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"Molecular Pathways And Epigenetic Profiles Involved in the Maintenance of Calcium homeostasis by 1,25(OH)2D3 and changes that occur with aging"

Vaishali Veldurthy
Infection, Immunity & Inflammation Track
MS (Oral Biology) University of Louisville

Thesis Advisor:
Sylvia Christakos, PhD
Department of Microbiology, Biochemistry and Molecular Genetics

Friday, May 5, 2017
10:00 A.M., MSB E609


Epigenomic control (inheritable changes in gene expression that are not mediated at the DNA sequence level) is a new and rapidly evolving field. Although roles of acetylation and phosphorylation in chromatin remodeling have been widely studied, recent findings have also indicated an important role for methylation. Our lab has recently obtained the first evidence that cooperative effects between specific histone methyltransferases and the vitamin D receptor may be a fundamentally important mechanism involved in regulating vitamin D target gene expression. Little is known however, about how epigenetic regulation of VDR and VDR function are altered with age. In this study we examined genes involved in calcium homeostasis and changes in VDR and VDR coactivator protein interaction with DNA that occur with aging.
In the intestine, TRPV6 mRNA significantly declined with age in both proximal and distal intestine. mRNA expression of renal CYP24A1, which is involved in the metabolic inactivation of 1,25(OH)2D3, increased with age, suggesting that increased catabolism of 1,25(OH)2D3 contributes to the decreased capacity with age to absorb calcium and age related bone loss. Although an age related decrease in renal VDR mRNA was observed, in vivo ChIP in kidney showed enhanced recruitment in response to 1,25(OH)2D3 of VDR and enhanced H3 arginine 17 methylation (mediated by the VDR coactivator CARM1) at vitamin D response elements in the mouse renal CYP24A1 gene with age (22-24 months vs 6 months). These findings are the first to address changes in VDR signaling and 1,25(OH)2D3 mediated epigenetic regulation that occur with aging. Klotho is a cofactor for FGF23 involved in phosphate and calcium homeostasis. A premature aging phenotype has been described in klotho deficient mice. We found that alterations in vitamin D target genes and bone defects in the klotho mutant mouse are in contrast to changes observed in aging mice and may reflect endocrine dysregulation in the klotho mutant mouse with a corresponding phosphate and calcium mineral imbalance due to high serum levels of 1,25(OH)2D3 and FGF23.
Using VDR transgenic mice to test directly the role of VDR in the distal intestine, my thesis has also elucidated the role of VDR in the distal intestine. The expression of full length human VDR specifically in the distal intestine of VDR null mice at levels equivalent to WT was sufficient to rescue the rachitic bone phenotype as well as the elevated PTH levels and hypocalcemia seen in VDR null mice. 1,25(OH)2D3 administration to these transgenic mice resulted in upregulation of VDR target genes in ileum, cecum and colon, indicating that the distal as well as the proximal intestine is an important target region for VDR mediated action. Using Affymetrix microarray to analyze gene expression profiles of transcriptome responses in the intestine, we identified novel 1,25(OH)2D3 targets which included lipocalin 2, haptoglobin, FKBP51, S100A8 and S100A9. These newly identified targets have various functions as chaperone proteins, antimicrobial peptides, steroid receptor regulators, sequesters of iron and siderophores. They were found to be upregulated upon 1,25(OH)2D3 treatment in both the duodenum and colon. Our study further emphasizes a role for 1,25(OH)2D3 in the immune system as well as in calcium homeostasis and the importance of the distal as well as the proximal intestinal segments in order to understand intestinal effects of vitamin D .

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