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Towards Realistic Modelling of Nucleosome Organization Inside Functional Chromatin Domains

Periodic Reporting for period 1 - InsideChromatin (Towards Realistic Modelling of Nucleosome Organization Inside Functional Chromatin Domains)

Reporting period: 2019-04-01 to 2020-09-30

The next big challenge to understand gene behaviour is deciphering how the genome is organized in space and how this organization influences its function. Inside Eukaryotic cells, genomic DNA is packed together with proteins in a hierarchical structure known as chromatin. Nucleosomes, the building blocks of chromatin, interact with each other to enable extreme packaging. The structure of chromatin has remained a topic of intense research and debate for over 30 years. Our understanding is limited by the lack of ‘close up views’ and molecular-level mechanistic information of how nucleosome interactions are regulated in vivo by many highly coupled factors (i.e. epigenetic marks, the binding of architectural proteins, aggregation of architectural proteins, and other intrinsic factors such as nucleosome mobility and spacing) and how they lead to formation of large-scale functionally different domains.
InsideChromatin aims to develop a groundbreaking multiscale approach that will push the current limits of realistic computational modelling of in vivo chromatin structure. The vision is to achieve the first multiscale
simulation study that resolves nucleosome organization inside structurally different Kb-scale domains, while accounting with atomistic resolution for the combination of epigenetic marks, architectural proteins, and nucleosome remodelling activity that distinguishes each domain. InsideChromatin will integrate atomistic simulations with two levels of coarse-graining and experimental data for validation to bridge nucleosome organization to physical properties in Mb-scale domains. InsideChromatin aims to bring us closer to the ‘holy grail’ of deciphering the connection between genome characteristics, structure, and function.
During this first period, InsideChromatin has developed a novel multiscale chromatin model that integrates atomistic representations, a chemically-specific coarse-grained model, and a minimal model. In tandem, it devises a transferable Debye-length exchange molecular dynamics approach to achieve enhanced sampling of high-resolution chromatin. This model reveals that nucleosome thermal fluctuations become significant at physiological salt concentrations and destabilize the 30-nm fiber. Nucleosome breathing favors stochastic folding of chromatin and promotes LLPS by simultaneously boosting the transient nature and heterogeneity of nucleosome–nucleosome contacts, and the effective nucleosome valency. Our results put forward the intrinsic plasticity of nucleosomes as a key element in the liquid-like behavior of chromatin, and help reconcile longstanding differences between fiber-based and in vivo chromatin models.
InsideChromatin has now developed a multiscale model of chromatin that pushes the current limits of realistic modelling of chromatin organization and goes beyond the state-of-the-art. With this technique, InsideChromatin has achieved the first multiscale simulation study that resolves individual nucleosomes inside phase-separated chromatin condensates, and discovered that the spontaneous breathing motions (i.e. partial DNA unwrapping) of nucleosomes increase the range of stability of chromatin liquid-liquid phase separation.
This is an illustration of the multiscale method of InsideChromatin