Abstract

DNA methylation is an essential epigenetic modification in mammals, as it plays important regulatory roles in multiple biological processes, such as gene transcription, maintenance of chromosomal structure and genomic stability, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Dysregulation of DNA methylation is associated with various human diseases, including cancer. For example, cancer cells usually show global DNA hypomethylation and regional DNA hypermethylation, which have been implicated in genomic instability and tumor suppressor silencing, respectively. Although great progress has been made in elucidating the biological functions of DNA methylation over the last several decades, how DNA methylation patterns and levels are regulated and dysregulated is not well understood. Using mouse embryonic stem cells (mESCs), an ideal model system for studying DNA methylation, I have discovered novel regulatory mechanisms that play important roles in de novo and maintenance DNA methylation. In one project, I show that Dnmt3L, a key regulator of de novo DNA methylation, facilitates Dnmt3a-mediated methylation by stabilizing Dnmt3a2, the major Dnmt3a isoform in mESCs, thus uncovering a new role for Dnmt3L and providing a plausible explanation for the functional specificity of Dnmt3L in vivo and for the reproductive phenotypes observed in genetic mouse models. In a separate project, I demonstrate that PRMT6 , an arginine methyltransferase responsible for asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a), negatively regulates maintenance DNA methylation by impairing the recruitment of the Dnmt1-Uhrf1 complex to chromatin, thereby identifying a novel crosstalk between histone arginine methylation and DNA methylation. Moreover, I show that PRMT6 upregulation contributes to global DNA hypomethylation in cancer. In summary, the research work in this talk advances our understanding of the regulatory network that controls DNA methylation changes in normal developmental processes and pathological conditions.