Epigenomic Alterations of the Human CYP11B Gene in Adrenal Zonation

The <i>CYP11B2</i> gene is sporadically expressed in the zona glomerulosa (ZG), whereas the <i>CYP11B1</i> gene is detected in the zona fasciculata (ZF)/reticularis (ZR), with predominant expression in the ZF. We studied the association between DNA methylation and adrenal zonation. Next, the <i>CYP11B2</i> methylation statuses in the adrenal medulla (n = 4) and pheochromocytomas (n = 7) were examined. The expression of <i>CYP11B2</i> in pheochromocytomas and non-functioning adenomas (NFAs) (n = 4) was also studied. Adrenals from five autopsy subjects were assessed for immunohistochemically defined adrenal zonation. We used laser capture microscopy to isolate DNA from each zone in adrenal tissues. <i>CYP11B1</i> was predominantly unmethylated in the ZF but heavily methylated in the ZG and the ZR. In contrast, <i>CYP11B2</i> was hypomethylated in the ZG compared with in the ZF and the ZR. In terms of the expression site and strength, the promoter methylation patterns for <i>CYP11B2</i> and <i>CYP11B1</i> showed capacities to express CYP11B enzymes. The DNA methylation patterns of the <i>CYP11B2</i> and <i>CYP11B1</i> promoters were closely associated with adrenal zonation. The unmethylated CpGs of <i>CYP11B2</i> were found in the adrenal medulla and pheochromocytomas. Gene expression of <i>CYP11B2</i> was detected in the pheochromocytomas. These results indicate the possibility that the synthesis of aldosterone occurs in the adrenal medulla. Further study is necessary to elucidate the pathophysiological roles for the synthesis of aldosterone in the adrenal medulla.