Specific hypomethylation programs underpin B cell activation in early multiple sclerosis.
Specific hypomethylation programs underpin B cell activation in early multiple sclerosis.
复制标题
特定的低甲基化程序支持多发性硬化早期的B细胞活化
DOI：
10.1073/pnas.2111920118
复制
发表时间：
2021-12-21
影响因子：
11.1
通讯作者：
Oksenberg JR
中科院分区：
文献类型：
--
作者：
Ma Q;Caillier SJ;Muzic S;University of California San Francisco MS-EPIC Team;Wilson MR;Henry RG;Cree BAC;Hauser SL;Didonna A;Oksenberg JR
Cellular and molecular mediators driving multiple sclerosis (MS) pathology have been discovered to a great extent. However, the early molecular events leading to aberrant immune responses remain largely unknown. In this study, we combined bisulfite sequencing with transcriptome profiling to characterize the epigenetic landscape of four peripheral immune cell populations isolated from newly diagnosed, untreated MS patients and healthy individuals. We demonstrate widespread hypomethylation in CD19+ B cells at clinical disease onset. Notably, this epigenetic signature is functionally linked with the overactivation of B cells. Altogether, our results pinpoint the role of aberrant DNA methylation in connecting defects in the periphery with central nervous system autoimmunity and corroborate the key role of B cells in the initial stages of MS. 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.
