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Epigenetic Regulation of Nr3c1 Expression in Hyperhomocysteinemia
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.689.9
Subject(s) - hyperhomocysteinemia , epigenetics , exon , biology , gene expression , endocrinology , dna methylation , methylation , medicine , gene silencing , regulation of gene expression , bisulfite sequencing , cystathionine beta synthase , gene , microbiology and biotechnology , homocysteine , methionine , genetics , amino acid
Epigenetic regulation of gene expression may play a role in the endothelial dysfunction associated with hyperhomocysteinemia (HHcy). The objective of this study is to determine if changes in glucocorticoid receptor gene ( Nr3c1 ) expression contributes to HHcy‐related vascular pathology. Nr3c1 expression is regulated by epigenetic mechanisms in non‐vascular tissue and glucocorticoids are vasculoprotective. Mice heterozygous for disruption of the cystathionineβ‐synthase gene ( Cbs +/−) and C57BL/6 mice ( Cbs +/+) were fed a control diet or a high methionine/low folate (HH) diet to induce HHcy. Total Nr3c1 mRNA levels in aorta, determined by real‐time PCR, were lower (p<0.001) in Cbs +/− and Cbs +/+ fed the HH diet with higher plasma total homocysteine levels than Cbs +/+ mice fed the control diet (22.6±5.7 and 7.17±1.8 vs 2.44±0.2 M, respectively, p<0.001). The 5’ portion of the Nr3c1 gene contains multiple first exons producing heterogeneous RNA transcripts, expressed in a tissue‐specific fashion. We identified expression of two transcripts in aorta arising from exons 1E and 1F and bisulfite pyrosequencing found increased methylation of the exon 1E and exon 1F promoter regions in mice with HHcy. These findings are the first to show methylation‐silencing of vascular Nr3c1 expression and suggest a role for epigenetic regulation of gene expression in HHcy‐related endothelial dysfunction.