# Transcriptional Control of Mouse FGF23 Expression in Health and Disease

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $233,063

## Abstract

PROJECT SUMMARY/ABSTRACT
FGF23 represents a recently discovered phosphaturic hormone whose primary physiological role is to regulate
phosphate content in the blood through direct actions in the kidney. FGF23 is expressed in osteoblasts and
osteocytes where its output is controlled by phosphate, 1,25(OH)2D3, and PTH. More recent studies now suggest
that inflammation and iron deficiency also upregulate FGF23 expression from multiple sources. Despite
considerable effort, however, little is known of the mechanisms through which the above regulators modulate
FGF23 expression. Using ChIP-seq analysis, we discovered 5 regulatory regions located at distal sites across
the mouse FGF23 gene locus that we hypothesized were responsible for FGF23 regulation in vivo. We deleted
each of these potential regulatory regions in the mouse genome using CRISPR/Cas9 methods, and have
explored their role in mediating the actions of phosphate, 1,25(OH)2D3, PTH and LPS via loss of function studies
through these segments in vivo. Our results support a proposal aimed at defining the molecular mechanisms
which underlie FGF23 regulation in health and disease. Aim 1: Refine the functional actions and interactions
of regulatory enhancers at the FGF23 gene locus that control tissue FGF23 expression in vivo. Several
additional strains of regulatory mutant mice will be created using a CRISPR/Cas9 approach and response to
phosphate, PTH, 1,25(OH)2D3 and LPS assessed to refine and potentially resolve the genomic sites of action
for each of these regulators, and to determine whether regions already identified comprise the entire regulatory
domain at the FGF23 locus. These studies will firmly establish the span of functional regulatory activities involved
in FGF23 expression. Aim 2: Determine the transcription factors, chromatin regulators and signaling
pathways and their interactions that mediate the regulation of FGF23 expression in tissues in vivo. We
will use ChIP-seq and ATAC-seq analyses and other techniques to resolve DNA sites of action, enabling the
unbiased identification of motifs, transcription factor and chromatin coregulators, and potential signaling
pathways that are involved. Aim 3: Identify the temporal role(s) of systemic factors in the regulation of
FGF23 expression in an oxalate-induced mouse model of chronic kidney disease. Oxalate-induced acute
kidney disease impacts the expression of FGF23 from bone and other tissues. We will examine the ability of
oxalate to induce FGF23 expression in tissues as a function of our FGF23 regulatory deletion models. These
studies will also focus on assessing the systemic and biological phenotypes that emerge in kidney, skeleton and
the vascular system due to amelioration of FGF23 upregulation following oxalate treatment. Our results are likely
to provide greater insight into the selective mechanisms through which FGF23 is regulated in vivo in health and
disease.

## Key facts

- **NIH application ID:** 10129370
- **Project number:** 5R01DK118174-03
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** J WESLEY PIKE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $233,063
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129370

## Citation

> US National Institutes of Health, RePORTER application 10129370, Transcriptional Control of Mouse FGF23 Expression in Health and Disease (5R01DK118174-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10129370. Licensed CC0.

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