Rett syndrome-causing mutations compromise MeCP2-mediated liquid-liquid phase separation of chromatin
Rett syndrome-causing mutations compromise MeCP2-mediated liquid-liquid phase separation of chromatin
复制标题
引起 Rett 综合征的突变会损害 MeCP2 介导的染色质液-液相分离
DOI：
10.1038/s41422-020-0288-7
复制
发表时间：
2020-02-28
期刊：
影响因子：
44.1
通讯作者：
Li, Pilong
中科院分区：
文献类型：
--
作者：
Wang, Liang;Hu, Mingli;Li, Pilong
Rett 综合征 (RTT) 是一种严重的产后神经发育障碍，由编码甲基 CpG 结合蛋白 2 (MeCP2) 的 X 连锁基因突变引起。 MeCP2 是调节基因表达的染色质组织者。引起 RTT 的突变已被证明会影响此功能。然而，MeCP2 组织染色质的机制尚不清楚。在本研究中，我们发现MeCP2可以在体外诱导核小体阵列的压缩和液-液相分离，并且DNA甲基化进一步增强MeCP2形成染色质凝聚物。有趣的是，引起 RTT 的突变会损害 MeCP2 介导的染色质相分离，而良性变异对此过程几乎没有影响。此外，MeCP2 与接头组蛋白 H1 竞争，在体外形成相互排斥的染色质凝聚物，在体内形成不同的异染色质灶。引起 RTT 的突变降低甚至消除了 MeCP2 与组蛋白 H1 竞争并形成染色质凝聚物的能力。总之，我们的结果确定了 MeCP2 介导的异染色质形成的相分离基础的新机制，并揭示了该过程与 RTT 病理学之间的潜在联系。
Rett syndrome (RTT), a severe postnatal neurodevelopmental disorder, is caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2). MeCP2 is a chromatin organizer regulating gene expression. RTT-causing mutations have been shown to affect this function. However, the mechanism by which MeCP2 organizes chromatin is unclear. In this study, we found that MeCP2 can induce compaction and liquid-liquid phase separation of nucleosomal arrays in vitro, and DNA methylation further enhances formation of chromatin condensates by MeCP2. Interestingly, RTT-causing mutations compromise MeCP2-mediated chromatin phase separation, while benign variants have little effect on this process. Moreover, MeCP2 competes with linker histone H1 to form mutually exclusive chromatin condensates in vitro and distinct heterochromatin foci in vivo. RTT-causing mutations reduce or even abolish the ability of MeCP2 to compete with histone H1 and to form chromatin condensates. Together, our results identify a novel mechanism by which phase separation underlies MeCP2-mediated heterochromatin formation and reveal the potential link between this process and the pathology of RTT.