Computational modelling of DNA compartmentalization via liquid-liquid phase separation

通过液-液相分离进行 DNA 区室化的计算模型

• 批准号: EP/X02332X/1
• 负责人: Rosana Collepardo-Guevara
• 金额: $ 24.26万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX02332X%2F1
• 关键词: Computational; modelling; DNA; compartmentalization; via

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

当今生物学中的一大开放挑战是破译基因组在太空中是如何组织的，以及这种组织如何影响其功能。在真核细胞内，基因组DNA与组蛋白紧密结合在一起，形成一种显著的结构，称为染色质。染色质的基本单位是核小体，核小体是包裹着DNA的蛋白质的八聚体。在过去的三年里，染色质及其相关的多价生物分子的液-液相分离已被认为是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控联系起来仍然是一个开放的挑战。我的建议将建立在Collepardo小组的专业知识的基础上，以了解液-液相分离在染色质组织形成过程中的作用。我将特别关注转录因子是如何影响染色质结构的。我们假设，通过使核小体变形，不同的转录因子，如Oct4和SOX2，可以不同地转换核小体的价态，并有目的地改变凝析油的稳定性。我的建议旨在研究转录因子是否/如何可能提供一种额外的机制来控制核内相分离和凝聚功能。通过结合体内数据和多尺度模拟方法，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中染色质结构的时空调制，并在相分离液滴中分解单个核小体和蛋白质