The incredible complexity of mammals, despite their relatively limited number of genes, stems in significant part from epigenetic regulatory mechanisms. Epigenetic changes are heritable, but readily reversible, changes in the expression/function of genomes that do not involve an alteration in DMA sequence information. DNA (de)methylation and histone modification are the two most common mechanisms of epigenetic change. Thus, epigenetics has emerged into a prominent field, as the biological roles of DNA methyltransferases (MTases) and histone-specific modifying enzymes [e.g., (de)acetylases,, (de)methylases, kinases and phosphatases] in chromatin remodeling and regulation of gene expression have been discovered. Our long-term goal is to understand how the initial methylation pattern (de novo methylation) is generated, i.e, mammalian DNA MTases select some CpG sequences for methylation while sparing others. This grant will dissect the structures and functions of the DnmtS family of DNA [cytosine-5] MTases and the methyl CpG binding protein MeCP2, which play important roles in genomic imprinting, chromatin (re)modeling and human diseases (ICF syndrome and Rett syndrome).
Our specific aims are: 1. To dissect the domain structures and functions of the DnmtSa and DnmtSb MTases. In ICF patients, mutations have been found in the catalytic domain of DnmtSb. 2. To determine whether DnmtSL acts as an autogenous regulator by self-oligomerization 3. To test the hypothesis that DnmtSL stimulates DnmtSa activity by unmasking its catalytic domain 4. To test the hypothesis that Rett syndrome can result from mutations in a self-association domain of MeCP2
| Ren, Ren; Horton, John R; Zhang, Xing et al. (2018) Detecting and interpreting DNA methylation marks. Curr Opin Struct Biol 53:88-99 |
| Patel, Anamika; Yang, Peng; Tinkham, Matthew et al. (2018) DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins. Cell 173:221-233.e12 |
| Hashimoto, Hideharu; Wang, Dongxue; Horton, John R et al. (2017) Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA. Mol Cell 66:711-720.e3 |
| Patel, Anamika; Zhang, Xing; Blumenthal, Robert M et al. (2017) Structural basis of human PR/SET domain 9 (PRDM9) allele C-specific recognition of its cognate DNA sequence. J Biol Chem 292:15994-16002 |
| Lee, Chen-Cheng; Peng, Shih-Huan; Shen, Li et al. (2017) The Role of N-?-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting. Mol Cell 68:89-103.e7 |
| Yang, Peng; Wang, Yixuan; Hoang, Don et al. (2017) A placental growth factor is silenced in mouse embryos by the zinc finger protein ZFP568. Science 356:757-759 |
| Estève, Pierre-Olivier; Zhang, Guoqiang; Ponnaluri, V K Chaithanya et al. (2016) Binding of 14-3-3 reader proteins to phosphorylated DNMT1 facilitates aberrant DNA methylation and gene expression. Nucleic Acids Res 44:1642-56 |
| Patel, A; Hashimoto, H; Zhang, X et al. (2016) Characterization of How DNA Modifications Affect DNA Binding by C2H2 Zinc Finger Proteins. Methods Enzymol 573:387-401 |
| Patel, Anamika; Horton, John R; Wilson, Geoffrey G et al. (2016) Structural basis for human PRDM9 action at recombination hot spots. Genes Dev 30:257-65 |
| Zeng, Yaxue; Yao, Bing; Shin, Jaehoon et al. (2016) Lin28A Binds Active Promoters and Recruits Tet1 to Regulate Gene Expression. Mol Cell 61:153-60 |
Showing the most recent 10 out of 103 publications
