A fundamental open challenge in molecular and cellular biology is to understand how the genome is organised in three-dimensional space and how this organisation influences gene function. Chromatin is a dynamic and heterogeneous material whose structure arises from the interplay of nucleosome breathing, histone modifications, DNA mechanics, architectural proteins, and phase separation. Despite decades of research, we lack mechanistic, high-resolution models that can integrate these factors and connect local biochemical regulation to chromatin folding across kilobase to megabase scales.
Understanding chromatin structure mechanistically is important for society because it underpins essential biological processes such as development, cellular identity, and genome maintenance. Its dysregulation is implicated in cancer, ageing, neurodegenerative disorders, and numerous epigenetic diseases. Developing realistic models of chromatin organisation is therefore critical for improving our understanding of gene regulation, for interpreting large-scale genomic and epigenomic data, and for informing future therapeutic strategies that target genome structure and function.
The overarching objective of this roject was to develop a new generation of multiscale computational models that achieve realistic, mechanistic descriptions of chromatin structure and biomolecular phase separation. Specifically, the project aimed to:
1. Develop a high-resolution coarse-grained model of chromatin.
2. Extend this model to describe functional chromatin domains.
3. Create approaches to predict chromatin structure at megabase scales.
4. Integrate chromatin and protein models to determine the role of liquid–liquid phase separation in genome and cellular organisation.
All these objectives were achieved. The project has delivered multiple multiscale simulation frameworks that combine molecular accuracy with large-scale predictive power, enabling the first realistic simulations of chromatin and biomolecular condensates across multiple levels of resolution. These models provide a mechanistic understanding of how nucleosome dynamics, DNA mechanics, histone variants and protein phase behaviour collectively regulate genome organisation. The resulting computational platform forms a robust foundation for future predictive studies linking molecular interactions to emergent behaviours of chromatin.
