Abstract
High levels of ethanol in liver cells cause significant epigenetic changes affecting histone post translational modifications and histone modifying enzymes responsible for histone acetylation and methylation. The present study is an in vitro study using HepG2 human cells transduced to over express CYP2E1 (E47) or not (C34), which were first treated with arachidonic acid, then Fe‐NAT prior to ethanol exposure (100 mM) for 24h. These HepG2 cells showed an increase in histone acetylation (H3K9 and H3K18) as well as an increase in histone methylation (H3K27me3), which was similar to the effect of ethanol on the liver in the in vivo study. In addition, the treated cells showed a significant increase in the levels of histone modifying enzymes, particularly the histone deacetylase Sirt1. With respect to methylation, the re‐methylation pathway, responsible for generating the methyl donor S‐adenosylmethionine, was also changed in this in vitro study. Methionine adenosyltransferase II, alpha (Mat2a) was significantly decreased in the ethanol treated cells compared to the controls. The increase in H3K27me3 indicated that other methylation mechanisms, such as an increase in the activity of an histone methyltransferase Ezh2, are involved in the increase of histone methylation. In addition, there was no difference in the response to ethanol between the E47 cells and the C34 control cells, which suggests that CYP2E1 induction by ethanol does not contribute to the changes in histone post translational modifications. Supported by NIH/NIAAA Grants 8116 and P50‐011999 Alcohol Center Grant, Liver/Pancreas.
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