With the tremendous progress in the development of high-throughput sequencing technologies during the last decade, many life science studies are no longer limited to data generation, but how to manage and analyze these high-throughput data are the real challenges for the majority of biologists. Research in my lab focuses on developing statistical and computational algorithms on high-throughput biological data to study the epigenetic priming effects on stem cell differentiation and embryonic development. The specific areas we study are described below.

Computational Algorithms for Epigenomics

One of the most important contributions of the bioinformatics community is the development of state-of-the-art computational algorithms for general or specific analysis problems. We have developed a number of computational algorithms for the analysis of high-throughput biological data. For general analysis, we have developed MACS, a widely used ChIP-seq peak caller (cited over 10,000 times), and GFOLD for ranking differentially expressed genes from RNA-seq. For specific epigenomics questions, we have contributed NPS and DiNuP for nucleosome positioning, GeSICA for genome segmentation from Hi-C data, and MethylPurify for tumor purity deconvolution from DNAmethylome. Recently, we developed a universal bioinformatics approach to systematically reveal the non-canonical functional mechanisms of chromatin regulators with high efficiency (Genome Biol 2020a), and we built a DNA methylation state transition model to reveal programmed epigenetic heterogeneity in human pre-implantation embryos (Genome Biol 2020b). We are currently working on a variety of challenging epigenomic questions.

Embryogenesis / Stem Cell Epigenomics

During the early embryogenesis and stem cell differentiation, epigenetic status changed dramatically and usually asymmetry between cells. Therefore, to reveal when and how the specific epigenetic pattern is established is of vital importance to understand the mechanisms of embryogenesis and stem cell differentiation. Over the past few years, we made a number of  observations on the features of epigenetic pattern during embryogenesis or in embryonic stem cells: (i) In zebrafish, the histone modification pattern associated with pluripotency and well-positioned nucleosome arrays appearing at thousands of promoters are established during the maternal-zygotic transition (Nature 2010, Genome Res 2014). (ii) In zebrafish, inherited DNA methylation signatures from gametes prime the establishment of accessible chromatin during zygotic genome activation by two distinct mechanisms (Genome Res 2018, Genome Res 2022). (iii) In mouse pre-implantation embryos, H3K4me3, H3K27me3 and H3K9me3 show distinct dynamic features (Nature 2016, Nat Cell Biol 2018). (iv) In the mouse pre-implantation embryo, H3K9me3 is required for the function of ICRs and a novel type of similar control regions (Nat Cell Biol 2022). We are currently conducting a number of projects to evaluate the mechanistic basis and impact of epigenetic dynamics during stem cell differentiation and embryonic development. The overall goal of this research program is to determine the epigenetic priming effects in stem cells, which will benefit clinical applications of stem cells.