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In Vivo Contribution of Cyp24a1 Promoter Vitamin D Response Elements
Mark B Meyer1, Seong Min Lee1, Jordan M Towne1
1Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Endocrinology
|October 3, 2024
Summary
Mutating promoter proximal vitamin D response elements (PRO VDREs) in mice significantly reduced CYP24A1 expression and vitamin D hormone induction. This study highlights the cooperative role of enhancers in regulating vitamin D catabolism.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- CYP24A1 enzyme catabolizes vitamin D metabolites, crucial for calcium homeostasis.
- CYP24A1 expression is tightly regulated by 1,25(OH)2D3, FGF23, and PTH, particularly in the kidney.
- Regulation involves promoter proximal (PRO) and distal downstream (DS) vitamin D response elements (VDREs).
Purpose of the Study:
- To investigate the in vivo roles of PRO VDREs in basal CYP24A1 expression, FGF23 activation, and PTH suppression.
- To elucidate the functional contribution of PRO VDREs in mediating vitamin D and FGF23 actions on CYP24A1.
- To understand the interplay between PRO VDREs and DS enhancers in CYP24A1 gene regulation.
Main Methods:
- Selective mutation of PRO VDREs in the mouse CYP24A1 gene.
- Assessment of Vitamin D Receptor (VDR) occupancy via ChIP assays.
- Quantification of CYP24A1 mRNA levels in kidney and intestine following hormonal treatments.
- Analysis of FGF23 and PTH signaling pathways affecting CYP24A1 expression.
Main Results:
- PRO VDRE mutation caused a significant loss of VDR occupancy and reduced 1,25(OH)2D3-induced CYP24A1 expression in the kidney.
- Intestinal CYP24A1 induction by 1,25(OH)2D3 was nearly eliminated upon PRO VDRE mutation.
- FGF23 induction of CYP24A1 was diminished but not abolished, maintaining synergy with 1,25(OH)2D3.
- PTH suppression of CYP24A1 remained unaffected, despite minor changes in CREB phosphorylation.
- VDR recruitment to DS enhancers was markedly reduced after PRO VDRE mutation.
Conclusions:
- PRO VDREs are essential for maximal 1,25(OH)2D3-induced CYP24A1 expression and VDR recruitment to distal enhancers.
- The DS1 enhancer region acts as a critical basal regulator of CYP24A1 activity.
- Cooperative interactions between PRO VDREs and DS enhancers are vital for regulating CYP24A1 by 1,25(OH)2D3 and FGF23.
- These findings clarify the intricate genomic control mechanisms governing vitamin D catabolism.
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