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Phase separation drives heterochromatin domain formation

机译：相分离驱动异染色质域形成

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摘要

Constitutive heterochromatin is an important component of eukaryotic genomes that has essential roles in nuclear architecture, DNA repair and genome stability(1), and silencing of transposon and gene expression(2). Heterochromatin is highly enriched for repetitive sequences, and is defined epigenetically by methylation of histone H3 at lysine 9 and recruitment of its binding partner heterochromatin protein 1 (HP1). A prevalent view of heterochromatic silencing is that these and associated factors lead to chromatin compaction, resulting in steric exclusion of regulatory proteins such as RNA polymerase from the underlying DNA(3). However, compaction alone does not account for the formation of distinct, multi-chromosomal, membrane-less heterochromatin domains within the nucleus, fast diffusion of proteins inside the domain, and other dynamic features of heterochromatin. Here we present data that support an alternative hypothesis: that the formation of heterochromatin domains is mediated by phase separation, a phenomenon that gives rise to diverse non-membrane-bound nuclear, cytoplasmic and extracellular compartments(4). We show that Drosophila HP1a protein undergoes liquid-liquid demixing in vitro, and nucleates into foci that display liquid properties during the first stages of heterochromatin domain formation in early Drosophila embryos. Furthermore, in both Drosophila and mammalian cells, heterochromatin domains exhibit dynamics that are characteristic of liquid phase-separation, including sensitivity to the disruption of weak hydrophobic interactions, and reduced diffusion, increased coordinated movement and inert probe exclusion at the domain boundary. We conclude that heterochromatic domains form via phase separation, and mature into a structure that includes liquid and stable compartments. We propose that emergent biophysical properties associated with phase-separated systems are critical to understanding the unusual behaviours of heterochromatin, and how chromatin domains in general regulate essential nuclear functions.
机译：组成型异染色质是真核基因组的重要组成部分，在核结构，DNA修复和基因组稳定性（1），转座子沉默和基因表达（2）中具有重要作用。异染色质高度富集重复序列，并通过在赖氨酸9处的组蛋白H3甲基化并募集其结合伴侣异染色质蛋白1（HP1）在表观遗传上定义。异色沉默的普遍观点是这些因素和相关因素导致染色质紧缩，从而导致潜在的调节蛋白（如RNA聚合酶）从底层DNA上被空间排阻（3）。但是，仅靠压实不能解释核内独特，多染色体，无膜的异染色质结构域的形成，结构域内蛋白质的快速扩散以及异染色质的其他动态特征。在这里，我们提供了支持另一种假设的数据：异染色质结构域的形成是由相分离介导的，这种现象引起了多种非膜结合的核，细胞质和细胞外区室（4）。我们显示果蝇HP1a蛋白在体外经历液-液混合，并成核成焦点，在果蝇早期胚胎的异染色质域形成的第一阶段显示液体特性。此外，在果蝇和哺乳动物细胞中，异染色质结构域均表现出液相分离所特有的动力学，包括对弱疏水相互作用破坏的敏感性，以及扩散减少，协调运动增加和在域边界处的惰性探针排斥。我们得出的结论是，异色域通过相分离形成，并成熟为包括液体和稳定隔室的结构。我们建议与相分离系统相关的新兴生物物理特性对于理解异染色质的异常行为以及染色质结构域通常如何调节基本核功能至关重要。

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  • 来源
    《Nature》 |2017年第7662期|241-245|共5页
  • 作者

    Strom Amy R.; Emelyanov Alexander V.; Mir Mustafa; Fyodorov Dmitry V.; Darzacq Xavier; Karpen Gary H.;

  • 作者单位

    Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA|Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA;

    Albert Einstein Coll Med, Dept Cell Biol, New York, NY USA;

    Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA;

    Albert Einstein Coll Med, Dept Cell Biol, New York, NY USA;

    Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA;

    Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA|Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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