Kidney-specific genetic control module (in mouse) governs endocrine regulation of the cytochrome P450 gene Cyp27b1 essential for vitamin D3 activation

The vitamin D endocrine system in mammals is very complex –– regulating mineral homeostasis via enzyme activities in the intestine, kidney, and bone. Metabolic activation of vitamin D3 to its hormonal form, 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3], i.e. most potent ligand for the vit D receptor (VDR), occurs in kidney via the cytochrome P450 enzyme CYP27B1. Despite its importance in vitamin D metabolism, molecular mechanisms underlying regulation of the Cyp27b1 gene are have remained elusive during the past 3-4 decades. That is why we at GEITP believe the present study [see the attached fascinating full paper and editorial] represents a landmark breakthrough.

Authors identified a kidney-specific control module –– governed by a renal cell-specific chromatin structure located distal to the Cyp27b1 transcribed gene –– that mediates unique basal as well as parathyroid hormone (PTH)-, fibroblast growth factor-23 (FGF23)-, and 1,25(OH)2D3-mediated regulation of Cyp27b1 gene expression. Genomics researchers typically look PROXIMAL to any gene to see if regulatory modules can be identified; this finding [herein] is therefore rather unique because the regulatory module is distal to the transcribed gene.

Selective genomic deletion of key components within this regulatory module in mice results in loss of either PTH induction, or FGF23- and 1,25(OH)2D3-mediated suppression of Cyp27b1 gene expression; loss of PTH induction causes a debilitating skeletal phenotype, whereas loss of FGF23- and 1,25(OH)2D3-mediated suppression confers a quasi-normal bone mineral phenotype –– through compensatory homeostatic mechanisms involving the Cyp24a1 gene activity. Authors found that Cyp27b1 is also expressed at low levels in non-renal cells, in which transcription was modulated exclusively by inflammatory factors via a process that was unaffected by deletion of the kidney-specific module.

These results reveal that differential regulation of Cyp27b1 expression represents a mechanism whereby 1,25(OH)2D3 can fulfill separate functional roles –– first in the kidney to control mineral homeostasis, and second in cells outside the kidney to regulate target genes linked to specific biological responses. Authors conclude, and rightly so, that these mouse findings open new avenues for approaching studies of vitamin D metabolism and its involvement in therapeutic strategies for human health and disease. For example, it is long been known that mutations in the human CYP27B1 gene are responsible for vitamin-D-dependent rickets.

J Biol Chem 2o17; 292: 17541-17558 and pp. 17559–17560 [editorial]

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