Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase  

作　　者：Bin-Zhong Li Zheng Huang Qing-Yan Cui Xue-Hui Song Lin Du Albert Jeltsch Ping Chen Guohong Li En Li Guo-Liang Xu 

机构地区：[1]The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [2]The Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China [3]Biochemistry Laboratory, School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, Bremen 28759, Germany [4]Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China [5]Novartis Institute of BioMedical Research, 898 Halei Road, Shanghai 201203, China

出　　处：《Cell Research》2011年第8期1172-1181,共10页细胞研究（英文版）

基　　金：We thank Gerd Pfeifer （Beckman Research Institute of City of Hope） and Taiping Chen （Novartis Institutes for Biomedical Research） for helpful discussions and Jiemin Wong （East China Normal University） for critical reading of the manuscript. We are grateful to Masaki Okano （RIKEN Center for Developmental Biol- ogy） for providing Dnmt triple knockout ES cells. This work was supported by grants from the Ministry of Science and Technology of China （2005CB522400 and 2006CB943900）, the National Natural Science Foundation of China （30730059） and the Shanghai Municipal Government （08dj 1400501, 0852S 11223） to GLX.

摘　　要：Cytosine methylation of genomic DNA controls gene expression and maintains genome stability. How a specific DNA sequence is targeted for methylation by a methyitransferase is largely unknown. Here, we show that histone H3 tails lacking iysine 4 （K4） methylation function as an allosteric activator for methyltransferase Dnmt3a by binding to its plant homeodomain （PHD）. In vitro, histone H3 peptides stimulated the methylation activity of Dnmt3a up to 8-fold, in a manner reversely correlated with the level of K4 methylation. The biological significance of allosteric regulation was manifested by molecular modeling and identification of key residues in both the PHD and the catalytic domain of Dnmt3a whose mutations impaired the stimulation of methylation activity by H3 peptides but not the binding of H3 peptides. Significantly, these mutant Dnmt3a proteins were almost inactive in DNA methylation when expressed in mouse embryonic stem cells while their recruitment to genomic targets was unaltered. We therefore propose a two-step mechanism for de novo DNA methylation - first recruitment of the methyltransferase probably assisted by a chromatin- or DNA-binding factor, and then allosteric activation depending on the interaction between Dnmt3a and the histone tails - the latter might serve as a checkpoint for the methylation activity.

关 键 词：de novo DNA methylation Dnmt3a Histone H3 tail PHD domain allosteric stimulation 

分 类 号：Q781[生物学—分子生物学] Q523