Transcriptomic Response to 1,25-Dihydroxyvitamin D in Human Fibroblasts with or without a Functional Vitamin D Receptor (VDR): Novel Target Genes and Insights into VDR Basal Transcriptional Activity.
The vitamin D receptor (VDR) mediates vitamin D actions beyond bone health. While VDR activation by 1,25-dihydroxyvitamin D (1,25D) leads to robust transcriptional regulation, less is known about VDR actions in the absence of 1,25D. We analyzed the transcriptomic response to 1,25D in fibroblasts bearing a severe homozygous hereditary vitamin D resistant rickets-related p.Arg30* VDR mutation (MUT) and in control fibroblasts (CO). Roughly 4.5% of the transcriptome was regulated by 1,25D in CO fibroblasts, while MUT cells without a functional VDR were insensitive to 1,25D. Novel VDR target genes identified in human fibroblasts included bone and cartilage factors CILP, EFNB2, and GALNT12. Vehicle-treated CO and MUT fibroblasts had strikingly different transcriptomes, suggesting basal VDR activity. Indeed, oppositional transcriptional effects in basal conditions versus after 1,25D activation were implied for a subset of target genes mostly involved with cell cycle. Cell proliferation assays corroborated this conjectured oppositional basal VDR activity, indicating that precise 1,25D dosage in target tissues might be essential for modulating vitamin D actions in human health.
['Costa|Pedro L F|PLF|', 'França|Monica M|MM|', 'Katayama|Maria L|ML|', 'Carneiro|Eduardo T|ET|', 'Martin|Regina M|RM|', 'Folgueira|Maria A K|MAK|', 'Latronico|Ana C|AC|', 'Ferraz-de-Souza|Bruno|B|']
D049109:Cell Proliferation D015536:Down-Regulation D005347:Fibroblasts D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D058977:Molecular Sequence Annotation D009154:Mutation D018167:Receptors, Calcitriol D014158:Transcription, Genetic D059467:Transcriptome D015854:Up-Regulation D014807:Vitamin D
vitamin D cell proliferation CYP24A1 calcitriol gene expression microarray