title: Absence of vitamin D receptor (VDR)-mediated PPARγ suppression causes alopecia in VDR-null mice.
abstract: 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 γ (PPARγ), PPARγ coactivator 1β (PGC1β), 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 thePPARγregulatory region precludes PPARγ occupancy of this site, based on the observation that PPARγ interacts with these sequences in VDR-/-but not WT keratinocytes. This contrasts with the VDR and PPARγ co-occupancy observed onPGC1βandLPLgene regulatory regions identified. Studies in mice with keratinocyte-specificPPARγhaploinsufficiency were performed to identify the functional consequences of enhancedPPARγexpression. PPARγ haploinsufficiency normalizedPPARγmRNA levels in VDR-/-keratinocytes and restored anagen responsivenessin vivoin VDR-/-mice, resulting in hair regrowth. Thus, absence of VDR-mediated PPARγ suppression underlies alopecia in VDR-/-mice.-Saini, V., Zhao, H., Petit, E. T., Gori, F., Demay, M. B. Absence of vitamin D receptor (VDR)-mediated PPARγ suppression causes alopecia in VDR-null mice.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Saini
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hengguang
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Petit
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gori
authors.affiliation: Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA demay@helix.mgh.harvard.edu.
authors.forename: Marie B
authors.initials: MB
authors.lastname: Demay
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000505:Alopecia / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone; D057895:Haploinsufficiency; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C462180:Dppa3 protein, mouse; D009687:Nuclear Proteins; C000620215:Ppargc1b protein, mouse; D047495:PPAR gamma; D018167:Receptors, Calcitriol; D012097:Repressor Proteins; D014157:Transcription Factors; D008071:Lipoprotein Lipase
keywords: hair cycle; keratinocyte stem cell; mouse model; vitamin D–resistant rickets