Histone H3 Phosphorylation (Ser10, Ser28) and Phosphoacetylation (K9S10) Are Differentially Associated with Gene Expression in Liver of Rats Treated In Vivo with Acute Ethanol
Histone H3 Phosphorylation (Ser10, Ser28) and Phosphoacetylation (K9S10) Are Differentially Associated with Gene Expression in Liver of Rats Treated In Vivo with Acute Ethanol
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DOI：
10.1124/jpet.111.186775
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发表时间：
2012-02-01
影响因子：
3.5
通讯作者：
Shukla, Shivendra D.
中科院分区：
文献类型：
--
作者：
James, Taryn T.;Aroor, Annayya R.;Shukla, Shivendra D.
乙醇对组蛋白的表观遗传修饰正在成为其对肝脏产生有害作用的机制之一。在这种情况下，我们研究了体内急性乙醇处理后肝脏中组蛋白 H3 Ser10 (P-H3-Ser10) 和 Ser28 (P-H3-Ser28) 磷酸化的作用。对雄性斯普拉格-道利大鼠腹膜内施用乙醇。进行乙醇剂量反应（1-5克/千克体重）和时程（1-4小时）实验，并监测各种参数。 4小时内肝脏脂肪变性和坏死（血清丙氨酸转氨酶）升高，提示肝损伤。 1 h 时 P-H3-Ser10 和 P-H3-Ser28 之间存在差异，后者对较低乙醇剂量更敏感。值得注意的是，两种丝氨酸的磷酸化在最高剂量（5 g/kg）下消失。我们还检查了 K9S10 处组蛋白 H3 的磷酸乙酰化，并观察到急剧增加。组蛋白 H3 磷酸化和磷酸乙酰化的变化还伴随着早期反应基因（c-fos、c-jun、丝裂原激活蛋白激酶磷酸酶-1）的表达。对乙醇施用 1.5 小时和 4 小时的样品进行染色质免疫沉淀分析表明，组蛋白 H3 Ser28 磷酸化的增加与 c-jun 和纤溶酶原激活物抑制剂-1 的启动子有关。总之，本研究首次证明肝脏在体内暴露于急性乙醇会诱导组蛋白H3的磷酸化和磷酸乙酰化，并且这些修饰差异性地参与基因的mRNA表达。
The epigenetic histone modification by ethanol is emerging as one of the mechanisms for its deleterious effects in the liver. In this context, we have investigated the role of histone H3 phosphorylation at Ser10 (P-H3-Ser10), and Ser28 (P-H3-Ser28) in liver after acute ethanol treatment in vivo. Ethanol was administered intraperitoneally in male Sprague-Dawley rats. Ethanol dose-response (1-5 g/kg body weight) and time-course (1-4 h) experiments were conducted, and various parameters were monitored. Steatosis and necrosis (serum alanine aminotransferase) of the liver increased in 4 h, suggesting liver injury. There were differences between P-H3-Ser10 and P-H3-Ser28 at 1 h, with the latter being more sensitive to lower ethanol doses. It was noteworthy that phosphorylation of both serines disappeared at the highest dose used (5 g/kg). We also examined phosphoacetylation of histone H3 at K9S10 and observed a dramatic increase. The changes in histone H3 phosphorylation and phosphoacetylation were also accompanied with expression of early response genes (c-fos, c-jun, mitogen-activated protein kinase phosphatase-1). Chromatin immunoprecipitation assays in samples from 1.5 and 4 h of ethanol administration indicated that increased histone H3 phosphorylation at Ser28 was associated with the promoters of c-jun and plasminogen activator inhibitor-1. In conclusion, this study demonstrates for the first time that in vivo exposure of liver to acute ethanol induced phosphorylation and phosphoacetylation of histone H3, and these modifications are differentially involved in the mRNA expression of genes.