Epigenomics and Computational Biology Lab

The central question in the personalized medicine era is how we interpret the gene regulatory effect of human genetic variants in a cell-type specific manner. Since the majority of important genetic variants are located in enhancer elements, and they regulate target genes through long-range chromatin looping interactions, characterization of noncoding regulatory sequences based on epigenomics and dissecting their regulatory effect on gene expression using 3D genome organization is essential. Further, it is also critical to uncover relevant cell types where the genetic variants or epigenetic dysregulation act their function in disease etiology. In this regard, we utilize combined approaches of single-cell omics and 3D epigenomics to dissect disease-specific gene regulation mechanisms using patients’ specimens. Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1β-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1β-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as wel