Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse

Valentina Medici, Diane I. Schroeder, Rima Woods, Janine M LaSalle, Yongzhi Geng, Noreene M. Shibata, Janet Peerson, Emir Hodzic, Sanjana Dayal, Hidekazu Tsukamoto, Kusum K. Kharbanda, Brittany Tillman, Samuel W. French, Charles H. Halsted

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1540-1549
Number of pages10
JournalAlcoholism: Clinical and Experimental Research
Volume38
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Cystathionine beta-Synthase
Betaine
Methylation
Gene expression
Alcoholic Fatty Liver
Ethanol
Gene Expression
Metabolism
Genes
Methionine
Nutrition
S-Adenosylhomocysteine
S-Adenosylmethionine
Methyltransferases
Diet
Liver
DNA
Peroxisome Proliferators
Dietary Supplements
Inbred C57BL Mouse

Keywords

  • Alcohol
  • Cystathionine Beta Synthase
  • DNA Methylation
  • S-Adenosylhomocysteine
  • S-Adenosylmethionine

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Psychiatry and Mental health
  • Toxicology

Cite this

Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse. / 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.

In: Alcoholism: Clinical and Experimental Research, Vol. 38, No. 6, 2014, p. 1540-1549.

Research output: Contribution to journalArticle

Medici, V, Schroeder, DI, Woods, R, LaSalle, JM, Geng, Y, Shibata, NM, Peerson, J, Hodzic, E, Dayal, S, Tsukamoto, H, Kharbanda, KK, Tillman, B, French, SW & Halsted, CH 2014, 'Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse', Alcoholism: Clinical and Experimental Research, vol. 38, no. 6, pp. 1540-1549. https://doi.org/10.1111/acer.12405
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. / Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse. In: Alcoholism: Clinical and Experimental Research. 2014 ; Vol. 38, No. 6. pp. 1540-1549.
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abstract = "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.",
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T1 - Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse

AU - Medici, Valentina

AU - Schroeder, Diane I.

AU - Woods, Rima

AU - LaSalle, Janine M

AU - Geng, Yongzhi

AU - Shibata, Noreene M.

AU - Peerson, Janet

AU - Hodzic, Emir

AU - Dayal, Sanjana

AU - Tsukamoto, Hidekazu

AU - Kharbanda, Kusum K.

AU - Tillman, Brittany

AU - French, Samuel W.

AU - Halsted, Charles H.

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N2 - 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.

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