Pitaksalee, R. et al. (2020) Differential CpG DNA methylation in peripheral naïve CD4+ T-cells in early rheumatoid arthritis patients. Clinical Epigenetics, 12, 54. (doi: 10.1186/s13148-020-00837-1) (PMID:32264938) (PMCID:PMC7137446)
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Abstract
Background: The genetic risk associated with rheumatoid arthritis (RA) includes genes regulating DNA methylation, one of the hallmarks of epigenetic re-programing, as well as many T-cell genes, with a strong MHC association, pointing to immunogenetic mechanisms as disease triggers leading to chronicity. The aim of our study was to explore DNA methylation in early, drug-naïve RA patients, towards a better understanding of early events in pathogenesis. Result: Monocytes, naïve and memory CD4+ T-cells were sorted from 6 healthy controls and 10 RA patients. DNA methylation was assessed using a genome-wide Illumina 450K CpG promoter array. Differential methylation was confirmed using bisulfite sequencing for a specific gene promoter, ELISA for several cytokines and flow cytometry for cell surface markers. Differentially methylated (DM) CpGs were observed in 1047 genes in naïve CD4+ T-cells, 913 in memory cells and was minimal in monocytes with only 177 genes. Naive CD4+ T-cells were further investigated as presenting differential methylation in the promoter of > 500 genes associated with several disease-relevant pathways, including many cytokines and their receptors. We confirmed hypomethylation of a region of the TNF-alpha gene in early RA and differential expression of 3 cytokines (IL21, IL34 and RANKL). Using a bioinformatics package (DMRcate) and an in-house analysis based on differences in β values, we established lists of DM genes between health and RA. Publicly available gene expression data were interrogated to confirm differential expression of over 70 DM genes. The lists of DM genes were further investigated based on a functional relationship database analysis, which pointed to an IL6/JAK1/STAT3 node, related to TNF-signalling and engagement in Th17 cell differentiation amongst many pathways. Five DM genes for cell surface markers (CD4, IL6R, IL2RA/CD25, CD62L, CXCR4) were investigated towards identifying subpopulations of CD4+ T-cells undergoing these modifications and pointed to a subset of naïve T-cells, with high levels of CD4, IL2R, and CXCR4, but reduction and loss of IL6R and CD62L, respectively. Conclusion: Our data provided novel conceptual advances in the understanding of early RA pathogenesis, with implications for early treatment and prevention.
Item Type: | Articles |
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Additional Information: | Funding: This work has been directly funded by a European Union-funded FP7-integrated project EURO-TEAM No. 305549 and partly supported by the IMI-funded project BeTheCure No 115142-2. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | McInnes, Professor Iain and Nijjar, Dr Jagtar |
Creator Roles: | McInnes, I.B.Conceptualization, Funding acquisition, Writing – review and editing Nijjar, J.S.Writing – review and editing |
Authors: | Pitaksalee, R., Burska, A. N., Ajaib, S., Rogers, J., Parmar, R., Mydlova, K., Xie, X., Droop, A., Nijjar, J.S., Chambers, P., Emery, P., Hodgett, R., McInnes, I.B., and Ponchel, F. |
College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
Research Centre: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology |
Journal Name: | Clinical Epigenetics |
Publisher: | BMC (Springer Nature) |
ISSN: | 1868-7075 |
ISSN (Online): | 1868-7083 |
Copyright Holders: | Copyright © 2020 The Authors |
First Published: | First published in Clinical Epigenetics 12:54 |
Publisher Policy: | Reproduced under a Creative Commons Licence |
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