Histone H3 phosphorylation (Ser10, Ser28) and phosphoacetylation (K9S10) are differentially associated with gene expression in liver of rats treated in vivo with acute ethanol.
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.
Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65203, USA.
Taryn T
TT
James
Annayya R
AR
Aroor
Robert W
RW
Lim
Shivendra D
SD
Shukla
D000107:Acetylation / Q000187:drug effects; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D053148:Caspase 3 / Q000097:blood; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005235:Fatty Liver, Alcoholic / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D006657:Histones / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009088:Mucoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000235:genetics; D012694:Serine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D006657:Histones; D009088:Mucoproteins; D017395:Plasminogen Activator Inhibitor 1; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; C010393:lysin, gastropoda; D000431:Ethanol; D012694:Serine; D000410:Alanine Transaminase; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D053148:Caspase 3