Correlative evidence has suggested that the methyl-CpG-binding protein MeCP2 contributes to the formation of heterochromatin condensates via liquid-liquid phase separation. This interpretation has been reinforced by the observation that heterochromatin, DNA methylation and MeCP2 co-localise within prominent foci in mouse cells. The findings presented here revise this view. MeCP2 localisation is independent of heterochromatin as MeCP2 foci persist even when heterochromatin organisation is disrupted. Additionally, MeCP2 foci fail to show hallmarks of phase separation in live cells. Importantly, we find that mouse cellular models are highly atypical as MeCP2 distribution is diffuse in most mammalian species, including humans. Notably, MeCP2 foci are absent in Mus spretus which is a mouse subspecies lacking methylated satellite DNA repeats. We conclude that MeCP2 has no intrinsic tendency to form condensates and its localisation is independent of heterochromatin. Instead, the distribution of MeCP2 in the nucleus is primarily determined by global DNA methylation patterns.

相关证据表明，甲基-CpG 结合蛋白 MeCP2 有助于通过液-液相分离形成异染色质缩合物。异染色质、DNA 甲基化和 MeCP2 共定位于小鼠细胞的突出病灶内的观察结果加强了这种解释。这里介绍的发现修正了这一观点。MeCP2 定位与异染色质无关，因为即使异染色质组织被破坏，MeCP2 病灶也会持续存在。此外，MeCP2 病灶在活细胞中未能显示出相分离的标志。重要的是，我们发现小鼠细胞模型是高度不典型的，因为 MeCP2 分布在大多数哺乳动物物种（包括人类）中是弥漫的。值得注意的是，Mus spretus 中不存在 MeCP2 病灶，Mus spretus 是一种缺乏甲基化卫星 DNA 重复序列的小鼠亚种。我们得出结论，MeCP2 没有形成凝聚物的内在倾向，其定位独立于异染色质。相反，MeCP2 在细胞核中的分布主要由整体 DNA 甲基化模式决定。