Integration of Genome-Wide DNA Methylation and Transcription Uncovered Aberrant Methylation-Regulated Genes and Pathways in the Peripheral Blood Mononuclear Cells of Systemic Sclerosis.

IF 2.3 Q2 RHEUMATOLOGY International Journal of Rheumatology Pub Date : 2018-09-02 eCollection Date: 2018-01-01 DOI:10.1155/2018/7342472
Honglin Zhu, Chengsong Zhu, Wentao Mi, Tao Chen, Hongjun Zhao, Xiaoxia Zuo, Hui Luo, Quan-Zhen Li
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引用次数: 21

Abstract

Objective. Systemic sclerosis (SSc) is a systemic connective tissue disease of unknown etiology. Aberrant gene expression and epigenetic modifications in circulating immune cells have been implicated in the pathogenesis of SSc. This study is to delineate the interaction network between gene transcription and DNA methylation in PBMC of SSc patients and to identify methylation-regulated genes which are involved in the pathogenesis of SSc. Methods. Genome-wide mRNA transcription and global DNA methylation analysis were performed on PBMC from 18 SSc patients and 19 matched normal controls (NC) using Illumina BeadChips. Differentially expressed genes (DEGs) and differentially methylated positions (DMPs) were integrative analyzed to identify methylation-regulated genes and associated molecular pathways. Results. Transcriptome analysis distinguished 453 DEGs (269 up- and 184 downregulated) in SSc from NC. Global DNA methylation analysis identified 925 DMPs located on 618 genes. Integration of the two lists revealed only 20 DEGs which harbor inversely correlated DMPs, including 12 upregulated (ELANE, CTSG, LTBR, C3AR1, CSTA, SPI1, ODF3B, SAMD4A, PLAUR, NFE2, ZYX, and CTSZ) and eight downregulated genes (RUNX3, PRF1, PRKCH, PAG1, RASSF5, FYN, CXCR6, and F2R). These potential methylation-regulated DEGs (MeDEGs) are enriched in the pathways related to immune cell migration, proliferation, activation, and inflammation activities. Using a machine learning algorism, we identified six out of the 20 MeDEGs, including F2R, CXCR6, FYN, LTBR, CTSG, and ELANE, which distinguished SSc from NC with 100% accuracy. Four genes (F2R, FYN, PAG1, and PRKCH) differentially expressed in SSc with interstitial lung disease (ILD) compared to SSc without ILD. Conclusion. The identified MeDEGs may represent novel candidate factors which lead to the abnormal activation of immune regulatory pathways in the pathogenesis of SSc. They may also be used as diagnostic biomarkers for SSc and clinical complications.

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全基因组DNA甲基化和转录的整合揭示了系统性硬化症外周血单个核细胞中异常甲基化调控基因和途径。
目标。系统性硬化症(SSc)是一种病因不明的系统性结缔组织疾病。循环免疫细胞中的异常基因表达和表观遗传修饰与SSc的发病机制有关。本研究旨在描述SSc患者PBMC中基因转录与DNA甲基化的相互作用网络,并鉴定参与SSc发病的甲基化调控基因。方法。使用Illumina BeadChips对18例SSc患者和19例匹配正常对照(NC)的PBMC进行全基因组mRNA转录和整体DNA甲基化分析。对差异表达基因(DEGs)和差异甲基化位点(dmp)进行综合分析,以鉴定甲基化调控基因和相关分子途径。结果。转录组分析在SSc和NC中鉴定出453个基因(269个上调,184个下调)。全球DNA甲基化分析鉴定出618个基因上的925个dmp。整合这两个列表,发现只有20个基因的DMPs呈负相关,包括12个上调基因(ELANE、CTSG、LTBR、C3AR1、CSTA、SPI1、ODF3B、SAMD4A、PLAUR、NFE2、ZYX和CTSZ)和8个下调基因(RUNX3、PRF1、PRKCH、PAG1、RASSF5、FYN、CXCR6和F2R)。这些潜在的甲基化调节的DEGs (MeDEGs)在与免疫细胞迁移、增殖、激活和炎症活动相关的途径中富集。使用机器学习算法,我们确定了20个medeg中的6个,包括F2R、CXCR6、FYN、LTBR、CTSG和ELANE,它们以100%的准确率区分了SSc和NC。4个基因(F2R、FYN、PAG1和PRKCH)在伴有间质性肺病(ILD)的SSc与无ILD的SSc中表达差异。结论。所鉴定的MeDEGs可能是导致SSc发病过程中免疫调节通路异常激活的新的候选因子。它们也可作为SSc和临床并发症的诊断性生物标志物。
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CiteScore
4.40
自引率
0.00%
发文量
9
审稿时长
24 weeks
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