2009年12月29日，《美国科学院院刊》（PNAS）发表了中国科学院上海生命科学研究院生物化学与细胞生物学研究所研究人员的研究工作 — “The N-terminus of histone H3 is required for de novo DNA methylation in chromatin”。该工作由周金秋和徐国良课题组合作完成，博士研究生胡佳磊承担了主要研究工作。
DNA甲基化在哺乳动物细胞中普遍存在，参与转录调控、细胞分化等许多重要的生物学过程，但目前关于DNA甲基化的发生机制尚不清楚。本项工作中，研究人员用酿酒酵母作为研究系统，在本身不存在甲基化的酵母基因组上建立DNA甲基化谱式，揭示了组蛋白H3 N端尾部对于DNA甲基化不可或缺的作用。进一步研究发现，辅助因子Dnmt3L能通过其PHD结构域与第四位赖氨酸未甲基化的组蛋白H3发生相互作用，进而招募DNA甲基转移酶Dnmt3a到靶位点发生起始性DNA甲基化。
这一研究首次从功能上揭示了组蛋白H3K4甲基化与DNA甲基化之间的直接联系，加深了人们对DNA甲基化发生机制的认识。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS December 14, 2009, doi: 10.1073/pnas.0905767106
The N-terminus of histone H3 is required for de novo DNA methylation in chromatin
Jia-Lei Hua,b, Bo O. Zhoua,b, Run-Rui Zhanga,b, Kang-Ling Zhangc, Jin-Qiu Zhoua,1 and Guo-Liang Xua,1
aThe 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;
bThe Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; and
cDepartment of Biochemistry, School of Medicine, Loma Linda University, Loma Linda, CA 92350
DNA methylation and histone modification are two major epigenetic pathways that interplay to regulate transcriptional activity and other genome functions. Dnmt3L is a regulatory factor for the de novo DNA methyltransferases Dnmt3a and Dnmt3b. Although recent biochemical studies have revealed that Dnmt3L binds to the tail of histone H3 with unmethylated lysine 4 in vitro, the requirement of chromatin components for DNA methylation has not been examined, and functional evidence for the connection of histone tails to DNA methylation is still lacking. Here, we used the budding yeast Saccharomyces cerevisiae as a model system to investigate the chromatin determinants of DNA methylation through ectopic expression of murine Dnmt3a and Dnmt3L. We found that the N terminus of histone H3 tail is required for de novo methylation, while the central part encompassing lysines 9 and 27, as well as the H4 tail are dispensable. DNA methylation occurs predominantly in heterochromatin regions lacking H3K4 methylation. In mutant strains depleted of H3K4 methylation, the DNA methylation level increased 5-fold. The methylation activity of Dnmt3a largely depends on the Dnmt3L's PHD domain recognizing the histone H3 tail with unmethylated lysine 4. Functional analysis of Dnmt3L in mouse ES cells confirmed that the chromatin-recognition ability of Dnmt3L's PHD domain is indeed required for efficient methylation at the promoter of the endogenous Dnmt3L gene. These findings establish the N terminus of histone H3 tail with an unmethylated lysine 4 as a chromatin determinant for DNA methylation.
