Regulation of mouse Cyp24a1 expression via promoter-proximal and downstream-distal enhancers highlights new concepts of 1,25-dihydroxyvitamin D₃ action

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• 作者：J. Wesley Pike ; ^{pike@biochem.wisc.edu} ; ^{jpike@wisc.edu} ; Mark B. Meyer
• 关键词：Cyp24a1 ; 1 ; 25(OH)2D3 ; VDR/RXR heterodimer ; C/EBP尾 ; Transcription ; Distal enhancers ; ChIP-seq analysis
• 刊名：Archives of Biochemistry and Biophysics
• 出版年：2012
• 期刊代码：116_00039861
• 类别：ch
• 出版时间：1 July, 2012
• 卷：523
• 期：1
• 页码：2-8
• 文件大小：417 K

摘要

CYP24A1 functions in vitamin D target tissues to degrade 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). Thus, the concentration of this enzyme and the regulation of its expression is a primary determinant of the overall biological activity of 1,25(OH)₂D₃ within cells. The principle regulator of CYP24A1 expression is 1,25(OH)₂D₃ itself, which functions through the vitamin D receptor to upregulate the transcriptional activity of the Cyp24a1 gene. In this report, we explore the mechanism of this regulation using recently developed ChIP-chip and ChIP-seq techniques that permit an unbiased search for enhancer elements that participate in this transcriptional control. Our studies both confirm a regulatory region defined earlier and located proximal to the transcriptional start site (TSS) of mouse Cyp24a1 (鈭?60 and 鈭?65 nt) and identify a novel intergenic region located downstream of the transcription unit that contains two enhancers (+35 and +37 kb) that facilitate 1,25(OH)₂D₃-dependent upregulation of Cyp24a1 expression. Interestingly, while C/EBP尾 also binds under basal conditions to a site located immediately upstream of the Cyp24a1 promoter (鈭?45 nt), occupancy by this factor is strikingly increased following 1,25(OH)₂D₃ treatment. The locations and activities of these regulatory regions that mediate 1,25(OH)₂D₃ actions were confirmed in mice in vivo. We conclude that the mechanism through which 1,25(OH)₂D₃ induces the CYP24A1 enzyme, thereby autoregulating its own destruction, involves both promoter-proximal as well as downstream-distal enhancers. These findings highlight new concepts regarding the molecular mechanism of action of 1,25(OH)₂D₃ and other hormonal regulators.