Role of chromosome in organizing space and time inside cells

最大的生物分子，基因组DNA，折叠成一种结构，其物理特性组织细胞内的空间和时间。我的跨学科研究计划应用统计物理学的方法来揭示影响DNA结构的约束以及该结构如何影响功能。我们将从三个方向进行研究。1)在细胞内，DNA折叠成染色质，染色质由DNA结合蛋白质“因子”的相互作用形成，有助于环的形成。这种循环还会影响因素的绑定位置，从而产生反馈。染色质折叠问题的这一独特方面不存在于其他生物分子如RNA和蛋白质的折叠中，其中相互作用仅由序列固定。目前旨在解决染色质折叠问题的方法缺乏这种自洽性。我们将开发一个模型，可以自洽地预测DNA结构和结合因子的分布。我们的模型将由我们的合作者Olivier Cuvier（CNRS）进行实验测试，他的实验室研究染色质调控。2)依赖于DNA折叠的一个关键细胞过程是转录。它由称为转录因子（TF）的蛋白质调节，这些转录因子结合称为增强子的序列，增强子调节RNA聚合酶的结合，从而读出基因。最近的实验可以在全基因组范围内测量增强子的功能，为破译TF的调控逻辑提供了前所未有的数据。目前分析这些数据的方法都是基于深度学习，无法提供清晰的机制洞察力。使用贝叶斯方法，我们将推断增强子功能的预测生物物理模型，可以提供有关TF，RNA聚合酶和结构之间的相互作用的信息。Nathan Lack的实验室（温哥华前列腺中心）已经测量了一个大型的参与激素信号传导的增强子库，我们将使用我们的方法来揭示这一途径的调控逻辑。在更广泛的层面上，我们希望我们在折叠和转录方面的工作能够突出染色质建模的必要性以及以自洽的方式依赖于它的过程。3)最后，DNA聚合物可以驱动细胞中的空间组织。在某些细菌中，遗传物质的分离是一个由双蛋白质系统控制的主动过程，该系统被认为利用DNA的熵弹性来驱动运动。其效率尚未在实验或模拟中表征。最近的实验工作也提出了DNA的熵力是否足以分离整个染色体的问题。我们将为这个双蛋白质系统开发一个机械化学模型，以探索这些重要的未回答的问题。我们在南希福尔德组（SFU）的合作者将根据类似的原理合成体外分子马达系统，我们希望我们的模型将有助于阐明体内和体外驱动运动的操作原理。

The largest biomolecule, genomic DNA, folds into a structure whose physical properties organize both space and time within a cell. My interdisciplinary research program applies methods from statistical physics to uncover the constraints that influence DNA structure and how that structure impacts function. We will pursue three directions of research. 1) Within a cell, DNA folds into chromatin that is shaped by the interactions of DNA-bound protein "factors" that aid loop formation. This looping also influences where factors bind, creating feedback. This unique aspect of the chromatin-folding problem is not present in the folding of other biomolecules like RNA and proteins where the interactions are fixed by the sequence alone. Current methods that aim to solve the chromatin-folding problem lack this self-consistency. We will develop a model that can self-consistently predict both DNA structure and the distribution of bound factors. Our models will be tested experimentally by our collaborator, Olivier Cuvier (CNRS) whose lab studies chromatin regulation. 2) A key cellular process that depends on the folding of DNA is transcription. It is regulated by proteins known as transcription factors (TFs) that bind sequences known as enhancers, which regulate the binding of RNA-polymerase that reads out genes. Recent experiments can measure the function of enhancers on a genome-wide scale, providing unprecedented data to decipher the regulatory logic of TFs. Current methods of analyzing this data are based on deep-learning, which does not provide clear mechanistic insight. Using Bayesian methods, we will infer a predictive biophysical model of enhancer function that can provide information about the interactions among TFs, RNA-polymerase and structure. Nathan Lack's Lab (Vancouver Prostate Centre) has measured a large library of enhancers involved in hormone signaling, and we will use our method to reveal the regulatory logic of this pathway. At a broader level, we expect our work on folding and transcription to highlight the necessity of modeling chromatin and the processes that depend on it in a self-consistent way. 3) Lastly, the DNA polymer can drive spatial organization in a cell. The segregation of genetic material in some bacteria is an active process governed by a two-protein system that is thought to exploit the entropic elasticity of DNA to drive motion. Its efficiency has yet to be characterized in either experiment or simulation. Recent experimental work has also called into question whether the entropic force of DNA is sufficient to segregate whole chromosomes. We will develop a mechano-chemical model for this two-protein system to explore these important unanswered questions. Our collaborators in the Nancy Forde group (SFU) will then synthesize in vitro molecular-motor systems based on similar principles, and we expect our models will help elucidate the operational principles that drive motion, both in vivo and in vitro.