Unravelling the versatile transcriptionally repressive effects of the vitamin D receptor, highlighting the regulation of calcium and energy homeostasis

The vitamin D receptor (VDR) is a well-known regulator of calcium and bone homeostasis. However, the mechanisms responsible for VDR-mediated signalling in different tissues remain incompletely understood, potentially because previous studies neglected the transcriptionally repressive effects of the VDR. In the current project, we will therefore investigate transgenic mouse models in which only transcriptional repression can take place (Vdr-delta-AF2 and Cyp27b1 knockout mice). This approach allows us not only to answer long-standing questions on the mechanisms of transcriptional repression (Aim 1), but also to gain novel insights in VDR-regulated transcriptional networks. Notwithstanding the fact that vitamin D is a major stimulator of intestinal and renal calcium (re)absorption, not all proteins involved in this process have been identified. Interestingly, previously performed transcriptome analyses in intestine and kidney of Vdr-delta-AF2 mice showed differential regulation of genes that function in mineral (re)absorption. We will evaluate whether these transporters are implicated in vitamin D-induced calcium (re)absorption (Aim 2). Our transcriptome analysis also revealed multiple differentially regulated genes involved in energy homeostasis, which is interesting in view of the lean phenotype of mice with defective VDR signaling. We will therefore investigate whether VDR-mediated alterations in intestinal and skeletal nutrient handling contribute to this phenotype (Aim3).