Collaborative Research: Interphase Chromatin as a Complex Active Fluid: Experiments and Microscopic to Mesoscopic Modeling

几乎每个人类细胞都含有一个3米长的遗传物质（DNA）的副本，这使我们与众不同。大约20年前，这些巨大DNA分子的基因序列被破译，这是一项了不起的成就。尽管知道了序列，但仍不清楚这些巨大的分子是如何以一种有用的遗传信息的方式被包装到细胞核（直径约为6微米的球体）中的。了解DNA中的信息是如何被细胞利用的，是现代医学进步和促进健康的基础。在细胞生长的一个阶段，细胞核的分子以一种未凝聚的聚合形式填充细胞，这种形式由于自然的热搅动而迅速移动。分子的运动尚不完全清楚，特别是由于分子的许多部分在原子核内紧密堆积而引起的相干运动。本研究的目的是利用实验、模拟和建模的强大组合来确定这种动态自组织的机制。通过提供相干运动起源的微观描述，提出的研究将改变我们对细胞核力学生物学的理解。该项目还将为研究生和本科生提供新的教育机会，他们将接受先进成像技术和分析、细胞生物学、聚合物动力学、流体力学以及数学和计算建模方面的培训。该合作项目将结合高分辨率活细胞成像实验与理论和计算模型，探索和阐明间期染色质动力学的微观起源及其对DNA时空自组织的影响。为了建立实验和模型之间的紧密联系，我们将在几种具有不同染色质空间分布的细胞系中进行实验。这些实验将在大范围的长度和时间尺度上提供相关运动的精确测量，并将用于破译染色质组织的内部活动力的贡献。此外，这些实验将指导基于粗粒度描述的染色质的理论和计算模型，这些描述将染色质作为一个受约束的流体动力学相互作用的柔性聚合物链，由代表活性酶的随机力偶极子驱动。我们将检验这一假设，即染色质动力学主要是通过流体动力学相互作用的内部活动的结果，并使用实验和模型之间的定量比较来阐明导致相干运动的活动事件的对称性、频率和强度。这些知识对于理解细胞核间期染色质动力学的生理学是至关重要的。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Almost every human cell contains a copy of the 3-meters of genetic material (DNA) that makes us unique. In an amazing achievement, the genetic sequence of these enormous DNA molecules was decoded about twenty years ago. Despite knowing the sequence, it remains unclear how these enormous molecules are packed into a cell nucleus (approximately a six micrometer diameter sphere) in a way that the genetic information can be useful. Understanding how the information in DNA is made available for use by the cell is fundamental for advances in modern medicine and to advancing health. During one phase in the growth of cells, the molecules of the nucleus fill it in an uncondensed polymeric form that rapidly moves because of natural thermal agitation. The molecular motion is not fully understood, especially the coherent motions caused by the close packing in the nucleus where many parts of the molecules move together. The goal of this research is to determine the mechanisms of this dynamic self-organization using a powerful combination of experiments, simulations and modeling. By providing a microscopic description for the origin of coherent motions, the proposed research will transform our understanding of the mechanobiology of the nucleus. This project also will provide novel educational opportunities for graduate and undergraduate students, who will receive training in advanced imaging techniques and analysis, cellular biology, polymer dynamics, fluid mechanics, as well as mathematical and computational modeling. This collaborative project will combine high-resolution live cell imaging experiments with theoretical and computational models to probe and illuminate the microscopic origins of interphase chromatin dynamics and its effect on the spatiotemporal self-organization of DNA. To develop a close connection between experiments and models, we will perform experiments in several cell lines with different spatial distributions of chromatin. These experiments will provide exquisite measurements of correlated motions over a wide range of length and time scales, and will be used to decipher the contributions of internal active forces on chromatin organization. Moreover, these experiments will guide theoretical and computational models based on coarse-grained descriptions of the chromatin as a confined and hydrodynamically interacting flexible polymer chain driven internally by stochastic force dipoles representing active enzymes. We will test the hypothesis that chromatin dynamics is primarily the consequence of internal activity via hydrodynamic interactions, and use quantitative comparisons between experiments and models to elucidate the symmetries, frequencies, and intensities of active events responsible for coherent motion. Such knowledge is critical for understanding the physiology of the interphase chromatin dynamics in the cell nucleus.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.