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Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse.
Alcohol Clin Exp Res. 2014 Jun; 38(6):1540-9.AC

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.

Authors+Show Affiliations

Department of Internal Medicine, University of California Davis, Sacramento, California.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

24730561

Citation

Medici, Valentina, et al. "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, 2014, pp. 1540-9.
Medici V, Schroeder DI, Woods R, et al. Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse. Alcohol Clin Exp Res. 2014;38(6):1540-9.
Medici, V., Schroeder, D. I., Woods, R., LaSalle, J. M., Geng, Y., Shibata, N. M., Peerson, J., Hodzic, E., Dayal, S., Tsukamoto, H., Kharbanda, K. K., Tillman, B., French, S. W., & Halsted, C. H. (2014). Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse. Alcoholism, Clinical and Experimental Research, 38(6), 1540-9. https://doi.org/10.1111/acer.12405
Medici V, et al. Methylation and Gene Expression Responses to Ethanol Feeding and Betaine Supplementation in the Cystathionine Beta Synthase-deficient Mouse. Alcohol Clin Exp Res. 2014;38(6):1540-9. PubMed PMID: 24730561.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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, Y1 - 2014/04/14/ PY - 2013/11/15/received PY - 2014/02/12/accepted PY - 2014/4/16/entrez PY - 2014/4/16/pubmed PY - 2015/2/13/medline KW - Alcohol KW - Cystathionine Beta Synthase KW - DNA Methylation KW - S-Adenosylhomocysteine KW - S-Adenosylmethionine SP - 1540 EP - 9 JF - Alcoholism, clinical and experimental research JO - Alcohol Clin Exp Res VL - 38 IS - 6 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. SN - 1530-0277 UR - https://www.unboundmedicine.com/medline/citation/24730561/Methylation_and_gene_expression_responses_to_ethanol_feeding_and_betaine_supplementation_in_the_cystathionine_beta_synthase_deficient_mouse_ L2 - https://doi.org/10.1111/acer.12405 DB - PRIME DP - Unbound Medicine ER -