Heterochromatin drives compartmentalization of inverted and conventional nuclei
Heterochromatin drives compartmentalization of inverted and conventional nuclei
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DOI：
10.1038/s41586-019-1275-3
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发表时间：
2019-06-20
期刊：
影响因子：
64.8
通讯作者：
Mirny, Leonid A.
中科院分区：
文献类型：
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作者：
Falk, Martin;Feodorova, Yana;Mirny, Leonid A.
哺乳动物细胞的细胞核显示出基因组(1，2)中活跃的常染色区和不活跃的异染色区的明显空间分离。在常规细胞核中，显微镜显示常染色质位于核内部，异染色质位于核外围(1，2)。全基因组染色体构象捕获(Hi-C)分析表明，这种分离是常染色质和异染色质间接触浓缩的格子模式(3)，以及它们之间的枯竭。已经提出了许多形成间隔室的机制，如异染色质与核层的吸引(2，4)，相似染色质的优先吸引(1，4-12)，活性染色质中较高水平的染色质迁移率(13-15)，以及常染色质(16，17)的转录相关聚集。然而，这些假设仍然没有定论，因为很难解开常规核中染色质内和染色质-板层的相互作用(18)。在夜间活动的哺乳动物(19，20)的视杆细胞倒置核中，间期染色体的显著重组为阐明空间区划的机制提供了机会。在这里，我们将倒棒核的Hi-C分析与显微镜和聚合物模拟相结合。我们发现，异染色质区域之间的吸引对于建立倒核周着丝粒异染色质、兼性异染色质和常染色质的区隔和同心壳都是至关重要的。当加入异染色质和板层之间的相互作用时，相同的模型重建了传统的核组织。此外，我们的模型允许我们排除涉及强常染色质相互作用的区隔机制。总之，我们的实验和建模表明，异染色区之间的吸引对于倒置核和常规核中活跃和不活跃基因组的相分离是必不可少的，而染色质与膜的相互作用对于从这些分离相建立传统结构是必要的。
The nucleus of mammalian cells displays a distinct spatial segregation of active euchromatic and inactive heterochromatic regions of the genome(1,2). In conventional nuclei, microscopy shows that euchromatin is localized in the nuclear interior and heterochromatin at the nuclear periphery(1,2). Genome-wide chromosome conformation capture (Hi-C) analyses show this segregation as a plaid pattern of contact enrichment within euchromatin and heterochromatin compartments(3), and depletion between them. Many mechanisms for the formation of compartments have been proposed, such as attraction of heterochromatin to the nuclear lamina(2,4), preferential attraction of similar chromatin to each other(1,4-12), higher levels of chromatin mobility in active chromatin(13-15) and transcription-related clustering of euchromatin(16,17). However, these hypotheses have remained inconclusive, owing to the difficulty of disentangling intra-chromatin and chromatin-lamina interactions in conventional nuclei(18). The marked reorganization of interphase chromosomes in the inverted nuclei of rods in nocturnal mammals(19,20) provides an opportunity to elucidate the mechanisms that underlie spatial compartmentalization. Here we combine Hi-C analysis of inverted rod nuclei with microscopy and polymer simulations. We find that attractions between heterochromatic regions are crucial for establishing both compartmentalization and the concentric shells of pericentromeric heterochromatin, facultative heterochromatin and euchromatin in the inverted nucleus. When interactions between heterochromatin and the lamina are added, the same model recreates the conventional nuclear organization. In addition, our models allow us to rule out mechanisms of compartmentalization that involve strong euchromatin interactions. Together, our experiments and modelling suggest that attractions between heterochromatic regions are essential for the phase separation of the active and inactive genome in inverted and conventional nuclei, whereas interactions of the chromatin with the lamina are necessary to build the conventional architecture from these segregated phases.