Genome-wide DNA methylation and mRNA transcription analysis revealed aberrant gene regulation pathways in dermatomyositis and polymyositis patients

Author:

Luo Hui1,Zhu Honglin1,Bao Ding1,Xiao Yizhi1,Zhou Bin1,Xiao Gong1,Zhang Lihua1,Gao Siming1,Li Liya1,Liu Yangtengyu1,Liu Di1,Wu Junjiao1,Meng Meng1,Chen Tao2,Zuo Xiaoxia1,Li Quan-Zhen1,Zhang Huali1

Affiliation:

1. Central South University

2. University of Texas Southwestern Medical Center

Abstract

Abstract Objectives: Idiopathic inflammatory myopathies (IIM) are a group of refractory systemic autoimmune diseases with unknown pathogenesis, including dermatomyositis (DM) and polymyositis (PM). DNA methylation is an important epigenetic mechanism to regulate gene expression, which plays important roles in IIM. Integrated analysis of the whole-genome DNA methylation and gene expression profiling will provide a comprehensive understanding of the pathogenesis of IIM. Methods: We performed whole-genome DNA methylation and transcription analysis in peripheral blood of 16 DM patients, 8 PM patients and 16 normal controls (NC) using Illumina Human Methyation 450K Beadchips and Illumina Human HT-12 v4.0 Expression Beadchips. Luminex multiplex assay was used to quantify 27 cytokine/chemokine in sera of 30 DM, 16 PM and 237 NC. Genome Studio was used to identify differential DNA methylation and mRNA transcription. Integrative analysis of DNA methylome, mRNA transcriptome and serum cytokines were performed using R, Perl and Circos software. Bioinformatic analysis were performed using DAVID and R. Real-time PCR, Bisulfite pyrosequencing and immunofluorescence were used for validation. Results: Genome-wide DNA methylation analysis identified 241 differential methylated CpG sites (74 hypermethylated and 167 hypomethylated) in DM, and 500 differential methylated CpG sites (153 hypermethylated and 347 hypomethylated) in PM. Transcriptome analysis identified 540 differential expressed genes (277 upregulated and 263 downregulated ) in DM and 242 differential expressed genes (181 upregulated and 61 downregulated) in PM. Integrated analysis of DNA methylome with transcriptome suggested a significant inverse-correlation between DNA methylation and gene expression. 93 upregulated genes associated with hypomethylated CpG sites while 176 down-regulated genes related with hypermethylated CpG sites both DM and PM. Analysis of the DNA methylation and mRNA transcription data identified differential methylated CpG sites and differential expressed genes which are shared and/or unique between DM and PM. Bioinformatics analysis suggested that dysregulated genes which are shared between DM and PM participated in common biologic process, such as immune response, inflammatory response and defense response. However, differential genes which are unique in DM and PM were found to be enriched in type I interferon signaling pathway and cytokine pathway, respectively. 18 interferon related genes were upregulated and hypomethylated, IL-5 was increased and hypomethylated, PDGF-BB was decreased and hypermethylated both in DM and PM. Real-time PCR and bisulfite pyrosequencing validated 13 top changed methylation sites and genes, and showed significant correlation between DNA methylation status and gene expression in most genes. Conclusions: Our study identified differentially methylated CpG sites which have potential regulatory effects on differential gene expression in DM and PM. We also revealed dysregulated CpG sites and genes involved in common and specific biologic process in DM and PM. Type I interferon signaling pathway was significantly enrichment in DM while Cytokine signaling pathway was significantly enrichment in PM. Our observations have laid the groundwork for further diagnostic and mechanistic studies of DM and PM.

Publisher

Research Square Platform LLC

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