Epigenetic Regulation of Aldosterone Synthase Gene by Sodium and Angiotensin II

Abstract

Background DNA methylation is believed to be maintained in adult somatic cells. Recent findings, however, suggest that all methylation patterns are not stable. We demonstrate that stimulatory signals can change the DNA methylation status around transcription factor binding sites and a transcription start site and activate expression of the aldosterone synthase gene ( CYP 11B2 ). Methods and Results DNA methylation of CYP 11B2 was analyzed in aldosterone‐producing adenomas, nonfunctioning adrenal adenomas, and adrenal glands and compared with the gene expression levels. CpG dinucleotides in the CYP 11B2 promoter were found to be hypormethylated in tissues with high expression, but not in those with low expression, of CYP 11B2 . Methylation of the CYP 11B2 promoter fused to a reporter gene decreased transcriptional activity. Methylation of recognition sequences of transcription factors, including CREB 1, NGFIB ( NR 4A1), and NURR 1 ( NR 4A2) diminished their DNA ‐binding activity. A methylated‐CpG‐binding protein MECP 2 interacted directly with the methylated CYP 11B2 promoter. In rats, low salt intake led to upregulation of CYP 11B2 expression and DNA hypomethylation in the adrenal gland. Treatment with angiotensin II type 1 receptor antagonist decreased CYP 11B2 expression and led to DNA hypermethylation. Conclusions DNA demethylation may switch the phenotype of CYP 11B2 expression from an inactive to an active state and regulate aldosterone biosynthesis.