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Most of the biological activities have an epigenetic basis. A given cell has its own epigenetic setup which allows for various biochemical events to proceed. Our major research efforts are focusing on mechanisms of gene regulation involving genome modifications, e.g. DNA cytosine methylation in mammalian development and human diseases. The key players are the cytosine-modifying enzymes, DNA methyltransferases (DNMTs) and dioxygenases commonly known as TET (Ten-eleven translocation) enzymes. Both DNMT and TET enzymes are essential for animal development and their mutations are widely associated with genetic disorders and cancer. Recent studies from our lab and others have indicated that dynamic DNA modifications are involved in stem cell maintenance, lineage commitment and cell reprogramming etc. While the importance of DNA modifications has long been recognized in biomedical sciences, advance in the understanding of biochemical process in embryo and physiologically relevant tissues is lacking. In addition to the major subject surrounding the mechanisms of DNA methylation and oxidation, we are also extending our research to the study of new types of DNA modifications and investigation of the role of aberrant DNA modifications in tumorigenesis, as well as identification of genetic and epigenetic players for the initiation of mammalian meiosis.

(1) TET and TDG independent mechanisms leading to DNA demethylation

It has been shown that excision of 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by TDG is a downstream event within the active demethylation pathway relying on the TET-catalyzed 5-methylcytosine (5mC) oxidation. Although TDG is required for DNA demethylation in ES cells and for the reprogramming of MEFs into iPSCs, it is dispensable for the demethylation in mouse zygotes (Guo et al., Cell Stem Cell 2014). This observation indicates there are other glycosylases or completely unknown mechanisms underlying the conversion of 5hmC, 5fC or 5caC into unmodified cytosines. Identifying enzymes to process the oxidized 5mC bases is a priority of our ongoing research.

(2) DNA-modifying enzymes in unicellular eukaryotes

Sequential oxidation of 5mC by TET dioxygenases results in a cascade of additional epigenetic marks and promotes DNA demethylation in mammals (He et al., Science 2011). However, the enzymatic activity and the function of TET homologs present in diverse eukaryotes remain largely unexplored. We have identified a TET homolog in the unicellular green alga Chlamydomonas reinhardtii, which is a 5mC-modifying enzyme (CMD1) catalyzing conjugation of a glyceryl moiety onto the methyl group of 5mC. Surprisingly, CMD1 utilizes L-ascorbic acid (vitamin C, VC) as an essential co-substrate. This study has the potential to reveal new eukaryotic DNA base modifications, and the associated biological function in the epigenetic regulation of environmental adaptation. The biochemistry and biology of DNA modifications remain rich for exploration.

(3) Origin and contribution of aberrant DNA modification in tumorigenesis

Tumor cells are known to be not only genetically but also epigenetically distinguishable from their tissue of origin. The epigenetic characteristics of tumor cells contribute to cellular heterogeneity and drug resistance. DNA-modifying enzymes are frequently dysregulated in human cancers. We study the dynamic DNA methylation and demethylation in cancer stem cells to define their role in cancer initiation and maintenance using lung cancer and leukemia mouse models. Through the cell type-specific deletion of DNMT and TET genes, we try to understand how cells undergo transformation to acquire unique characteristics to support their rapid proliferation and move forward along tumorigenesis. This research is expected to gain insights into cancer initiation and progression and holds promise to promote the development of innovative strategies for cancer treatment.

(4) The transition from mitosis to meiosis

Germ cells increase in number by mitotic divisions until undergoing meiosis to generate haploid gametes. Many genes essential for the execution of the meiotic process have been identified and the meiotic events are well characterized. In contrast, how a diploid germ cell initiates meiosis is poorly understood. The major goal of our germ cell research is to understand the genetic and epigenetic control mechanisms underlying the switch from a mitotic to meiotic state. We take advantage of the combination of in vivo genetic analysis and in vitro cell/organ culture to identify determinants for mitotic exit and meiotic initiation during mouse spermatogenesis. One technical challenge to tackle is to recapitulate meiosis in culture efficiently. This research may help to facilitate the generation of haploid gametes in vitro for potential application in reproductive health.

(5) Epigenetics and Oogenesis

Fertilization provides an opportunity for transmitting not only genetic information but also epigenetic information from parents to early embryos. Oocytes, in particular, exert a profound impact on embryogenesis by transmitting not only a large amount of RNAs and proteins but also certain epigenetic marks. It has been demonstrated that the maternal epigenome plays vital roles in oogenesis and early embryogenesis. We take advantage of a gain-of-function mutant of Tet3 to explore its role in oogenesis. It turns out that enhanced dioxygenase activity leads to abnormal oogenesis and thus severely affects embryonic development potential. This research will expand our understanding of Tet enzyme activity, and gain insights into the principle of DNA methylation reprogramming in the broad context of chromatin structural dynamics during gamete and embryo development.