Novel insights into systemic sclerosis using a sensitive computational method to analyze whole-genome bisulfite sequencing data

Clinical Epigenetics

Research

Kathleen Oros Klein¹  Tianyuan Lu²  Sahir R. Bhatnagar²  Jeffrey C. Y. Yu²  Yixiao Zeng²  Kaiqiong Zhao²  Celia M. T. Greenwood³  Marie Hudson³  Inés Colmegna⁴  Maximilien Lora⁵  Andrew Leask⁶ 

[1] Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Sainte Catherine, H3T 1E2, Montreal, Canada;McGill University, 845 Sherbrooke St W, H3A 0G4, Montreal, Canada;McGill University, 845 Sherbrooke St W, H3A 0G4, Montreal, Canada;Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte Sainte Catherine, H3T 1E2, Montreal, Canada;McGill University, 845 Sherbrooke St W, H3A 0G4, Montreal, Canada;Research Institute of the McGill University Health Center, Montreal, Canada;Research Institute of the McGill University Health Center, Montreal, Canada;University of Saskatchewan, Saskatoon, Canada;

关键词: Scleroderma;    Systemic sclerosis;    DNA methylation;    Whole genome bisulfite sequencing;    Differentially methylated regions;    Smoothing;   

DOI  :  10.1186/s13148-023-01513-w

 received in 2022-11-25, accepted in 2023-05-28,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAbnormal DNA methylation is thought to contribute to the onset and progression of systemic sclerosis. Currently, the most comprehensive assay for profiling DNA methylation is whole-genome bisulfite sequencing (WGBS), but its precision depends on read depth and it may be subject to sequencing errors. SOMNiBUS, a method for regional analysis, attempts to overcome some of these limitations. Using SOMNiBUS, we re-analyzed WGBS data previously analyzed using bumphunter, an approach that initially fits single CpG associations, to contrast DNA methylation estimates by both methods.MethodsPurified CD4+ T lymphocytes of 9 SSc and 4 control females were sequenced using WGBS. We separated the resulting sequencing data into regions with dense CpG data, and differentially methylated regions (DMRs) were inferred with the SOMNiBUS region-level test, adjusted for age. Pathway enrichment analysis was performed with ingenuity pathway analysis (IPA). We compared the results obtained by SOMNiBUS and bumphunter.ResultsOf 8268 CpG regions of ≥ 60 CpGs eligible for analysis with SOMNiBUS, we identified 131 DMRs and 125 differentially methylated genes (DMGs; p-values less than Bonferroni-corrected threshold of 6.05–06 controlling family-wise error rate at 0.05; 1.6% of the regions). In comparison, bumphunter identified 821,929 CpG regions, 599 DMRs (of which none had ≥ 60 CpGs) and 340 DMGs (q-value of 0.05; 0.04% of all regions). The top ranked gene identified by SOMNiBUS was FLT4, a lymphangiogenic orchestrator, and the top ranked gene on chromosome X was CHST7, known to catalyze the sulfation of glycosaminoglycans in the extracellular matrix. The top networks identified by IPA included connective tissue disorders.ConclusionsSOMNiBUS is a complementary method of analyzing WGBS data that enhances biological insights into SSc and provides novel avenues of investigation into its pathogenesis.

【 授权许可】

CC BY   
© The Author(s) 2023

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