Multiomics analysis of narcolepsy T cells: global hypomethylation in solo-WCGW motif linked to T cell proliferation

Abstract

AbstractNarcolepsy type 1 (NT1) is a chronic sleep disorder caused by the loss of orexin-producing cells in the lateral hypothalamus. The involvement of immune system abnormalities has been suggested, as indicated by the presence of autoreactive CD4+and CD8+T cells. However, it is difficult to sample precisely when this immune abnormality occurs, and previous studies examining cytokines and gene expression have not elucidated the mechanism of the immune abnormality. By focusing our analysis on epigenetic memory encoded in DNA methylation, we performed a genome-wide DNA methylation analysis using CD4+and CD8+T cells of NT1 patients. Analysis of differentially methylated regions as well as integrative analyses with genomic and transcriptomic data obtained from the same samples suggested that cell chemotaxis pathways are implicated in the etiology of NT1. Although causality in disease from methylation changes is generally unclear, changes linked to SNP genotypes in chemotaxis pathways suggested a likely disease cause. Additionally, we found global hypomethylation in both the CD4+and CD8+T cells of NT1 cases (CD4+:P= 1.69E-67; CD8+:P= 4.83E-12). The hypomethylation level in NT1 was correlate well with hypoSC, an index related to cell division (R2= 0.64,P= 1.61E-12). Further, these NT1-associated hypomethylated sites were significantly more abundant in solo- WCGW (sequences without neighboring CpGs, where W is a purine base,P= 9.87E-194). Solo- WCGW tends to lose DNA methylation over the course of cell divisions, suggesting enhanced T cell proliferation in NT1.