Statistical physics models for the regulation of the structure of chromatin

我的研究项目应用计算物理学的方法来解决物理约束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，这些模型来自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DNA包装到细胞的小体积中。DNA是精心排列的，其结构影响着细胞的许多功能。 我有两项研究工作，及时解决这个过程中未回答的问题。 我们与CNRS图卢兹的染色质生物学家Olivier Cuvier合作，正在开发一种预测机制模型，用于研究细胞中DNA的结构如何调节可以读取的遗传信息。在真核细胞中，DNA被包装成一种称为染色质的结构。它是一种高度环状的结构，这是由于与DNA结合的蛋白质之间的相互作用。环的适当形成决定了基因是否被打开。通过分析居维叶实验室的数据，我的团队能够发现一个复杂的蛋白质之间的相互作用网络，这些蛋白质被称为绝缘体，它们调节DNA循环和基因表达。利用最近开发的实验技术，居维叶实验室将绘制出基因组的哪些部分是物理接触的，以及绝缘体网络的突变如何改变地图。我的团队将把这些数据拟合到统计物理模型中，以确定特定的接触能，从而开发出一种基于聚合物的模型，用于研究绝缘体如何调节染色质结构。通过更好地理解循环中涉及的机械过程，我们希望能够预测基因何时何地表达。 我们的第二个努力是专注于揭示简单的物理机制，大自然使用这些机制来组织最微小的细胞（即细菌）中的分子部分。我们已经表明，基因组DNA的聚合物的熵可以驱动蛋白质聚集体定位到极点。在一些细菌中，极性定位蛋白质与分离复制DNA的机制相互作用并帮助其分离。这种分离机制也是动态模式化的，最近的体外测量对其机制有了一些了解。然而，这两个相互作用的系统如何在重要的复制过程中稳健地图案化细胞还没有很好地理解。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。 刚刚描述的研究计划将为学员提供多样化的技能。过去的受训人员从事计算生物学的职业，从学术界到工业研究环境。这些研究人员在加拿大不断增长的生物技术领域需求量很大。

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.