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 serine-10 (P-H3-S10), and serine 28 (P-H3-S28) in liver after acute ethanol treatment in vivo. Ethanol was administered intraperitoneally (IP) in male Sprague-Dawley rats. Ethanol dose response (1-5g/ Kg body weight) and time course (1-4 h) experiments were conducted and various parameters were monitored. Steatosis, and necrosis (serum ALT) of the liver increased in 4h suggesting liver injury. There were differences between P-H3-S10 and P-H3-S28 at 1h, the latter was more sensitive to lower ethanol doses. Interestingly, phosphorylation of both serines disappeared at the highest dose used (5g/Kg). We also examined phosphoacetylation of histone H3 at K9/S10 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, MKP-1). Chromatin immunoprecipitation (ChIP) assays in samples from 1.5h and 4h of ethanol administration indicated that increased histone H3 phosphorylation at serine 28 was associated with the promoters of c-Jun and PAI-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.
- Received August 8, 2011.
- Revision received October 20, 2011.
- Accepted October 21, 2011.
- The American Society for Pharmacology and Experimental Therapeutics