Computational modelling of DNA compartmentalization via liquid-liquid phase separation

One of the big open challenges in biology today is deciphering how the genome is organized in space and how this organization influences its function. Inside Eukaryotic cells, genomic DNA is densely packed together with histone proteins into a remarkable structure known as chromatin. The basic unit of chromatin is the nucleosome, an octamer of proteins around which the DNA is wrapped. In the past three years, liquid-liquid phase separation of chromatin, and its associated multivalent biomolecules, has gained acceptance as a fundamental organizing principle of the cell nucleus. Because chromatin phase separation is a collective phenomena, linking biophysical features of individual nucleosomes to its modulation remains an open challenge. My proposal will build on the expertise of the Collepardo group to understand the role of liquidliquid phase separation on chromatin organization during the formation of 'transcription factories'. Particularly, I will focus on how transcription factors affect chromatin architecture. We hypothesize that by deforming nucleosomes, different transcription factors, like Oct4 and SOX2, can transform the nucleosome valencies differently and purposely change the stability of condensates. My proposal aims to investigate if/how transcription factors might offer an additional mechanism to control intranuclear phase separation and condensate functions. By using a combination of in-vivo data and the multiscale simulation approaches, we aim to uncover the biophysical mechanisms that dictate the spatiotemporal modulation of chromatin structure inside multicomponent phaseseparated droplets rich in coactivators, resolving individual nucleosomes and proteins inside phase-separated droplets