Mechanistic Insights into Mammalian DNA Methylation ABSTRACT DNA methylation is a major epigenetic mechanism that is essential for transcriptional silencing of retrotransposons, genomic imprinting and X-chromosome inactivation. Aberrant DNA methylation patterns lead to genomic and chromosomal instability and silencing of tumor suppressor genes, which contribute to the development of cancer and many other human diseases. DNA methylation patterns in mammalian genomes are dynamically established and maintained by two groups of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B, which together establish DNA methylation patterns during gametogenesis and early embryogenesis, and DNMT1, which propagates DNA methylation patterns in differentiated cells. The molecular mechanisms of both groups of DNMTs remain a long-standing and fundamental question. The long-term goals of the PI's research are: (a) to provide a comprehensive understanding of how the DNA methylation machinery is regulated, and (b) to determine the relationship between the regulation of DNA methylation and human diseases. The biochemical and cellular functions of DNMTs are subject to both intramolecular and intermolecular regulations. How these regulations cooperate in controlling mammalian DNA methylation has not been well characterized. Our research program will focus on addressing these important challenges of mammalian DNA methylation through an approach that integrates structural biology with biochemistry, molecular biology and cell biology. The objective of this application is to provide a deep mechanistic understanding of DNMT1-mediated maintenance DNA methylation and DNMT3A-mediated de novo DNA methylation. We will provide structural basis for the conformational dynamics of DNMT1 and its regulatory protein UHRF1, the interaction between DNMT1 and UHRF1, and the substrate recognition of DNMT3A. Guided by these structural studies, we will further investigate how the regulations of DNMTs influence genomic DNA methylation. Together, these studies will bring our mechanistic understanding of mammalian DNA methylation to the next level.
Mammalian DNA methyltransferases are essential for establishing and maintaining DNA methylation patterns during animal development. Aberrant DNA methylation patterns are associated with numerous human diseases, including cancer and neurological disorders. This proposal will lead to a better understanding of the regulatory mechanisms of DNMT1- and DNMT3A-mediated DNA methylation, and ultimately result in the development of new strategies for the therapeutic intervention of many human diseases.
|Wang, Boxiao; Thurmond, Stephanie; Hai, Rong et al. (2018) Structure and function of Zika virus NS5 protein: perspectives for drug design. Cell Mol Life Sci 75:1723-1736|
|Gao, Linfeng; Tan, Xiao-Feng; Zhang, Shen et al. (2018) An Intramolecular Interaction of UHRF1 Reveals Dual Control for Its Histone Association. Structure 26:304-311.e3|
|Zhang, Zhi-Min; Lu, Rui; Wang, Pengcheng et al. (2018) Structural basis for DNMT3A-mediated de novo DNA methylation. Nature 554:387-391|
|Zhang, Zhi-Min; Ma, Ka-Wai; Gao, Linfeng et al. (2017) Mechanism of host substrate acetylation by a YopJ family effector. Nat Plants 3:17115|
|Wang, Boxiao; Tan, Xiao-Feng; Thurmond, Stephanie et al. (2017) The structure of Zika virus NS5 reveals a conserved domain conformation. Nat Commun 8:14763|