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Consistent with this, elevated FGF23 levels are associated with inflammatory markers as well as parathyroid hormone (PTH) in various disease states, including chronic kidney disease (CKD). However, the molecular mechanisms underpinning <jats:italic>Fgf23<\/jats:italic> transcription in response to these regulators are largely unknown. We therefore utilized chromatin immunoprecipitation followed by DNA sequencing (ChIP\u2010seq) data from an osteocyte cell line to identify potential regulatory regions of the <jats:italic>Fgf23<\/jats:italic> gene. Based on ChIP\u2010seq analysis of enhancer\u2010associated histone modifications, including H3K4 methylation and H3K9 acetylation, we discovered several potential enhancers for <jats:italic>Fgf23<\/jats:italic>, one of which was located 16kb upstream of the gene's transcriptional start site. Deletion of this putative enhancer from the mouse genome using CRISPR\u2010Cas9 technology led to lower bone, thymus, and spleen expression of <jats:italic>Fgf23<\/jats:italic> mRNA without altering circulating levels of the intact hormone, although as previously reported, only bone displayed significant basal expression. Nevertheless, lack of the \u221216kb enhancer blunted FGF23 upregulation in a tissue\u2010specific manner by the acute inflammatory inducers lipopolysaccharide (LPS), interleukin\u20101\u2010beta (IL\u20101\u03b2), and tumor necrosis factor\u2010alpha (TNF\u03b1) in bone, non\u2010osseous tissues, and in circulation. Lack of the \u221216kb enhancer also inhibited PTH\u2010induced bone <jats:italic>Fgf23<\/jats:italic> mRNA. Moreover, the absence of this <jats:italic>Fgf23<\/jats:italic> enhancer in an oxalate diet\u2010induced murine CKD model prevented the early onset induction of osseous, renal, and thymic <jats:italic>Fgf23<\/jats:italic> mRNA levels and led to a significant blunting of elevated circulating intact FGF23 levels. These results suggest that \u221216kb enhancer mediates the induction of <jats:italic>Fgf23<\/jats:italic> by inflammation and PTH and facilitates the increase in FGF23 expression in a murine model of CKD. As exemplified herein, these <jats:italic>Fgf23<\/jats:italic> enhancer\u2010deleted mice will provide a unique model in which to study the role of FGF23 expression in inflammatory diseases. \u00a9 2017 The Authors. <jats:italic>JBMR Plus<\/jats:italic> is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jbm4.10023","type":"journal-article","created":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T14:02:41Z","timestamp":1509112961000},"page":"31-46","source":"Crossref","is-referenced-by-count":58,"title":["A Novel Distal Enhancer Mediates Inflammation\u2010, PTH\u2010, and Early Onset Murine Kidney Disease\u2010Induced Expression of the Mouse <i>Fgf23<\/i> Gene"],"prefix":"10.1093","volume":"2","author":[{"given":"Melda","family":"Onal","sequence":"first","affiliation":[{"name":"Department of Biochemistry University of Wisconsin\u2010Madison Madison WI USA"},{"name":"Department of Physiology and Biophysics University of Arkansas for Medical Sciences Little Rock, AR USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex H","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff D","family":"Thostenson","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Arkansas for Medical Sciences Little Rock AR USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy A","family":"Benkusky","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Wisconsin\u2010Madison Madison WI USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark B","family":"Meyer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Wisconsin\u2010Madison Madison WI 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