Histone H3 Phosphorylation (Ser10, Ser28) and Phosphoacetylation (K9S10) Are Differentially Associated with Gene Expression in Liver of Rats Treated In Vivo with Acute Ethanol

Abstract

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.

Reduction of Nfia gene expression and subsequent target genes by binge alcohol in the fetal brain

“…Recently, it has been reported that alcohol exposure alters chromatin signatures, which results in genetic and phenotypic changes [21][22][23]. In the present study, we also found that some chromatin modifiers were altered under binge alcohol consumption.…”

Different Mechanisms for Histone Acetylation by Ethanol and Its Metabolite Acetate in Rat Primary Hepatocytes

“…In primary hepatocytes ethanol increased histone H3 phosphorylation at serine 10 and serine 28 residues ; this has also been shown to occur in vivo (James et al, 2012). Furthermore, ethanol in vivo caused increases in the dually modified histone H3, i.e., H3AcK9 and H3AcK9 phosphorylated at serine 10 (James et al, 2012;Aroor et al, 2014). Whether this unique dual modification also occurs in primary hepatocytes remained unknown.…”

Decoding liver injury: A regulatory role for histone modifications

“…In contrast, the antioxidant N-acetyl cystein (NAC) neutralized ethanol-induced global acetylation on H3K9 in hepatocytes (Choudhury et al , 2010). Several other groups also reported that histone modifications (acetylation, methylation, and phosphorylation) were involved in gene regulation in alcoholic liver diseases (Ghezzi et al , 2013, James et al , 2012, Pal-Bhadra et al , 2007. p300, a HAT, was up-regulated in alcohol-fed rat livers to stimulate H3K9acetylation ( Bardag-Gorce et al , 2007).…”