Absence of vitamin D receptor (VDR)-mediated PPARγ suppression causes alopecia in VDR-null mice

Vitamin D receptor (VDR) mutations in humans and mice cause alopecia. VDR-null (VDR-/-) mice exhibit lack of postmorphogenic hair cycles as a result of impaired keratinocyte stem cell (KSC) function. To identify the molecular basis for abnormal KSC function, RNA sequencing of wild-type(WT) and VDR-/- KSCs was performed. These studies demonstrated that >80% of differentially expressed genes are up-regulated in VDR-/- KSCs; thus, the VDR is a transcriptional suppressor in WT KSCs. Peroxisome proliferator-activated receptor gamma (PPAR gamma), PPAR gamma coactivator 1 beta (PGC1 beta), and lipoprotein lipase (LPL) were among the up-regulated genes identified. Chromatin immunoprecipitation analyses demonstrated that these genes are direct VDR targets in WT keratinocytes. Notably, VDR occupancy of the PPAR gamma regulatory region precludes PPAR gamma occupancy of this site, based on the observation that PPAR gamma interacts with these sequences in VDR-/- but not WT keratinocytes. This contrasts with the VDR and PPAR gamma co-occupancy observed on PGC1 beta and LPL gene regulatory regions identified. Studies in mice with keratinocyte-specific PPAR gamma haploinsufficiency were performed to identify the functional consequences of enhanced PPAR gamma expression. PPAR gamma haploinsufficiency normalized PPAR gamma mRNA levels in VDR-/- keratinocytes and restored anagen responsiveness in vivo in VDR-/- mice, resulting in hair regrowth. Thus, absence of VDR-mediated PPAR gamma suppression underlies alopecia in VDR-/- mice.