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.
Highlights
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular dysfunction, immune abnormalities, chronic inflammation, and interstitial and perivascular fibrosis in the skin and internal organs [1]
Hierarchical clustering of the differentially expressed genes (DEGs) demonstrated that the patterns of expression profiles clearly distinguished normal controls (NC) from SSc patients with the exception that four SSc were misclassified in the NC group (Figure 1(b); Supplementary Table 2)
We found the differentially methylated positions (DMPs) were located in the promoter regions of 12 genes (60%), including hypomethylated DMPs on seven upregulated genes (CSTA, CTSG, CTSZ, ELANE, LTBR, NFE2, and ODF3B) and hypermethylated DMPs on the five downregulated genes (CXCR6, FYN, PAG1, PRF1, and RUNX3)
Summary
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular dysfunction, immune abnormalities, chronic inflammation, and interstitial and perivascular fibrosis in the skin and internal organs [1]. The environmental influence via epigenetic mechanisms, altered status of DNA methylation, contributes to the environment-host interaction in the development of SSc [7, 8]. It has been reported that more than 60 methylation-regulated genes were associated with autoimmunity in SSc [5, 9, 10]. There were no studies that investigate the correlation between gene expression and DNA methylation at global genome level in SSc. The advances in genome-wide technologies have provided unprecedented opportunities to expand our view of the relationship among the genome, methylome, and transcriptome. The integration of epigenetic and genetic data promises to gain insight into the mechanisms affecting epigenetic alteration, gene expression, and disease susceptibility [11, 12]
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