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J. Biol. Chem., Vol. 280, Issue 27, 25506-25511, July 8, 2005

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Tissue-specific Changes in H19 Methylation and Expression in Mice with Hyperhomocysteinemia^*

Angela M. Devlin, Teodoro Bottiglieri¶, Frederick E. Domann||, and Steven R. Lentz**

From the Departments of Internal Medicine and^|| Radiation Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, the^** Veterans Affairs Medical Center, Iowa City, Iowa 52246, and the ^¶Baylor Institute of Metabolic Disease, Dallas, Texas 75226

Expression of the imprinted genes H19 and insulin-like growth factor 2 (Igf2), which lie in close proximity on mouse chromosome 7, is regulated by methylation of a differentially methylated domain (DMD) located 5' to H19. Biallelic expression of H19 has been observed in renal disease patients with hyperhomocysteinemia, a cardiovascular disease risk factor. The present study determined whether hyperhomocysteinemia produces decreased tissue methylation capacity, hypomethylation of the H19 DMD, and altered expression of H19 and Igf2 in adult mice. Mice heterozygous for disruption of the gene for cystathionine--synthase (Cbs+/–) and C57BL/6 (Cbs+/+) mice were fed a hyperhomocysteinemic or control diet, respectively, from weaning until 9–12 months of age. Higher plasma total homocysteine (p < 0.001) was found in hyperhomocysteinemic mice than in control mice (95 ± 12 versus 5.0 ± 0.3 µmol/liter). Hyperhomocysteinemia was accompanied by higher levels of S-adenosylhomocysteine (p < 0.05) and lower S-adenosylmethionine/S-adenosylhomocysteine ratios (p < 0.001) in liver and brain. The effect of hyperhomocysteinemia on H19 DMD methylation was tissue-specific. In liver, hyperhomocysteinemic mice had decreased H19 DMD methylation (p < 0.001). In brain, hyperhomocysteinemia was accompanied by increased H19 DMD methylation (p < 0.001) and a decrease in the ratio of H19/Igf2 transcripts (p < 0.05). In aorta, hyperhomocysteinemia produced an increase in H19 DMD methylation (p < 0.001) and a 2.5-fold increase in expression of H19 transcripts (p < 0.05). Levels of H19 transcripts in aorta correlated positively with plasma total homocysteine concentration (p < 0.05, r = 0.620). We conclude that hyperhomocysteinemia produces tissue-specific changes in H19 DMD methylation and increased vascular expression of H19 in adult mice.

Received for publication, May 2, 2005 , and in revised form, May 17, 2005.

^* This work was supported by the Office of Research and Development, United States Department of Veterans Affairs, National Institutes of Health Grants HL63943 and NS24621, and American Heart Association Beginning Grant-in-aid 0465315Z (to A. M. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Nutrition Research Program, University of British Columbia, BC Research Institute for Children's and Women's Health, 950 West 28th Ave., Vancouver, Canada.

To whom correspondence should be addressed: Dept. of Internal Medicine, C32 GH, The University of Iowa, IA 52242. Tel.: 319-356-4048; Fax: 319-335-8848; E-mail: steven-lentz{at}uiowa.edu.

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