Polymer Modelling of Genome Organisation in Healthy and Ageing Cells

Understanding how the human genome organises itself within the cell nucleus has been a long-standing challenge in biophysics. With the advance in sequencing technology and molecular experimental techniques, and the ability to perform massively parallelised simulations, it has become more feasible to dissect the principles governing the large-scale, chromosome-wide organisation of the genome.

In this talk, I will present simulation work on genome reorganisation when a human cell transforms from a healthy state to one of two ageing-related conditions: cellular senescence and progeria. Cellular senescence is a stress-induced response in which a cell irreversibly exits from the cell cycle. Progeria is a disease with which patients suffer from ageing symptoms early in their childhood. My work focuses on the roles played by two nuclear components, heterochromatin and the nuclear lamina, on such genome reorganisation. I will describe a polymer modelling framework for simulating chromatin, the material that constitutes our genome. Using this model, I will show that the reorganisation can be explained as a phase transition between different polymeric conformations. I will show that the model can reproduce the changes in the genomic network that have been observed in experiments. Importantly, the model predicts a mechanism that can explain the metastability of senescence and the difficulty for senescent cells to return to a healthy state. Finally, I will discuss some of my current simulations on polymer adsorption and their relation to genome rearrangement in senescence.