2009年12月29日,，《美國科學院院刊》（PNAS）發(fā)表了中國科學院上海生命科學研究院生物化學與細胞生物學研究所研究人員的研究工作 — “The N-terminus of histone H3 is required for de novo DNA methylation in chromatin”,。該工作由周金秋和徐國良課題組合作完成,，博士研究生胡佳磊承擔了主要研究工作,。
DNA甲基化在哺乳動物細胞中普遍存在,，參與轉(zhuǎn)錄調(diào)控,、細胞分化等許多重要的生物學過程,，但目前關于DNA甲基化的發(fā)生機制尚不清楚,。本項工作中,，研究人員用釀酒酵母作為研究系統(tǒng)，在本身不存在甲基化的酵母基因組上建立DNA甲基化譜式,，揭示了組蛋白H3 N端尾部對于DNA甲基化不可或缺的作用,。進一步研究發(fā)現(xiàn)，輔助因子Dnmt3L能通過其PHD結(jié)構(gòu)域與第四位賴氨酸未甲基化的組蛋白H3發(fā)生相互作用,，進而招募DNA甲基轉(zhuǎn)移酶Dnmt3a到靶位點發(fā)生起始性DNA甲基化,。
這一研究首次從功能上揭示了組蛋白H3K4甲基化與DNA甲基化之間的直接聯(lián)系，加深了人們對DNA甲基化發(fā)生機制的認識,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
