(A) study on gene regulatory mechanism of complex human disorders using single-cell multi-omics approach

Abstract

Functional interpretation of noncoding genetic variants associated with human complex diseases remains a challenge. Further, the cell type-dependent role of non-coding regulatory elements associated with complex genetic diseases remains to be elucidated. To broaden our understanding on these issues, I investigated Parkinson’s disease (PD) and lung adenocarcinoma as my complex disease model. I established cell type-resolved transcriptomic and epigenomic landscapes of the human substantia nigra (SN) from PD and control cases, and primary lung tumor and normal tissues. My multi-omics approach provided a reference for the functional cell type in cis-regulatory elements (cREs), and assessed their regulatory effect on transcription and their association with disease risk genetic variants. Using high-resolution three-dimensional (3D) chromatin contact maps, I effectively uncovered putative target genes of dysregulated cREs and genetic risk loci in individual cell types. The investigation of biological processes involved in these target genes allowed the identification of novel candidate genes for these complex diseases. Lastly, the present study provides insights into specific molecular signatures in specific cell types responsible for the pathogenesis and disease susceptibility.