On the physics of intranuclear organization

Abstract

Eukaryotic nuclei, despite their diverse and crowded chemical milieu, can achieve precise spatiotemporal organization of their contents and chemistry, despite lacking access to membrane-bound organelles. It has recently become apparent that the cells accomplish this feat by leveraging physical processes such as liquid-liquid phase separation driven by multivalent macromolecular interactions to form biomolecular condensates which can serve as membrane-less organelles for the precise, vectorial organization of intranuclear contents. In particular, the hierarchical and functional packaging of DNA into chromatin is mediated by phase separation. Epigenetic modifications of histone proteins, which DNA wraps around to form nucleosomes, are key determinants of nucleosomes’ condensability and chromatin’s higher-order structure. Chromatin structure, by regulating access of transcriptional machinery to the genome, in turn, has broad implications for cellular processes such as gene regulation and cellular differentiation. Furthermore, there exists a bi-directional feedback between 1D epigenomic sequence and 3D chromatin structure as the former is spread and maintained by enzymes that have a “reader-writer” functionality that allows them to similarly modify nucleosomes close to each other in sequence but not necessarily in space. Recent advances suggest chromatin has the properties of a viscoelastic network and exhibits non-trivial dynamics. Therefore, the dynamics of chromatin structure and the spread and maintenance of epigenetic marks are intimately and inextricably linked yet poorly understood. Part I of this thesis is devoted to understanding the complex interplay between chromatin structural dynamics and stochastic reaction networks describing histone modifications. Furthermore, given the prominent role phase separation plays in intranuclear organization, we devote Part II of this thesis to study the impact of competition between specific and non-specific interactions on liquid-liquid phase separation coupled to percolation and thereby attempt to elucidate the molecular grammar of phase separating biomolecules and evolutionary pressures that shape them.