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

合作研究：间期染色质作为复杂的活性流体：实验和微观到介观建模

基本信息

批准号：
1762506
负责人：
Alexandra Zidovska
金额：
$ 39.89万
依托单位：
New York University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1762506&HistoricalAwards=false
关键词：
Collaborative Research Interphase Chromatin Complex

项目摘要

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.

几乎每个人类细胞都包含3米遗传物质（DNA）的副本，这使我们与众不同。在一个惊人的成就中，这些巨大的DNA分子的遗传序列被解码了大约二十年前。尽管知道了序列，但仍不清楚这些巨大的分子如何将遗传信息有用的方式包装到细胞核中（大约是六微米的球体）。了解细胞中DNA中的信息是如何使用的，这对于现代医学的进步和提高健康是基本的。在细胞生长的一个阶段，细胞核的分子以无合心的聚合物形式填充，该形式由于天然的热搅动而迅速移动。分子运动尚未完全理解，尤其是由于分子许多部分一起移动的细胞核中的紧密堆积而引起的相干运动。这项研究的目的是使用实验，仿真和建模的强大组合来确定这种动态自组织的机制。通过为相干运动的起源提供微观描述，提出的研究将改变我们对细胞核机械生物学的理解。该项目还将为研究生和本科生提供新的教育机会，他们将接受高级成像技术和分析，细胞生物学，聚合物动力学，流体力学以及数学和计算建模的培训。这个协作项目将将高分辨率的活细胞成像实验与理论和计算模型相结合，以探测和阐明相间染色质动力学的显微镜起源及其对DNA时空自我组织的影响。为了在实验和模型之间建立密切的联系，我们将在具有不同空间分布的染色质分布的几个细胞系中执行实验。这些实验将在各个长度和时间尺度上提供精美的相关运动测量，并将用于破译内部活性力对染色质组织的贡献。此外，这些实验将基于对染色质的粗粒描述作为理论和计算模型，作为由代表活性酶的随机力偶极子内部驱动的密闭和流体动力相互作用的柔性聚合物链。我们将检验以下假设：染色质动力学主要是通过流体动力相互作用进行内部活动的结果，并使用实验和模型之间的定量比较来阐明负责连贯运动的活动活动的对称性，频率和强度。这种知识对于理解细胞核中相间染色质动力学的生理学至关重要。该奖项反映了NSF的法定任务，并且使用基金会的知识分子优点和更广泛的影响审查标准，被认为值得通过评估来获得支持。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Symmetry-based classification of forces driving chromatin dynamics

基于对称性的染色质动力学驱动力分类

DOI：
10.1039/d2sm00840h
发表时间：
2022
期刊：
Soft Matter
影响因子：
3.4
作者：
Eshghi, Iraj;Zidovska, Alexandra;Grosberg, Alexander Y.
通讯作者：
Grosberg, Alexander Y.

Structural and Dynamical Signatures of Local DNA Damage in Live Cells

DOI：
10.1016/j.bpj.2019.10.042
发表时间：
2020-05-05
期刊：
BIOPHYSICAL JOURNAL
影响因子：
3.4
作者：
Eaton, Jonah A.;Zidovska, Alexandra
通讯作者：
Zidovska, Alexandra

Mechanical stress affects dynamics and rheology of the human genome

机械应力影响人类基因组的动力学和流变学

DOI：
10.1039/d1sm00983d
发表时间：
2021
期刊：
Soft Matter
影响因子：
3.4
作者：
Caragine, Christina M.;Kanellakopoulos, Nikitas;Zidovska, Alexandra
通讯作者：
Zidovska, Alexandra

Euchromatin Activity Enhances Segregation and Compaction of Heterochromatin in the Cell Nucleus

常染色质活性增强细胞核中异染色质的分离和压缩

DOI：
10.1103/physrevx.12.041033
发表时间：
2022
期刊：
Physical Review X
影响因子：
12.5
作者：
Mahajan, Achal;Yan, Wen;Zidovska, Alexandra;Saintillan, David;Shelley, Michael J.
通讯作者：
Shelley, Michael J.

Model chromatin flows: numerical analysis of linear and nonlinear hydrodynamics inside a sphere