Premium
Methylation and Gene Expression Responses to Ethanol Feeding and Betaine Supplementation in the Cystathionine Beta Synthase‐Deficient Mouse
Author(s) -
Medici Valentina,
Schroeder Diane I.,
Woods Rima,
LaSalle Janine M.,
Geng Yongzhi,
Shibata Noreene M.,
Peerson Janet,
Hodzic Emir,
Dayal Sanjana,
Tsukamoto Hidekazu,
Kharbanda Kusum K.,
Tillman Brittany,
French Samuel W.,
Halsted Charles H.
Publication year - 2014
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12405
Subject(s) - cystathionine beta synthase , betaine , homocystinuria , beta (programming language) , gene expression , atp synthase , ethanol , biochemistry , methylation , chemistry , gene , microbiology and biotechnology , biology , genetics , enzyme , methionine , cysteine , amino acid , computer science , programming language
Background Alcoholic steatohepatitis (ASH) is caused in part by the effects of ethanol (EtOH) on hepatic methionine metabolism. Methods To investigate the phenotypic and epigenetic consequences of altered methionine metabolism in this disease, we studied the effects of 4‐week intragastric EtOH feeding with and without the methyl donor betaine in cystathionine beta synthase (CβS) heterozygous C57BL/6J mice. Results The histopathology of early ASH was induced by EtOH feeding and prevented by betaine supplementation, while EtOH feeding reduced and betaine supplementation maintained the hepatic methylation ratio of the universal methyl donor S‐adenosylmethionine (SAM) to the methyltransferase inhibitor S‐adenosylhomocysteine (SAH). MethylC‐seq genomic sequencing of heterozygous liver samples from each diet group found 2 to 4% reduced methylation in gene bodies, but not promoter regions of all autosomes of EtOH‐fed mice, each of which were normalized in samples from mice fed the betaine‐supplemented diet. The transcript levels of nitric oxide synthase ( Nos2 ) and DNA methyltransferase 1 ( Dnmt1 ) were increased, while those of peroxisome proliferator receptor‐ α ( Pparα ) were reduced in EtOH‐fed mice, and each was normalized in mice fed the betaine‐supplemented diet. DNA pyrosequencing of CβS heterozygous samples found reduced methylation in a gene body of Nos2 by EtOH feeding that was restored by betaine supplementation and was correlated inversely with its expression and positively with SAM/SAH ratios. Conclusions The present study has demonstrated relationships among EtOH induction of ASH with aberrant methionine metabolism that was associated with gene body DNA hypomethylation in all autosomes and was prevented by betaine supplementation. The data imply that EtOH‐induced changes in selected gene transcript levels and hypomethylation in gene bodies during the induction of ASH are a result of altered methionine metabolism that can be reversed through dietary supplementation of methyl donors.