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Nature:北师大王占新教授课题组揭示表观遗传调控核心复合物PRC2招募到基因组上重要位点的分子机制

摘要 : 2017年9月7日,国际学术权威刊物自然出版集团《Nature》杂志在线发表了北京师范大学生命科学学院细胞增殖及调控生物学教育部重点实验室王占新教授课题组题为“Polycomb-like proteins link the PRC2 complex to CpG islands”的文章

2017年9月7日,国际学术权威刊物自然出版集团《Nature》杂志在线发表了北京师范大学生命科学学院细胞增殖及调控生物学教育部重点实验室王占新教授课题组题为“Polycomb-like proteins link the PRC2 complex to CpG islands”的文章,研究报道了PCL家族蛋白调控PRC2复合物在染色质上定位的机理研究突破进展。王占新实验室的博士生李豪杰和蒋君翊以及哈佛大学医学院施扬教授实验室的博士后Robert Liefke为本文的共同第一作者,王占新教授为通讯作者。

PCL家族蛋白是PRC2复合物的结合蛋白,该研究首次发现PCL家族蛋白的EH结构域识别含有非甲基化CpG序列的DNA元件,并通过结构生物学的方法揭示了PCL蛋白家族成员(PHF1和MTF2) 识别这种特定DNA元件以及识别含有H3K36me3修饰的组蛋白的分子机理。在体内,非甲基化CpG序列的DNA主要出现在基因组的CpG岛上,王占新实验室通过与哈佛大学施扬教授实验室合作,发现在小鼠胚胎干细胞内PCL家族蛋白成员通过对基因组上非甲基化CpG序列的特异识别,帮助PRC2复合物招募到染色质的CpG岛上。该研究首次发现并证实了PCL家族蛋白是连接PRC2与CpG岛的纽带,该工作为PRC2复合物在染色质上CpG岛特异的招募提供了直接的实验证据,解决了困惑人们多年的关于PRC2在染色质上选择性定位的这一重要问题,为进一步理解PCL家族蛋白在PRC2复合物中的生理功能,以及靶向与PRC2相关疾病开辟了一个全新的思路。

附图:PCL proteins link the PRC2 complex to CpG islands

原文链接:

Polycomb-like proteins link the PRC2 complex to CpG islands

原文摘要:

The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression1, 2 and has essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like (PCL) proteins, such as PHF1, MTF2 and PHF19, are PRC2-associated factors that form sub-complexes with PRC2 core components3, and have been proposed to modulate the enzymatic activity of PRC2 or the recruitment of PRC2 to specific genomic loci4, 5, 6, 7, 8, 9, 10, 11, 12, 13. Mammalian PRC2-binding sites are enriched in CG content, which correlates with CpG islands that display a low level of DNA methylation14. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood. Here we solve the crystal structures of the N-terminal domains of PHF1 and MTF2 with bound CpG-containing DNAs in the presence of H3K36me3-containing histone peptides. We show that the extended homologous regions of both proteins fold into a winged-helix structure, which specifically binds to the unmethylated CpG motif but in a completely different manner from the canonical winged-helix DNA recognition motif. We also show that the PCL extended homologous domains are required for efficient recruitment of PRC2 to CpG island-containing promoters in mouse embryonic stem cells. Our research provides the first, to our knowledge, direct evidence to demonstrate that PCL proteins are crucial for PRC2 recruitment to CpG islands, and further clarifies the roles of these proteins in transcriptional regulation in vivo.

来源: Nature 浏览次数:0

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