Description:

“Decoding the human genome by multi-omics in cell-free DNA and single-cells”

My long-term research interest is to decode the human genome. My lab's recent research focus is on developing computational methods for cell-free DNA (cfDNA) and high-throughput experimental methods for single-cell multi-omics. 

In single-cell multi-omics, we developed several approaches to jointly profile multiple epigenetic marks within the same single cells. We developed Methyl-HiC to capture the three-dimensional (3D) genome topology and DNA methylome together in the same DNA molecule. We revealed the coordinated DNA methylation status between distal genomic segments that are in spatial proximity in the nucleus. We next extended it to the single-cell level to jointly profile DNA methylation and 3D genome within the same nuclei from heterogeneous cells. We further extend Methyl-HiC to NOMe-HiC, which can simultaneously profile single nucleotide polymorphisms, DNA methylation, chromatin accessibility, and 3D genome from the same DNA molecule, together with the transcriptome in a single assay. Finally, we extend it to the single-cell resolution to delineate heterogeneity across multiple molecular measurements in a mixed-cell population. 

In cell-free DNA, we developed a set of computational tools to facilitate the study of cellular epigenomes non-invasively by fragmentation patterns measured from cfDNA whole-genome sequencing (WGS). Current research on the development of computational methods for cfDNA fragmentation patterns is significantly limited by the controlled access of the cfDNA WGS. We built and maintained a comprehensive database and browser to host >3,000 uniformly processed and curated de-identified cfDNA WGS for the liquid biopsy community. Further based on the public dataset, we developed a computational method to de novo characterize the genome-wide fragmentation hotspots at cfDNA WGS. In healthy, hotspots are enriched in gene-regulatory elements, including open chromatin regions, promoters, and hematopoietic-specific enhancers. The aberration of hotspots detected in early-stage cancers allows us to understand the gene-regulatory mechanism in early-stage diseases and diagnose early-stage cancers and their tissues of origin with high performance. The computational methods developed for cfDNA fragmentation in our lab will eventually pave the roads for our understanding of the variation of cis-regulatory elements non-invasively across different physiological and pathological conditions.