Statistical physics models for the regulation of the structure of chromatin

染色质结构调控的统计物理模型

• 批准号: RGPIN-2015-06150
• 负责人: Emberly, Eldon
• 金额: $ 2.04万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=682810
• 关键词: Statistical; physics; models; regulation; structure

My research program applies methods of computational physics to address the question of how physical constraints lead to complex spatial organization in a cell. It is focused on developing data driven models that draw from strong collaborations with experimental biologists. An important physical process in cell biology is the packaging of DNA into the small volume of the cell. DNA is meticulously arranged; the structure of which affects a host of cellular functions. I have two research efforts that address timely unanswered questions about this process.*** In collaboration with Olivier Cuvier, a chromatin biologist at CNRS Toulouse, we are working on the development of a predictive mechanistic model for how the structuring of DNA in a cell regulates the genetic information that can get read out. In eukaryotic cells, DNA is packaged into a structure known as chromatin. It is a highly looped structure due to interactions between proteins that are bound to the DNA. The appropriate formation of loops determines whether a gene gets turned on or not. Analyzing data from the Cuvier lab, my group was able to uncover a complex network of interactions between proteins known as insulators which regulate DNA looping and gene expression. Using recently developed experimental techniques, the Cuvier lab will map out which parts of the genome are physically in contact, and how mutations to the insulator network can alter the map. My group will fit this data to a statistical physics model to determine the specific contact energies, leading to the development of a polymer based model for how insulators regulate chromatin structure. With a better understanding of the mechanistic processes involved in looping, we hope to be able to make predictions about when and where a gene will be expressed.*** Our second effort is focused on uncovering simple physical mechanisms that Nature uses to organize its molecular parts within the tiniest of cells, namely bacteria. We have shown that the entropy of the polymer of genomic DNA can drive localization of protein aggregates to the poles. In some bacteria, polar localized proteins interact with and aid the machinery that segregates replicating DNA. This segregation machinery is also dynamically patterned and recent in vitro measurements have given some insight into its mechanism. However, how the both interacting systems pattern the cell robustly during the important process of replication is not well understood. By modeling the coupled system, our hope is to be able to uncover the design principles of these biomolecular machines.*** The program of research just described will provide trainees with a diverse skill set. Past trainees have pursued careers in computational biology from academia to the industrial research setting. Such researchers are in high demand in Canada's growing biotech sector.**

我的研究项目应用计算物理学的方法来解决物理限制如何导致细胞中复杂的空间组织的问题。它专注于开发数据驱动的模型，这些模型源于与实验生物学家的密切合作。细胞生物学中的一个重要物理过程是将DNA包装到小体积的细胞中。DNA是精心安排的；它的结构影响着细胞的许多功能。我有两项研究工作可以及时解决这一过程中尚未得到解答的问题。*我们与图卢兹国家研究中心的染色质生物学家奥利维尔·库维尔合作，致力于开发一种预测性机制模型，研究DNA在细胞中的结构如何调节可以读出的遗传信息。在真核细胞中，DNA被包装成一种称为染色质的结构。由于与DNA结合的蛋白质之间的相互作用，它是一个高度环状的结构。环路的适当形成决定了基因是否被激活。通过分析Cuvier实验室的数据，我的团队能够发现被称为绝缘体的蛋白质之间相互作用的复杂网络，这些蛋白质调控DNA循环和基因表达。使用最近开发的实验技术，库维尔实验室将绘制出基因组的哪些部分在物理上相互接触，以及绝缘体网络的突变如何改变图谱。我的团队将把这些数据与统计物理模型相匹配，以确定特定的接触能，从而开发出一个基于聚合物的模型，用于研究绝缘体如何调节染色质结构。通过更好地了解循环过程中涉及的机械过程，我们希望能够预测基因将在何时何地表达。*我们的第二项努力专注于揭示简单的物理机制，自然利用这些机制在最微小的细胞--即细菌--中组织其分子部分。我们已经证明，基因组DNA聚合物的熵可以将蛋白质聚集体定位到极点。在一些细菌中，极性定位的蛋白质与分离复制DNA的机制相互作用，并帮助分离复制DNA。这种分离机制也是动态图案化的，最近的体外测量对其机制有了一些洞察。然而，在重要的复制过程中，这两个相互作用的系统是如何牢固地塑造细胞的还没有被很好地理解。通过对耦合系统进行建模，我们希望能够揭示这些生物分子机器的设计原理。*刚才描述的研究计划将为学员提供多样化的技能集。过去的学员都在从事计算生物学方面的工作，从学术界到工业研究领域。在加拿大日益增长的生物技术领域，这类研究人员的需求很高。**