Computational modelling of DNA compartmentalization via liquid-liquid phase separation

当今生物学面临的最大挑战之一是破译基因组在空间中的组织方式以及这种组织如何影响其功能。在真核细胞内，基因组DNA与组蛋白紧密地堆积在一起，形成一种称为染色质的非凡结构。染色质的基本单位是核小体，核小体是DNA包裹的蛋白质八聚体。在过去的三年中，染色质及其相关的多价生物分子的液-液相分离已经被接受为细胞核的基本组织原则。由于染色质相分离是一种集体现象，将单个核小体的生物物理特征与其调节联系起来仍然是一个开放的挑战。我的建议将建立在Collepardo小组的专业知识，以了解在“转录因子”形成过程中液-液相分离对染色质组织的作用。特别是，我将集中在转录因子如何影响染色质结构。我们假设，通过变形核小体，不同的转录因子，如Oct 4和SOX 2，可以不同地改变核小体的价态，并有目的地改变凝聚物的稳定性。我的提议旨在研究转录因子是否/如何提供一种额外的机制来控制核内相分离和冷凝功能。通过使用体内数据和多尺度模拟方法的组合，我们的目标是揭示生物物理机制，这些机制决定了富含共激活剂的多组分相分离液滴内染色质结构的时空调节，分辨相分离液滴内的单个核小体和蛋白质

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