Fgf23 Control of Hox Expression and Function and Implications for Chronic Kidney Disease

Abstract

FGF23 is a hormone that controls metabolic phosphate and vitamin D synthesis in mammals and is overexpressed in chronic kidney disease (CKD). Previous studies have shown that FGF23 initiates transcriptional reprogramming within kidney cells, and therefore epigenetic changes may occur when FGF23 levels are high, revealing therapeutic target genes for patients with CKD and other FGF23-related diseases. In my research, I performed RNAseq and ATACseq on HEK-mKL cells treated with recombinant FGF23 to determine potential transcriptional and genomic reprogramming downstream of FGF23 bioactivity. My results showed significantly decreased chromatin accessibility at the promoters of sixteen HOX genes with a 40-70% expression decrease of HOXB5 and HOXD12 validated by qPCR. Testing kidney mRNA isolated from CKD mouse models showed increased Hox expression, suggesting that these genes are dysregulated during CKD. HOXD12 overexpression in HEK-mKL cells showed significant increase in CYP27B1 expression and in pEMT genes SNAI1 and MMP9. HOXB5 and HOXD12 protein products were tracked using immunofluorescence. Collectively, these data demonstrate that FGF23 suppresses HOX transcription, which is dysregulated in CKD and may contribute to increased CYP27B1 and pEMT phenotype. These results may better define the transcriptional landscape during CKD.