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Abstract: TH-OR049

In Vivo Deletion of Complex Genomic Enhancers Reveal a Kidney-Specific, Endocrine-Deficient Cyp27b1 Pseudo-Null Mouse and Loss of Reciprocally Regulated Cyp24a1 by FGF23 and PTH

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic


  • Meyer, Mark B., University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Benkusky, Nancy A., University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Lee, Seong Min, University of Wisconsin-Madison, Madison, Wisconsin, United States
  • Jones, Glenville, Queens University, Kingston, Ontario, Canada
  • Pike, J. Wesley, University of Wisconsin-Madison, Madison, Madison, Wisconsin, United States

Cyp27b1 and Cyp24a1 are reciprocally regulated in the kidney by the key hormones PTH, FGF23, and 1,25(OH)2D3. Our recent genomic studies in mice identified a complex kidney-specific enhancer module located within the introns of adjacent Mettl1 (M1) and Mettl21b (M21) genes that mediate basal and PTH induction of Cyp27b1 as well as suppression by FGF23 and 1,25(OH)2D3. Gross deletion of these segments in mice has severe consequences on skeletal health, but does not affect Cyp27b1 regulation in non-renal target cells (NRTCs).


Using CRISPR/Cas9-mediated deletions of genomic enhancers (non-coding segments) in mice, we can separate tissue specific responses in both Cyp27b1 and Cyp24a1. We used ChIP-seq from adult human kidney cortex to explore conservation to mouse.


Our current studies reveal a bimodal activity in the M1 intronic enhancer with components responsible for induction of Cyp27b1 by PTH and repression by 1,25(OH)2D3. The deletion of both M1 and M21 submodules fully eliminates basal Cyp27b1 expression and regulation in the kidney, leading to a systemic and skeletal phenotype similar to that of the Cyp27b1-KO mouse due to depletion of 1,25(OH)2D3 and high PTH. Cyp24a1 levels in the double KO mouse were low due to compensatory regulation by elevated PTH and reduced FGF23. However, expression of Cyp27b1 and retention of its regulation by inflammation (LPS) in the NRTCs remained unperturbed. Importantly, dietary normalization of calcium, phosphate, PTH, and FGF23 rescues this aberrant phenotype and creates an ideal in vivo model with which to study NRTC production of 1,25(OH)2D3 and its potential impact on disease. Using a separate set of mouse enhancer deletions, we found that basal as well as PTH and FGF23 regulation of Cyp24a1 in the kidney was controlled by a set of downstream enhancers distinct from those that mediate 1,25(OH)2D3. Finally, we confirm the presence of a conserved chromatin landscape for both CYP27B1 and CYP24A1 in human similar to the mouse.


Collectively, these studies define a finely balanced homeostatic control mechanism employed by PTH and FGF23 with catastrophic toxicity protection from 1,25(OH)2D3 in the genomic regulation of vitamin D metabolism and its accompanied control of mineral maintenance.


  • NIDDK Support