Polymer Modeling Predicts Chromosome Reorganization in Senescence

Michael Chiang, Davide Michieletto, Chris A. Brackley, Nattaphong Rattanavirotkul, Hisham Mohammed, Davide Marenduzzo, Tamir Chandra

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)P3212-3223.e6
JournalCell Reports
Volume28
Issue number12
DOIs
Publication statusPublished - 17 Sep 2019

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