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Computational modelling of genome organisation - Understanding the compaction of DNA within cells

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First Year PhD Report

Under physiological conditions, DNA is negatively charged – resulting in large repulsive electrostatic forces between segments of the DNA chain. Despite this, our genome is highly compact – with each of our cells containing around 2 metres of DNA within a nucleus of only 10 micro-metres in diameter. In order to help achieve this compaction, DNA wraps around positively charged proteins to form nucleosomes – which self-assemble into a highly dynamic and liquid-like structure known as chromatin.

Understanding the dynamics and structure of chromatin can help shed light on the functional organisation of the genome: hopefully leading to better understanding of cellular mechanisms, from the regulation of gene transcription to the development of neurological disorders such as ALS . A crucial experimental discovery came in 2019 from the Rosen Lab (Texas, USA ), showing that chromatin forms liquid droplets under physiological conditions. The Collepardo Lab has developed a multi-scale coarse-grained model of chromatin at three levels of resolution, to investigate the individual molecular mechanisms involved in chromatin dynamics and phase separation through molecular dynamics simulations. We find that nucleosome breathing – the intrinsic ability of DNA to spontaneously unwrap and rewrap around nucleosomes at physiological conditions- promotes phase separation and increases the heterogenetity of ­nucleosome contacts.

My talk will focus on our coarsest or “minimal” model – the resolution level required to investigate the collective behaviour of phase separation. I will explain how using this model, our direct coexistence molecular dynamics simulations recapitulate the experimental phase behaviour of 12-nucleosome chromatin arrays, and simultaneously provide a framework to assess the physical parameters explaining chromatin phase separation.

This talk is part of the Theory - Chemistry Research Interest Group series.

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