Polymer Modeling Predicts Chromosome Reorganization in Senescence
Polymer Modeling Predicts Chromosome Reorganization in Senescence
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DOI：
10.1016/j.celrep.2019.08.045
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发表时间：
2019-09-17
期刊：
影响因子：
8.8
通讯作者：
Chandra, Tamir
中科院分区：
文献类型：
--
作者：
Chiang, Michael;Michieletto, Davide;Chandra, Tamir
层相关结构域（LAD）覆盖了人类基因组的很大一部分，并被认为在塑造核结构景观中发挥着重要作用。在这里，我们进行聚合物模拟，显微镜和质谱分析，解剖异染色质和核纤层介导的相互作用在核组织中发挥的作用。我们的模型解释了生长细胞中异染色质和常染色质的常规组织以及在癌基因诱导的衰老和早衰中发现的病理组织。我们表明，实验观察到的变化，在衰老和早衰细胞的接触的地方可以解释为由于系统中的相变而产生的。在我们的模拟中，LAD是高度随机的，就像在实验中一样。我们的模型表明，一旦建立，衰老表型应该是亚稳态的，即使层介导的相互作用恢复。总之，我们的模拟揭示了一个通用的物理机制，可以调节异染色质分离和LAD形成在广泛的哺乳动物细胞核。
Lamina-associated domains (LADs) cover a large part of the human genome and are thought to play a major role in shaping the nuclear architectural landscape. Here, we perform polymer simulations, microscopy, and mass spectrometry to dissect the roles played by heterochromatin- and lamina-mediated interactions in nuclear organization. Our model explains the conventional organization of heterochromatin and euchromatin in growing cells and the pathological organization found in oncogene-induced senescence and progeria. We show that the experimentally observed changes in the locality of contacts in senescent and progeroid cells can be explained as arising due to phase transitions in the system. Within our simulations, LADs are highly stochastic, as in experiments. Our model suggests that, once established, the senescent phenotype should be metastable even if lamina-mediated interactions were reinstated. Overall, our simulations uncover a generic physical mechanism that can regulate heterochromatin segregation and LAD formation in a wide range of mammalian nuclei.