Effects of intron conversion in the human gene on its transcription and blood pressure regulation in transgenic mice.

The human cytochrome P450 family 11 subfamily B member 2 () gene encodes aldosterone synthase, the rate-limiting enzyme in the biosynthesis of aldosterone. In some humans, undergoes a unique intron conversion whose function is largely unclear. The intron conversion is formed by a replacement of the segment of DNA within intron 2 of with the corresponding region of the gene. We show here that the intron conversion is located in an open chromatin form and binds more strongly to the transcriptional regulators histone acetyltransferase P300 (p300), NFκB, and CCAAT enhancer-binding protein α (CEBPα). Reporter constructs containing the intron conversion had increased promoter activity on transient transfection in H295R cells compared with WT intron 2. We generated humanized transgenic (TG) mice containing all the introns, exons, and 5'- and 3'-flanking regions of the gene containing either the intron conversion or WT intron 2. We found that TG mice containing the intron conversion have () increased plasma aldosterone levels, () increased mRNA and protein levels, and () increased blood pressure compared with TG mice containing WT intron 2. Results of a ChIP assay showed that chromatin obtained from the adrenals of TG mice containing the intron conversion binds more strongly to p300, NFκB, and CEBPα than to WT intron 2. These results uncover a functional role of intron conversion in and suggest a new paradigm in blood pressure regulation.