1α,25(OH)2D3-induced DNA methylation suppresses the human CYP27B1 gene

Abstract: CYP27B1 is a critical enzyme of Vitamin D biosynthesis that hydroxylates 25(OH)D3 at the final step of the biosynthetic pathway. The CYP27B1 gene is expressed primarily in kidney and negatively controlled by Vitamin D receptor. We have characterized the negative vitamin D response element and its binding protein, a bHLH transcription factor. This factor directly binds to the 1αnVDRE and activates transcription, but its transcriptional activity is suppressed by the ligand-activated Vitamin D receptor through recruitment of histone deacetylase. We have shown that histone deacetylation is a critical step for chromatin structure remodeling in suppression of the CYP27B1 gene. We have further demonstrated that, in addition to histone acetylation, this transrepression by VDR requires DNA methylation in the CYP27B1 gene promoter. Thus, transcriptional regulation of the CYP27B1 gene appears to be mediated by dual epigenetic modifications. [Copyright &y& Elsevier]