Kidney Week

Abstract: TH-OR055

ETV1 Transcription Factor Mediates Fibroblast Growth Factor 23 (FGF-23) Genomic Control of Vitamin D Metabolism and PTH Suppression

Session Information

• New Developments in Bones, Stones, and Mineral Metabolism
  November 06, 2025 | Location: Room 370A, Convention Center
  Abstract Time: 04:30 PM - 04:40 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Meyer, Mark B., University of Wisconsin-Madison, Madison, Wisconsin, United States

Mark B. Meyer, PhD

• Towne, Jordan M, University of Wisconsin-Madison, Madison, Wisconsin, United States

Jordan M Towne, MS

• Cichanski, Shannon R., University of Wisconsin-Madison, Madison, Wisconsin, United States

Shannon R. Cichanski

• Lee, Seong Min, University of Wisconsin-Madison, Madison, Wisconsin, United States

Seong Min Lee, PhD

• Solis, Emmanuel, Indiana University School of Medicine, Indianapolis, Indiana, United States

Emmanuel Solis

• White, Kenneth E., Indiana University School of Medicine, Indianapolis, Indiana, United States

Kenneth E. White, PhD

Background

Calcium and phosphate levels are controlled by active vitamin D, 1,25(OH)₂D₃ (1,25D), which is made in the kidney proximal tubule (PT) cells by the CYP27B1 enzyme and degraded by the CYP24A1 enzyme. PTH activates Cyp27b1 (C27) and suppresses Cyp24a1 (C24) whereas FGF23 suppresses C27 and activates C24. 1,25D itself suppresses C27 and activates C24. In vivo, the balance of serum PTH and FGF23 determines the homeostatic levels of vitamin D hormone. While genomic actions of PTH activation and 1,25D act through CREB and VDR, respectively, the mechanisms of PTH suppression of C24 and, importantly, genomic control by FGF23 have remained a critical knowledge gap.

Methods

To discover this factor(s), we examined kidney expression data to identify candidate transcription factors (TFs), performed ChIP-seq in vivo on candidate TFs, and tested their activation by FGF23, 1,25D, and PTH in reporters in vitro.

Results

We found that the E twenty-six (ETS) family member ETV1 binds to the genome at PT cell-specific genomic enhancers for C24 and was increased by FGF23 treatments (~8-fold) in the mouse kidney. Genome-wide, >80% of FGF23-stimulated ETV1 genomic binding overlapped with 1,25D-induced VDR binding. FGF23 + 1,25D cotreatment synergistically regulated C24 in vivo, and VDR and ETV1 physically interact as co-IP in the presence of FGF23 + 1,25D increased association. In vitro, C24 mRNA increased from 4-50-fold with FGF23 and 1,25D alone to >400-fold in combination. ETV1 bound to the Etv1 promoter as well, driving its own production. Mutation of an ETS binding site (EBS) prevented the activation of a C24 promoter reporter in vitro by FGF23 and opposed the synergistic increase (1,25D + FGF23). Surprisingly, when mice were treated with PTH, ETV1 was completely removed from C24 enhancers even with pre-treatment of FGF23. In fact, ETV1 genome-wide binding was reduced from 4,790 sites to 22 sites, a remarkable depletion.

Conclusion

Taken together, our data indicate that ETV1 binds to specific EBS to control C24 in response to FGF23 in partnership with 1,25D-induced VDR. Strikingly, ETV1 is also involved in PTH-mediated suppression. These studies help answer a long-standing mechanistic question of FGF23 genomic actions in kidney and point to ETV1 as being at the nexus of PTH and FGF23 signaling that controls vitamin D metabolism.

Funding

• Other NIH Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20254tvczr50