Polymer Modelling Predicts Chromosome Reorganisation in Senescence

TL;DR

This study uses polymer simulations combined with microscopy and mass spectrometry to understand how heterochromatin and lamina interactions influence nuclear organization, revealing phase transitions and metastability in senescent cells.

Contribution

It introduces a polymer model that explains nuclear architecture changes in senescence and related conditions, highlighting phase transitions and stochastic LAD formation as key mechanisms.

Findings

LAD contacts are highly stochastic, matching experimental observations.

Nuclear organization changes in senescence can be explained by phase transitions.

Senescent phenotype remains metastable even if lamina interactions are restored.

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 organisation. Our model explains the conventional organisation of heterochromatin and euchromatin in growing cells and the pathological organisation 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.