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Genes Immun. 2016 Jun;17(4):213-9. doi: 10.1038/gene.2016.12. Epub 2016 Mar 17.

Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases.

Author information

1
Centre for Immunology, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
2
Gene Expression Laboratory, Salk Institute, La Jolla, CA, USA.
3
Storr Liver Unit, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
4
Howard Hughes Medical Institute, Salk Institute, La Jolla, CA, USA.

Abstract

The vitamin D receptor (VDR) is a ligand-activated transcription factor that regulates gene expression in many cell types, including immune cells. It requires binding of 1,25 dihydroxy vitamin D3 (1,25D3) for activation. Many autoimmune diseases show latitude-dependent prevalence and/or association with vitamin D deficiency, and vitamin D supplementation is commonly used in their clinical management. 1,25D3 is regulated by genes associated with the risk of autoimmune diseases and predominantly expressed in myeloid cells. We determined the VDR cistrome in monocytes and monocyte-derived inflammatory (DC1) and tolerogenic dendritic cells (DC2). VDR motifs were highly overrepresented in ChIP-Seq peaks in stimulated monocyte (40%), DC1 (21%) and DC2 (47%), P<E(-100) for all. Of the nearly 11 000 VDR-binding peaks identified across the genome in DC1s, 1317 were shared with DC2s (91% of DC2 sites) and 1579 with monocytes (83% of monocyte sites). Latitude-dependent autoimmune disease risk polymorphisms were highly overrepresented within 5 kb of the peaks. Several transcription factor recognition motifs were highly overrepresented in the peaks, including those for the autoimmune risk gene, BATF. This evidence indicates that VDR regulates hundreds of myeloid cell genes and that the molecular pathways controlled by VDR in these cells are important in maintaining tolerance.

PMID:
26986782
PMCID:
PMC4895389
DOI:
10.1038/gene.2016.12
[Indexed for MEDLINE]
Free PMC Article

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