Epigenetic mechanisms regulate Mallory Denk body formation in the livers of drug-primed mice

Abstract

The mechanism of Mallory Denk body formation is still not fully understood, but growing evidence implicates epigenetic mechanisms in MDB formation. In a previous study the epigenetic memory of MDB formation remained intact for at least four months after withdrawal from the DDC diet. In the present study, mice were fed a diet containing DDC or a diet containing DDC and Sadenosylmethionine (SAMe) to investigate the epigenetic memory of MDB formation. DDC feeding caused an increase in histone 3 acetylation, a decrease in histone 3 trimethylation, and an increase in histone ubiquitination. The addition of SAMe to the DDC diet prevented the DDC induced decrease of H3K4 and H3K9 trimethylation and the increase in histone ubiquitinylation. Changes in histone modifying enzymes, (HATs and HDACs) were also found in the liver nuclear extracts of the DDC/ SAMe fed mice. Data mining of microarray analysis confirmed that gene expression changed with DDC refeeding, particularly the SAMe-metabolizing enzymes, Mat2a, AMD, AHCY and Mthfr. SAMe supplementation prevented the decrease of AHCY and GNMT, and prevented the increase in Mthfr, which provide a mechanism to explain how DDC inhibits methylation of histones. The results indicate that SAMe prevented the epigenetic cellular memory involved in the MDB formation

Gene expression modifications in the liver caused by binge drinking and S-adenosylmethionine feeding. The role of epigenetic changes

“…In that model, decreased trimethylation of H3K9 and H3K4 and methylation of DNA were related to changes in gene expression and MDB formation [5]. The changes in H3K9 and H3K4 were prevented by SAMe treatment, as were the changes in gene expression and MDB formation (5).…”

“…The level of histone methyl transferase SUV39H1 that methylates H3K9 was reduced and SAMe also prevented this effect of the drug [5]. SAMe also prevented an increase in the level of the histone methyltransferase SET4/9 induced by the drug [5]. SET7/9 regulates the methylation of H3K4.…”

“…The changes in H3K9 and H3K4 were prevented by SAMe treatment, as were the changes in gene expression and MDB formation (5). The level of histone methyl transferase SUV39H1 that methylates H3K9 was reduced and SAMe also prevented this effect of the drug [5]. SAMe also prevented an increase in the level of the histone methyltransferase SET4/9 induced by the drug [5].…”

“…In that model, decreased trimethylation of H3K9 and H3K4 and methylation of DNA were related to changes in gene expression and MDB formation [5]. The changes in H3K9 and H3K4 were prevented by SAMe treatment, as were the changes in gene expression and MDB formation (5). The level of histone methyl transferase SUV39H1 that methylates H3K9 was reduced and SAMe also prevented this effect of the drug [5].…”

“…In a prior study on mice acutely fed a liver toxin, SAMe feeding prevented the toxic effects of the drug by preventing demethylation of histones [5]. Therefore, we expected that SAMe donation of methyl groups to methylate histones would silence gene expression that normally would be up regulated by binge drinking [1].…”