title: Cistromic and genetic evidence that the vitamin D receptor mediates susceptibility to latitude-dependent autoimmune diseases.
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.
authors.affiliation: Centre for Immunology, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: D R
authors.initials: DR
authors.lastname: Booth
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Ding
authors.affiliation: Centre for Immunology, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: G P
authors.initials: GP
authors.lastname: Parnell
authors.affiliation: Centre for Immunology, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: F
authors.initials: F
authors.lastname: Shahijanian
authors.affiliation: Storr Liver Unit, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Coulter
authors.affiliation: Centre for Immunology, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: S D
authors.initials: SD
authors.lastname: Schibeci
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Atkins
authors.affiliation: Centre for Immunology, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Stewart
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA, USA.|Howard Hughes Medical Institute, Salk Institute, La Jolla, CA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Gene Expression Laboratory, Salk Institute, La Jolla, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Downes
authors.affiliation: Storr Liver Unit, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Liddle
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D011110:Polymorphism, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D014807:Vitamin D / Q000378:metabolism
chemical_list: C099359:BATF protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D018167:Receptors, Calcitriol; D014807:Vitamin D