Polymer Modelling of the 4D Epigenome

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• Dr Davide Michieletto; University of Edinburgh
• Thursday 26 July 2018, 13:00-14:00
• Babraham - The Cambridge Building; Kings Hedges Room.

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Models of chromosome folding based on polymer physics principles have provided us with much mechanistic insight into the role of transcription factors and other generic binding proteins in folding the genome. These models heavily rely on the presence of permanent epigenetic patterns. Yet, we now know that histone post-translational modification and DNA methylation are highly dynamic processes and epigenetic patterns change during differentiation, ageing, disease and reprogramming. On the other hand, epigenetic patterns are also highly robust, as they can be remembered after cell division. In order to reconcile these apparently contrasting observations (epigenetic plasticity and epigenetic memory) we propose a new polymer model in which the 3D diffusion of the chromatin fibre is coupled to time-varying epigenetic states along its backbone. In other words, we propose the first “4D” polymer model for the epigenome. A key prediction of our model is that 3D cis/trans interactions are necessary to establish and maintain stable epigenetic domains, which can be remembered even after major disruptive events such as cell division. By impairing 3D interactions, we observe that domains can appear only transiently and could not be remembered. Finally, we observe that epigenetic plasticity can be recovered by including “genomic bookmarks” such as PSC in Drosophila and GATA in humans. Intriguingly, we find that genomic bookmarks (and not architectural boundaries such as CTCF ) are the key elements required to correctly recapitulate Polycomb domains in Drosophila. Our generic model can be used to explain epigenetic memory after cell division, but can also be applied to cellular ageing and reprogramming.

https://www2.ph.ed.ac.uk/~dmichiel/

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