Our research is focused on the design and application of bioinformatics algorithms to elucidate global regulatory mechanisms in normal development and diseases such as cancer. We have a solid track record in large-scale genomics data analysis and the development of widely used open-source bioinformatics software, such as MACS (>10,000 citations) for ChIP-seq and BSMAP (>1,200 citations) for DNA methylation. In collaboration with experimental biologists, we have used bioinformatics to gain novel biological insights into development, aging, stem cell, neurologic disorders, and various cancers. Our major contributions to science include the following: (1) We uncovered several novel links between chromatin modifications and cancer driver gene regulation; (2) Our work on alternative polyadenylation (APA) is the first of its kind to connect APA regulation to many human complex traits and diseases. (3) Our work regarding cell heterogeneity in DNA methylation has now been quickly adopted in clinical trials for early cancer detection by liquid biopsy.