A model for transmission of the H3K27me3 epigenetic mark
A model for transmission of the H3K27me3 epigenetic mark
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DOI：
10.1038/ncb1787
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发表时间：
2008-11-01
影响因子：
21.3
通讯作者：
Helin, Kristian
中科院分区：
文献类型：
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作者：
Hansen, Klaus H.;Bracken, Adrian P.;Helin, Kristian
通过表观遗传机制组织染色质对于建立和维持发展中和成人生物的细胞身份至关重要。尚未解决此过程的关键问题是如何将表观遗传标记传递到细胞分裂期间的下一个细胞产生。在这里，我们提供了一个模型来解释组蛋白3（H3K27me3）的三甲基化Lys 27，该模型如何由含EZH2的含有EZH2的Polycomb抑制性复合物2（PRC2）催化。我们表明，PRC2复合物与H3K27me3标记结合，并在G1相和持续的DNA复制位点与该标记共定位。有效的结合需要包含EZH2，EED和SUZ12的完整三聚体PRC2复合物，但独立于EZH2的催化集域。使用异源报道系统，我们表明，转录起始位点上游的PRC2复合物瞬时募集足以通过内源性PRC2在随后的细胞分裂过程中维持抑制作用。因此，我们建议一旦建立了H3K27me3，它就会募集PRC2复合物以保持DNA复制位点的标记，从而导致H3K27在掺入新合成的组蛋白期间对女儿链的甲基化。这种机制可确保维持增殖细胞中H3K27me3表观遗传标记，不仅在组合组蛋白合成的DNA复制过程中，还包括在S阶段外，从而保留了染色质结构和转录程序。
Organization of chromatin by epigenetic mechanisms is essential for establishing and maintaining cellular identity in developing and adult organisms. A key question that remains unresolved about this process is how epigenetic marks are transmitted to the next cell generation during cell division. Here we provide a model to explain how trimethylated Lys 27 of histone 3 (H3K27me3), which is catalysed by the EZH2-containing Polycomb Repressive Complex 2 (PRC2), is maintained in proliferating cells. We show that the PRC2 complex binds to the H3K27me3 mark and colocalizes with this mark in G1 phase and with sites of ongoing DNA replication. Efficient binding requires an intact trimeric PRC2 complex containing EZH2, EED and SUZ12, but is independent of the catalytic SET domain of EZH2. Using a heterologous reporter system, we show that transient recruitment of the PRC2 complex to chromatin, upstream of the transcriptional start site, is sufficient to maintain repression through endogenous PRC2 during subsequent cell divisions. Thus, we suggest that once the H3K27me3 is established, it recruits the PRC2 complex to maintain the mark at sites of DNA replication, leading to methylation of H3K27 on the daughter strands during incorporation of newly synthesized histones. This mechanism ensures maintenance of the H3K27me3 epigenetic mark in proliferating cells, not only during DNA replication when histones synthesized de novo are incorporated, but also outside S phase, thereby preserving chromatin structure and transcriptional programs.