Methylation and Gene Expression Responses to Ethanol Feeding and Betaine Supplementation in the Cystathionine Beta Synthase-Deficient Mouse

Autor: Emir Hodzic, Yongzhi Geng, Charles H. Halsted, Noreene M. Shibata, Diane I. Schroeder, Samuel W. French, Brittany Tillman, Valentina Medici, Hidekazu Tsukamoto, Kusum K. Kharbanda, Janine M. LaSalle, Janet M Peerson, Rima Woods, Sanjana Dayal
Rok vydání: 2014
Předmět:
S-Adenosylmethionine
Nitric Oxide Synthase Type II
Medicine (miscellaneous)
Inbred C57BL
Toxicology
Substance Misuse
Alcohol Use and Health
Mice
chemistry.chemical_compound
Methionine
Betaine
2.1 Biological and endogenous factors
Psychology
DNA (Cytosine-5-)-Methyltransferases
Aetiology
Liver Disease
Substance Abuse
Methylation
Alcoholic
S-Adenosylhomocysteine
Alcoholism
Psychiatry and Mental health
Liver
DNA methylation
Homocystinuria
Cystathionine Beta Synthase
Alcohol
Fatty Liver
Alcoholic
DNA (Cytosine-5-)-Methyltransferase 1
Chronic Liver Disease and Cirrhosis
Clinical Sciences
Biology
DNA methyltransferase
Article
Complementary and Integrative Health
mental disorders
Genetics
medicine
Animals
PPAR alpha
Nutrition
Ethanol
Prevention
Neurosciences
DNA Methylation
medicine.disease
Molecular biology
Cystathionine beta synthase
Fatty Liver
Mice
Inbred C57BL
Gene Expression Regulation
chemistry
Dietary Supplements
DNMT1
biology.protein
Digestive Diseases
Zdroj: Alcoholism, clinical and experimental research, vol 38, iss 6
ISSN: 0145-6008
DOI: 10.1111/acer.12405
Popis: 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.
Databáze: OpenAIRE
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