Please use this identifier to cite or link to this item:
https://doi.org/10.1186/s13073-017-0404-6
Title: | A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus | Authors: | Kumar D. Puan K.J. Andiappan A.K. Lee B. Westerlaken G.H.A. Haase D. Melchiotti R. Li Z. Yusof N. Lum J. Koh G. Foo S. Yeong J. Alves A.C. Pekkanen J. Sun L.D. Irwanto A. Fairfax B.P. Naranbhai V. Common J.E.A. Tang M. Chuang C.K. Jarvelin M.-R. Knight J.C. Zhang X. Chew F.T. Prabhakar S. Jianjun L. Wang D.Y. Zolezzi F. Poidinger M. Lane E.B. Meyaard L. Rötzschke O. |
Keywords: | bisulfite regulator protein signal inhibitory receptor on leukocyte 1 transcription factor PU 1 transcription factor YY1 unclassified drug immunoglobulin receptor SIRL1 protein, human adult Article atopic dermatitis binding affinity binding site chromatin immunoprecipitation cohort analysis controlled study CpG island disease activity disease association DNA methylation female flow cytometry gel mobility shift assay gene gene expression gene frequency gene function gene identification genetic association genotype human human cell male molecular docking molecular pathology monocyte promoter region protein determination protein DNA binding protein expression protein function sequence analysis single nucleotide polymorphism upregulation VSTM1 gene Asian continental ancestry group atopic dermatitis gene expression regulation genetics metabolism young adult Asian Continental Ancestry Group Dermatitis, Atopic DNA Methylation Female Gene Expression Regulation Humans Male Monocytes Polymorphism, Single Nucleotide Promoter Regions, Genetic Receptors, Immunologic Young Adult |
Issue Date: | 2017 | Citation: | Kumar D., Puan K.J., Andiappan A.K., Lee B., Westerlaken G.H.A., Haase D., Melchiotti R., Li Z., Yusof N., Lum J., Koh G., Foo S., Yeong J., Alves A.C., Pekkanen J., Sun L.D., Irwanto A., Fairfax B.P., Naranbhai V., Common J.E.A., Tang M., Chuang C.K., Jarvelin M.-R., Knight J.C., Zhang X., Chew F.T., Prabhakar S., Jianjun L., Wang D.Y., Zolezzi F., Poidinger M., Lane E.B., Meyaard L., Rötzschke O. (2017). A functional SNP associated with atopic dermatitis controls cell type-specific methylation of the VSTM1 gene locus. Genome Medicine 9 (1) : 18. ScholarBank@NUS Repository. https://doi.org/10.1186/s13073-017-0404-6 | Abstract: | Background: Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet. Methods: Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS). Results: We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10-6 for rs612529 for association to atopic dermatitis (AD). Conclusion: Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment. © 2017 The Author(s). | Source Title: | Genome Medicine | URI: | https://scholarbank.nus.edu.sg/handle/10635/173794 | ISSN: | 1756994X | DOI: | 10.1186/s13073-017-0404-6 |
Appears in Collections: | Staff Publications Elements |
Show full item record
Files in This Item:
File | Description | Size | Format | Access Settings | Version | |
---|---|---|---|---|---|---|
10_1186_s13073-017-0404-6.pdf | 6.72 MB | Adobe PDF | OPEN | None | View/Download |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.