1. Specific hypomethylation programs underpin B cell activation in early multiple sclerosis.
- Author
-
Ma Q, Caillier SJ, Muzic S, Wilson MR, Henry RG, Cree BAC, Hauser SL, Didonna A, and Oksenberg JR
- Subjects
- B-Lymphocytes pathology, Cell Differentiation, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Profiling, Genome-Wide Association Study, Humans, Multiple Sclerosis genetics, Multiple Sclerosis pathology, Transcriptional Activation, B-Lymphocytes metabolism, Lymphocyte Activation, Multiple Sclerosis metabolism
- Abstract
Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
- Full Text
- View/download PDF