A Strong Dysregulated Myeloid Component in the Epigenetic Landscape of Systemic Sclerosis: An Integrated DNA Methylome and Transcriptome Analysis

Abstract

ObjectiveNon‐genetic factors influence Systemic Sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome‐wide association study (EWAS).MethodsWe analyzed DNA methylation data from whole blood samples in 179 SSc patients and 241 unaffected individuals, to identify differentially methylated positions (DMPs) with a FDR<0.05. These results were further integrated with RNA‐seq data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels.ResultsThis analysis yielded 525 DMPs enriched in immune‐related pathways, being leukocyte cell‐cell adhesion the most significant (FDR=4.91x10‐9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach we observed an enrichment of neutrophil related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer‐binding protein (CEBP) transcription factor family in SSc, which is crucial in the myeloid lineage development.ConclusionOur findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.image