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

Author(s)

Costa, Pedro L. F. ^{[1, 2]} ; Franca, Monica M. ^{[1, 2, 3, 4]} ; Katayama, Maria L. ^[5] ; Carneiro, Eduardo T. ^{[1, 2]} ; Martin, Regina M. ^[3] ; Folgueira, Maria A. K. ^[5] ; Latronico, Ana C. ^[3] ; Ferraz-de-Souza, Bruno ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Lab Endocrinol Celular & Mol LIM 25, Div Endocrinol, Hosp Clin HCFMUSP, Fac Med, BR-01246903 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Unidade Doencas Osteometab, Div Endocrinol, Hosp Clin HCFMUSP, Fac Med, BR-01246903 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Lab Hormonios & Genet Mol LIM 42, Div Endocrinol, Hosp Clin HCFMUSP, Fac Med, BR-05403900 Sao Paulo, SP - Brazil

^[4] Univ Chicago, Dept Med, Endocrinol Sect, 5841 S Maryland Ave, Chicago, IL 60637 - USA

^[5] Univ Sao Paulo, Dept Radiol & Oncol, ICESP, Fac Med FMUSP, BR-01246000 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: CELLS; v. 8, n. 4 APR 2019.
• Web of Science Citations: 0

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. (AU)

• FAPESP's process: 11/12696-4 - Functional genomic analysis of the transcriptional regulation by nuclear receptors in hereditary Vitamin D resistant rickets
• Grantee: Bruno Ferraz de Souza
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 14/03561-6 - Transcription factors vitamin D receptor (VDR) and retinoid X receptor (RXR) genomic location analysis through chromatin immunoprecipitation
• Grantee: Pedro Luís Flora da Costa
• Support Opportunities: Scholarships in Brazil - Scientific Initiation