Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nature. 2020 Oct;586(7829):440-444. doi: 10.1038/s41586-020-2574-4. Epub 2020 Jul 22.
Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing. Mutations in the MECP2 gene cause the progressive neurodevelopmental disorder Rett syndrome, which is associated with severe mental disability and autism-like symptoms that affect girls during early childhood. Although previously thought to be a dense and relatively static structure, heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate. Here we show that MeCP2 is a dynamic component of heterochromatin condensates in cells, and is stimulated by DNA to form liquid-like condensates. MeCP2 contains several domains that contribute to the formation of condensates, and mutations in MECP2 that lead to Rett syndrome disrupt the ability of MeCP2 to form condensates. Condensates formed by MeCP2 selectively incorporate and concentrate heterochromatin cofactors rather than components of euchromatic transcriptionally active condensates. We propose that MeCP2 enhances the separation of heterochromatin and euchromatin through its condensate partitioning properties, and that disruption of condensates may be a common consequence of mutations in MeCP2 that cause Rett syndrome.
甲基化 CpG 结合蛋白 2（MeCP2）是组成性异染色质的关键组成部分，对于染色体维持和转录沉默至关重要。MECP2 基因突变会导致进行性神经发育障碍瑞特综合征，其与严重的精神残疾和自闭症样症状有关，这些症状会在女童幼儿期出现。尽管先前认为异染色质是一种密集且相对静态的结构，但现在认为异染色质具有类似于液体的凝聚物的特性。在这里，我们表明 MeCP2 是细胞中异染色质凝聚物的动态组成部分，并受 DNA 刺激形成液体状凝聚物。MeCP2 包含几个有助于凝聚物形成的结构域，导致瑞特综合征的 MECP2 基因突变会破坏 MeCP2 形成凝聚物的能力。由 MeCP2 形成的凝聚物选择性地包含和浓缩异染色质辅因子，而不是常染色质转录活性凝聚物的成分。我们提出，MeCP2 通过其凝聚物分区特性增强了异染色质和常染色质的分离，而凝聚物的破坏可能是导致瑞特综合征的 MeCP2 基因突变的常见后果。
