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

Area of Science:

• Epigenetics and Gene Regulation
• Cardiovascular Disease Risk Factors
• Molecular Biology

Background:

• Imprinted genes H19 and Igf2 expression is regulated by methylation of the H19 differentially methylated domain (DMD).
• Hyperhomocysteinemia, a cardiovascular disease risk factor, is linked to biallelic H19 expression in renal disease patients.
• The study investigates the impact of hyperhomocysteinemia on methylation and gene expression in mice.

Purpose of the Study:

• To determine if hyperhomocysteinemia leads to decreased tissue methylation capacity.
• To investigate the effect of hyperhomocysteinemia on H19 DMD methylation.
• To analyze alterations in H19 and Igf2 gene expression in adult mice under hyperhomocysteinemic conditions.

Main Methods:

• Mice heterozygous for cystathionine-beta-synthase (Cbs+/-) and wild-type C57BL/6 (Cbs+/+) mice were fed hyperhomocysteinemic or control diets.
• Plasma total homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine/S-adenosylhomocysteine ratios were measured.
• H19 DMD methylation and H19/Igf2 transcript levels were analyzed in liver, brain, and aorta tissues.

Main Results:

• Hyperhomocysteinemic mice exhibited elevated plasma homocysteine and altered S-adenosylmethionine/S-adenosylhomocysteine ratios in liver and brain.
• Hyperhomocysteinemia induced tissue-specific changes in H19 DMD methylation: decreased in liver, increased in brain and aorta.
• Vascular H19 transcript expression significantly increased in hyperhomocysteinemic mice, correlating with homocysteine levels.

Conclusions:

• Hyperhomocysteinemia induces tissue-specific epigenetic modifications at the H19 DMD in adult mice.
• Elevated homocysteine levels are associated with increased H19 gene expression in the vasculature.
• These findings highlight a potential mechanism linking hyperhomocysteinemia to cardiovascular alterations via epigenetic dysregulation.