Epigenetic mechanisms regulate Mallory Denk body formation in the livers of drug-primed mice.
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 4 months after withdrawal from the DDC diet. In the present study, mice were fed a diet containing DDC or a diet containing DDC and S-adenosylmethionine (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 ubiquitinylation. 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 provides 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.
Bardag-Gorce
Fawzia
F
Department of Pathology, Harbor-UCLA Medical Center, 1000 W. Carson St., Torrance, CA 90509, USA.
Oliva
Joan
J
Villegas
Jessica
J
Fraley
Sara
S
Amidi
Fataneh
F
Li
Jun
J
Dedes
Jennifer
J
French
Barbara
B
French
Samuel W
SW
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004336:Drug Antagonism; D004338:Drug Combinations; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006657:Histones / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000633:toxicity
D002273:Carcinogens; D004338:Drug Combinations; D006657:Histones; C488922:Mallory body protein, mouse; D011506:Proteins; D012333:RNA, Messenger; D012436:S-Adenosylmethionine