Analysis of NGS data for disease understanding

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease facilitated by aberrant immune responses directed against cells and tissues, resulting in inflammation and organ damage. The majority of cells involved in the pathogenesis of SLE originate from bone marrow (BM) derived haematopoietic stem and progenitor cells (HSPCs). Previous research suggests that in SLE, haematopoiesis is dysregulated, with a skewing toward the myeloid lineage at the expense of lymphopoiesis. Also, HSPCs acquire a primed phenotype with a "trained immunity" signature, which may contribute to inflammation and flare risk. However, whether the epigenetic profile is implicated in this particular dysregulation, is still unknown. DNA methylation can regulate gene expression by inhibiting the binding of transcription factors (TFs) to DNA. Such TFs can be cis-regulatory elements (CREs) that typically regulate gene transcription by binding to other transcription factors as CCCTC-binding factor (CTCF). Herein, we show that differentially expressed genes (DEGs) and more specifically genes that are involved in myeloid-related pathways are possible regulated by distant methylated regulatory factors. We found that CREs, specifically enhancers that are up to 2Mb away from DEGs are methylated, while other transcription factors in those distances such as CTCF binding sites are also altered by methylation. Here, we show these modifications along with the expressions of DEGs and at the same time, we indicate the significance of their relationship. The findings suggest that interactions of distant methylated CREs and TFBS with DEGs cause HSPCs to reprogramme towards myeloid lineage, which may contribute to increased immunological responses and flares in SLE