Polymer Modeling Predicts Chromosome Reorganization in Senescence

Abstract

Summary: 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. : Chiang et al. use polymer simulations to investigate the roles of heterochromatin and lamina interactions on nuclear reorganization in cellular senescence. Their model captures chromatin organization in growing, senescent, and progeroid cells and predicts that a polymeric phase transition underlies the ensuing rearrangements in the chromatin contact network. Keywords: nuclear lamina, heterochromatin, cellular senescence, progeria, polymer simulations, genome organization, phase transitions