Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes
Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes
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DOI：
10.1074/jbc.m412428200
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发表时间：
2005-05-20
影响因子：
4.8
通讯作者：
Hasegawa, K
中科院分区：
文献类型：
--
作者：
Kawamura, T;Ono, K;Hasegawa, K
胚胎干细胞（ES）分化为心肌细胞需要激活心脏特异性基因程序。组蛋白乙酰转移酶（HATs）和组蛋白去乙酰化酶（hdac）通过与特定转录因子的关联而被募集到靶基因，从而控制基因的表达模式。其中一种HATs， p300，作为心脏特异性转录因子如GATA-4的辅助激活因子。p300的HAT活性是GATA-4乙酰化和DNA结合及其完整转录活性以及促进转录活性染色质结构所必需的。然而，在胚胎干细胞向心肌细胞分化过程中，HATs和hdac在GATA-4翻译后修饰中的作用尚不清楚。在胚胎样体发育的胚胎干细胞模型中，在胚胎干细胞向心肌细胞分化过程中，乙酰化形式的GATA-4及其DNA结合随着p300的表达而增加。用特异性HDAC抑制剂曲古抑素A （trichostatin A， TSA）处理ES细胞，可诱导心房利钠因子启动子GATA位点附近的组蛋白3/4乙酰化。此外，在胚胎干细胞分化过程中，TSA增加了GATA-4乙酰化形式及其DNA结合的增加。最后，TSA促进了分化过程中心肌特异性Nkx-2.5启动子和内源性心肌β -肌球蛋白重链调控下绿色荧光蛋白的表达。这些发现表明GATA-4和组蛋白的乙酰化参与了胚胎干细胞向心肌细胞的分化。
Differentiation of embryonic stem (ES) cells into cardiac myocytes requires activation of a cardiac-specific gene program. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) govern gene expression patterns by being recruited to target genes through association with specific transcription factors. One of the HATs, p300, serves as a coactivator of cardiac-specific transcription factors such as GATA-4. The HAT activity of p300 is required for acetylation and DNA binding of GATA-4 and its full transcriptional activity as well as for promotion of a transcriptionally active chromatin configuration. However, the roles of HATs and HDACs in post-translational modification of GATA-4 during the differentiation of ES cells into cardiac myocytes remain unknown. In an ES cell model of developing embryoid bodies, an acetylated form of GATA-4 and its DNA binding increased concomitantly with the expression of p300 during the differentiation of ES cells into cardiac myocytes. Treatment of ES cells with trichostatin A (TSA), a specific HDAC inhibitor, induced acetylation of histone-3/4 near GATA sites within the atrial natriuretic factor promoter. In addition, TSA augmented the increase in an acetylated form of GATA-4 and its DNA binding during the ES cell differentiation. Finally, TSA facilitated the expression of green fluorescence protein under the control of the cardiac-specific Nkx-2.5 promoter and of endogenous cardiac beta- myosin heavy chain during the differentiation. These findings demonstrate that acetylation of GATA-4 as well as of histones is involved in the differentiation of ES cells into cardiac myocytes.