1. Investigating 3D epigenome in development and diseases. The 3D chromatin organization between cis-regulatory sequences and genes plays a cruicial role in human health and diseases. We investigate the 3D gene regulatory landscapes in biologically relevant cell types by leveraging iPSC models and isolating rare cell types from the developing human brain. Through the identification of cell type-specific, long-range chromatin interactions between promoters and distal cis-regulatory elements, we aim to provide novel insights into gene regulatory mechanisms during development, prioritize neuropsychiatric disease-associated SNPs, and elucidation the contribution of distal non-coding genetic variations to complex neurological disorders.
2. Functional characterization of candidate cis-regulatory elements. We are conducting genome-scale CRISPR screens to characterize tens of thousands of candidate cis-regulatory elements that have been annotated based on biochemical signature using iPSC models, including iPSCs, iPSC-derived neurons and microglia. In addition, we have developed new tools, including CRISPRpath and CRISPRview, enabling us to characterize candidate cis-regulatory elements more efficiently and in a cell type-specific manner using heterogeneous primary cells, respectively.
3. Linking variants to function for complex diseases at the single base resolution. We recently developed the first genome-scale approach, PRIME, to characterize variants at the base-pair resolution with precision. We are expanding the utility of PRIME to identified risk variants in disease relevant cell types. Moreover, we prioritize and functionally characterizing Alzheimer’s disease (AD)-associated non-coding variants by integrating 3D epigenome annotations, genetic fine-mapping, single-cell CRISPRi screens, and, prime-editing in iPSC-derived microglia. This addresses the long-standing question of how non-coding variants could contribute to complex diseases by affecting gene regulation and biological functions in a cell type-specific manner.