Whole-genome bisulfite sequencing in systemic sclerosis provides novel targets to understand disease pathogenesis

Tianyuan Lu,Maximilien Lora,Celia M T Greenwood,Kathleen Oros Klein,Marie Hudson,Inés Colmegna

doi:10.1186/s12920-019-0602-8

Tianyuan Lu, Maximilien Lora + Show 4 more

Open Access

https://doi.org/10.1186/s12920-019-0602-8

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Journal: BMC Medical Genomics	Publication Date: Oct 24, 2019
Citations: 16	License type: open-access

Affiliation: McGill University, Jewish General Hospital

Abstract

BackgroundSystemic sclerosis (SSc) is a rare autoimmune connective tissue disease whose pathogenesis remains incompletely understood. Increasing evidence suggests that both genetic susceptibilities and changes in DNA methylation influence pivotal biological pathways and thereby contribute to the disease. The role of DNA methylation in SSc has not been fully elucidated, because existing investigations of DNA methylation predominantly focused on nucleotide CpGs within restricted genic regions, and were performed on samples containing mixed cell types.MethodsWe performed whole-genome bisulfite sequencing on purified CD4+ T lymphocytes from nine SSc patients and nine controls in a pilot study, and then profiled genome-wide cytosine methylation as well as genetic variations. We adopted robust statistical methods to identify differentially methylated genomic regions (DMRs). We then examined pathway enrichment associated with genes located in these DMRs. We also tested whether changes in CpG methylation were associated with adjacent genetic variation.ResultsWe profiled DNA methylation at more than three million CpG dinucleotides genome-wide. We identified 599 DMRs associated with 340 genes, among which 54 genes exhibited further associations with adjacent genetic variation. We also found these genes were associated with pathways and functions that are known to be abnormal in SSc, including Wnt/β-catenin signaling pathway, skin lesion formation and progression, and angiogenesis.ConclusionThe CD4+ T cell DNA cytosine methylation landscape in SSc involves crucial genes in disease pathogenesis. Some of the methylation patterns are also associated with genetic variation. These findings provide essential foundations for future studies of epigenetic regulation and genome-epigenome interaction in SSc.

Highlights

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease whose pathogenesis remains incompletely understood
Detection of single nucleotide polymorphisms (SNP)-CpG associations We explored short-range SNP-CpG associations around a selected subset of CpG-based Differentially methylated region (DMR) identified in the comparison between SSc cases (N = 9) versus female controls (N = 4) that could be deemed consequential for SSc
We identified 238 significant SNP-CpG associations, where the involved CpG-based DMRs were distributed across 54 genes (Additional file 16: Table S16)

Summary

Introduction

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease whose pathogenesis remains incompletely understood. Increasing evidence suggests that genetic risk factors are strongly associated with SSc. Though the human leukocyte antigen (HLA) class II region is traditionally considered the most genetically associated with SSc [7,8,9], non-HLA loci and corresponding genes have been identified [10, 11]. Though the human leukocyte antigen (HLA) class II region is traditionally considered the most genetically associated with SSc [7,8,9], non-HLA loci and corresponding genes have been identified [10, 11] These SSc-susceptibility loci are estimated to account for only a small proportion of the disease risk [11]

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