, 2012, 7(4): e35717.
［17］Wang J, Li A, Wang Z, Feng X, Olson EN, Schwartz RJ. Myocardin sumoylation transactivates cardiogenic genes in pluripotent 10T1/2 fibroblasts［J］. Mol Cell Biol, 2007, 27(2): 622-632.
［19］Chen JF, Wang S, Wu Q, Cao D, Nguyen T, Chen Y, et al. Myocardin marks the earliest cardiac gene expression and plays an important role in heart development［J］. Anat Rec (Hoboken), 2008, 291(10): 1200-1211.
［20］Kang X, Qi Y, Zuo Y, Wang Q, Zou Y, Schwartz RJ, et al. SUMO-specific protease 2 is essential for suppression of polycomb group protein-mediated gene silencing during embryonic development［J］. Mol Cell, 2010, 38(2): 191-201.
［21］He A, Shen X, Ma Q, Cao J, Von Gise A, Zhou P, et al. PRC2 directly methylates GATA4 and represses its transcriptional activity［J］. Genes Dev, 2012, 26(1): 37-42.
［22］Bruneau BG. The developmental genetics of congenital heart disease［J］. Nature, 2008, 451(7181): 943-948.
［23］Hoffman JI, Kaplan S. The incidence of congenital heart disease［J］. J Am Coll Cardiol, 2002, 39(12): 1890-1900.
［24］Chen Y, Han ZQ, Yan WD, Tang CZ, Xie JY, Chen H, et al. A novel mutation in GATA4 gene associated with dominant inherited familial atrial septal defect［J］. J Thorac Cardiovasc Surg, 2010, 140(3): 684-687.
［25］Granados-Riveron JT, Pope M, Bu'Lock FA, Thornborough C, Eason J, Setchfield K, et al. Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations［J］. Congenit Heart Dis, 2012, 7(2): 151-159.
［26］Zhang W, Li X, Shen A, Jiao W, Guan X, Li Z. GATA4 mutations in 486 Chinese patients with congenital heart disease［J］. Eur J Med Genet, 2008, 51(6): 527-535.
［27］Schlesinger J, Schueler M, Grunert M, Fischer JJ, Zhang Q, Krueger T, et al. The cardiac transcription network modulated by Gata4, Mef2a, Nkx2.5, Srf, histone modifications, and microRNAs［J］. PLoS Genet, 2011, 7(2): e1001313.
