Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease
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- 作者：Adam E Handel (1) (2)
Geir K Sandve (3)
Giulio Disanto (1)
Antonio J Berlanga-Taylor (1)
Giuseppe Gallone (1)
Heather Hanwell (1)
Finn Drabl?s (4)
Gavin Giovannoni (2)
George C Ebers (1)
Sreeram V Ramagopalan (1) (2) - 关键词：Vitamin D ; Autoimmune disease ; ChIP ; seq ; Functional genomics
- 刊名：BMC Medicine
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：11
- 期：1
- 全文大小：503KB
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50. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1741-7015/11/163/prepub - 作者单位：Adam E Handel (1) (2)
Geir K Sandve (3)
Giulio Disanto (1)
Antonio J Berlanga-Taylor (1)
Giuseppe Gallone (1)
Heather Hanwell (1)
Finn Drabl?s (4)
Gavin Giovannoni (2)
George C Ebers (1)
Sreeram V Ramagopalan (1) (2)
1. Medical Research Council Functional Genomics Unit and Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
2. Blizard Institute, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London, E1 2AT, UK
3. Department of Informatics, University of Oslo, Gaustadalléen 23 B, N-0373, Oslo, Norway
4. Bioinformatics & Gene Regulation, Norwegian University of Science and Technology, Erling Skjalgsons gt. 1, N-7006, Trondheim, Norway
文摘
Background Vitamin D insufficiency has been implicated in autoimmunity. ChIP-seq experiments using immune cell lines have shown that vitamin D receptor (VDR) binding sites are enriched near regions of the genome associated with autoimmune diseases. We aimed to investigate VDR binding in primary CD4+ cells from healthy volunteers. Methods We extracted CD4+ cells from nine healthy volunteers. Each sample underwent VDR ChIP-seq. Our results were analyzed in relation to published ChIP-seq and RNA-seq data in the Genomic HyperBrowser. We used MEMEChIP for de novo motif discovery. 25-Hydroxyvitamin D levels were measured using liquid chromatography–tandem mass spectrometry and samples were divided into vitamin D sufficient (25(OH)D ?5 nmol/L) and insufficient/deficient (25(OH)D <75 nmol/L) groups. Results We found that the amount of VDR binding is correlated with the serum level of 25-hydroxyvitamin D (r = 0.92, P= 0.0005). In vivo VDR binding sites are enriched for autoimmune disease associated loci, especially when 25-hydroxyvitamin D levels (25(OH)D) were sufficient (25(OH)D ?5: 3.13-fold, P<0.0001; 25(OH)D <75: 2.76-fold, P<0.0001; 25(OH)D ?5 enrichment versus 25(OH)D <75 enrichment: P= 0.0002). VDR binding was also enriched near genes associated specifically with T-regulatory and T-helper cells in the 25(OH)D ?5 group. MEME ChIP did not identify any VDR-like motifs underlying our VDR ChIP-seq peaks. Conclusion Our results show a direct correlation between in vivo 25-hydroxyvitamin D levels and the number of VDR binding sites, although our sample size is relatively small. Our study further implicates VDR binding as important in gene-environment interactions underlying the development of autoimmunity and provides a biological rationale for 25-hydroxyvitamin D sufficiency being based at 75 nmol/L. Our results also suggest that VDR binding in response to physiological levels of vitamin D occurs predominantly in a VDR motif-independent manner.