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.

中文翻译：

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引起Rett综合征的突变损害了MeCP2介导的染色质液液相分离。

Rett综合征（RTT）是一种严重的出生后神经发育障碍，是由编码甲基CpG结合蛋白2（MeCP2）的X连锁基因突变引起的。MeCP2是调节基因表达的染色质组织器。已显示导致RTT的突变会影响此功能。但是，MeCP2组织染色质的机制尚不清楚。在这项研究中，我们发现MeCP2可以在体外诱导核小体阵列的压实和液相分离，而DNA甲基化进一步增强了MeCP2形成的染色质冷凝物。有趣的是，引起RTT的突变会破坏MeCP2介导的染色质相分离，而良性变体对此过程几乎没有影响。此外，MeCP2与接头组蛋白H1竞争，在体外形成互斥的染色质冷凝物，在体内形成独特的异染色质病灶。导致RTT的突变降低或什至消除了MeCP2与组蛋白H1竞争并形成染色质浓缩物的能力。在一起，我们的结果确定了一种新的机制，相分离是MeCP2介导的异染色质形成的基础，并揭示了该过程与RTT病理之间的潜在联系。