Dataset Information

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.

ABSTRACT: 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.

SUBMITTER: Costa PLF

PROVIDER: S-EPMC6523947 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

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

Cells 20190405 4

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 fibr ...[more]

PMID: 30959822

Similar Datasets

Project description:To determine whether 1,25-dihydroxyvitamin D (1,25(OH)2 D) can exert an anti-osteoporosis role through anti-aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH)2 D deficiency due to deletion of the enzyme, 25-hydroxyvitamin D 1α-hydroxylase, while on a rescue diet. 1,25(OH)2 D deficiency accelerated age-related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence-associated secretory phenotype (SASP). Supplementation of exogenous 1,25(OH)2 D3 corrected the osteoporotic phenotype caused by 1,25(OH)2 D deficiency or natural aging by inhibiting the p16/p19 pathway. The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor (VDR) were significantly reduced by mechanisms including increased oxidative stress, DNA damage, and cellular senescence. We also demonstrated that p16 deletion largely rescued the osteoporotic phenotype caused by 1,25(OH)2 D3 deficiency, whereas 1,25(OH)2 D3 could up-regulate the enzyme Ezh2 via VDR-mediated transcription thereby enriching H3K27me3 and repressing p16/p19 transcription. Finally, we demonstrated that treatment with 1,25(OH)2 D3 improved the osteogenic defects of human BM-MSCs caused by repeated passages by stimulating their proliferation and inhibiting their senescence via the VDR-Ezh2-p16 axis. The results of this study therefore indicate that 1,25(OH)2 D3 plays a role in preventing age-related osteoporosis by up-regulating Ezh2 via VDR-mediated transcription, increasing H3K27me3 and repressing p16 transcription, thus promoting the proliferation and osteogenesis of BM-MSCs and inhibiting their senescence, while also stimulating osteoblastic bone formation, and inhibiting osteocyte senescence, SASP, and osteoclastic bone resorption.

Dataset Information

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.

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets