Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia

Angela M Devlin; Teodoro Bottiglieri; Frederick E Domann; Steven R Lentz

doi:10.1074/jbc.M504815200

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Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia

Journal article

Open access

Peer reviewed

Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia

Angela M Devlin, Teodoro Bottiglieri, Frederick E Domann and Steven R Lentz

The Journal of biological chemistry, Vol.280(27), pp.25506-25511

07/08/2005

DOI: 10.1074/jbc.M504815200

PMID: 15899898

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Abstract

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-beta-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 micromol/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.

RNA, Untranslated - metabolism

Mice, Inbred C57BL

Gene Expression Regulation - physiology

Hyperhomocysteinemia - metabolism

Brain - physiology

DNA Methylation

Animals

Insulin-Like Growth Factor II - genetics

Mice, Mutant Strains

RNA, Long Noncoding

Liver - physiology

Hyperhomocysteinemia - genetics

Mice

Aorta - physiology

Details

Title: Subtitle: Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia
Creators: Angela M Devlin - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA
Teodoro Bottiglieri
Frederick E Domann
Steven R Lentz
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.280(27), pp.25506-25511
DOI: 10.1074/jbc.M504815200
PMID: 15899898
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: HL63943 / NHLBI NIH HHS NS24621 / NINDS NIH HHS
Language: English
Date published: 07/08/2005
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Surgery; Radiation Oncology; Internal Medicine
Record Identifier: 9984047659002771

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