Format

Send to

Choose Destination
PLoS One. 2018 Oct 31;13(10):e0206511. doi: 10.1371/journal.pone.0206511. eCollection 2018.

Increased DNA methylation of SLFN12 in CD4+ and CD8+ T cells from multiple sclerosis patients.

Author information

1
Computational Biology Graduate Group, University of California, Berkeley, Berkeley, CA, United States of America.
2
Genetic Epidemiology and Genomics Laboratory, Division of Epidemiology, School of Public Health, University of California, Berkeley, Berkeley, CA, United States of America.
3
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
4
Department of Neurology, Oslo University Hospital, Oslo, Norway.
5
Department for Mechanical, Electronics and Chemical Engineering, Oslo Metropolitan University, Oslo, Norway.
6
MS-Centre Hakadal, Hakadal, Norway.
7
Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway.
8
Translational & Integrative Analytics, Biogen, Inc., Cambridge, MA, United States of America.
9
Statistical Genetics & Genetic Epidemiology, Biogen, Inc., Cambridge, MA, United States of America.
10
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
11
Centre for Information Based Medicine, Hunter Medical Research Institute, Newcastle, Australia.
12
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
13
School of Medicine and Public Health, University of Newcastle, Newcastle, Australia.
14
Molecular Genetics, Pathology North, John Hunter Hospital, Newcastle, Australia.
15
Department of Neurology, John Hunter Hospital, Newcastle, Australia.

Abstract

DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS.

PMID:
30379917
PMCID:
PMC6209300
DOI:
10.1371/journal.pone.0206511
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Dipen P. Sangurdekar and Paola G. Bronson are employees at Biogen, Inc. Stine Marit Moen reports an unrestricted travel grant from Biogen Idec and speaker's fees from Biogen Idec and Novartis. Hanne F. Harbo reports personal fees from Biogen Norway, Merck Norway, and Genzyme Norway, and grants and personal fees from Novartis Norway. Pål Berg-Hansen reports grants and personal fees from Novartis and personal fees from Biogen Idec and Teva. Jeannette Lechner-Scott reports grants and personal fees from Biogen, Novartis, and TEVA, and personal fees from Sanofi Genzyme, Roche, and Merck. Tone Berge reports unrestricted grants from Biogen Idec and Sanofi Genzyme. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central Icon for Norwegian BIBSYS system
Loading ...
Support Center