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MeCP2 links heterochromatin condensates and neurodevelopmental disease

机译：MECP2链接杂体蛋白缩合物和神经发育疾病

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摘要

The chromatin protein MeCP2 is a component of dynamic, liquid-like heterochromatin condensates, and the ability of MeCP2 to form condensates is disrupted by mutations in theMECP2gene that occur in the neurodevelopmental disorder Rett syndrome.Methyl CpG binding protein 2 (MeCP2) is a key component of constitutive heterochromatin, which is crucial for chromosome maintenance and transcriptional silencing(1-3). Mutations in theMECP2gene cause the progressive neurodevelopmental disorder Rett syndrome(3-5), 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(1,2), heterochromatin is now understood to exhibit properties consistent with a liquid-like condensate(6,7). 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 inMECP2that 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.
机译：染色质蛋白MeCP2是动态，液体状的异铬胺缩合物的组分，并且MECP2形成缩合物的能力在神经开发障碍Rett综合征中发生的Themecp2庚烷中的突变中断。甲基CpG结合蛋白2（MECP2）是一个关键组成型异铬胺，其对染色体维持和转录沉默至关重要（1-3）。 ThemCP2庚烷中的突变导致进步神经发育障碍Rett综合征（3-5），其与严重的精神残疾和自闭症样症状相关，这些症状在幼儿期间会影响女孩。虽然以前认为是致密且相对静态的结构（1,2），但现在被理解为表现出与液体样缩合物（6,7）一致的性质。在这里，我们表明MeCP2是细胞中异铬蛋白凝聚液的动态分量，并且由DNA刺激以形成液体状缩合物。 MECP2含有几个导致缩合液形成的结构域，突变导致Rett综合征破坏MeCP2形成凝析液的能力。 MECP2形成的缩合物选择性地掺入并浓缩异铬胺蛋白辅因子，而不是欧有族转录活性缩合物的组分。我们提出MeCP2通过其冷凝物分配性能增强异铬胺和欧洲甜酰胺的分离，并且所述缩合物的破坏可能是导致RETT综合征的MECP2中突变的常见后果。

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  • 来源
    《Nature》 |2020年第7829期|440-444|共5页
  • 作者

    Li Charles H.; Coffey Eliot L.; DallAgnese Alessandra; Hannett Nancy M.; Tang Xin; Henninger Jonathan E.; Platt Jesse M.; Oksuz Ozgur; Zamudio Alicia V.; Afeyan Lena K.; Schuijers Jurian; Liu X. Shawn; Markoulaki Styliani; Lungjangwa Tenzin; LeRoy Gary; Svoboda Devon S.; Wogram Emile; Lee Tong Ihn; Jaenisch Rudolf; Young Richard A.;

  • 作者单位

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|MIT Dept Biol Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|MIT Dept Biol Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|Massachusetts Gen Hosp Dept Med Div Gastroenterol Boston MA 02114 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|MIT Dept Biol Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|MIT Dept Biol Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|Univ Med Ctr Utrecht Ctr Mol Med Utrecht Netherlands;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|Columbia Univ Med Ctr Dept Physiol & Cellular Biophys New York NY USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    NYU Sch Med Dept Biochem & Mol Pharmacol New York NY USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|MIT Dept Biol Cambridge MA 02142 USA;

    Whitehead Inst Biomed Res 9 Cambridge Ctr Cambridge MA 02142 USA|MIT Dept Biol Cambridge MA 02142 USA;

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