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Chromatin Structure and Dynamics from Nanometer to Micrometer Length Scales

从纳米到微米长度尺度的染色质结构和动力学

基本信息

批准号：
1818328
负责人：
Juan De Pablo
金额：
$ 37.42万
依托单位：
University of Chicago
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：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1818328&HistoricalAwards=false
关键词：
Chromatin Structure Dynamics Nanometer Micrometer

项目摘要

The central aim of this project is to develop computational models capable of describing the structure, dynamics and ultimately the function of DNA in the cell nucleus. In the cell, as much as a meter of DNA can be packaged into a dense aggregate that measures only a micrometer. This aggregate consists of a DNA protein complex that is referred to as chromatin, and its structure is central to gene regulation. Chromatin exhibits a truly hierarchical structure, in which modifications at the smallest length scales influence structure and dynamics over much longer distances. Importantly, deregulation, or "misreading," of the underlying DNA has been implicated in numerous diseases, including cancer. Despite the inherent function of chromatin, its structure in the cell nucleus largely remains a mystery. This work will seek to resolve that structure, and potentially shed light on the origin and spread of various genetic disorders. The project will be carried out by the principal investigator and graduate students. In addition to receiving advanced training on the modeling and research aspects of the project, these students will receive communications training and will participate in programs conceived to provide local communities with an understanding of the role chromatin plays in our daily life. As such, this work will offer an opportunity to engage young students in future scientific careers.This work promises to answer important biophysical questions regarding the emergence of large scale biological behavior from small scale molecular interactions. The proposed comprehensive model of chromatin will link one-dimensional primary structure and dynamics to three-dimensional secondary and tertiary structure and motion. It will rely on existing experimental data pertaining to multiple length scales, and it will couple top-down and bottom-up modeling design approaches. To do so, a strategy will be adopted in which advanced sampling techniques are used to extract free energy differences between different experimentally-proposed chromatin configurations. A guiding principle in the development of the model will be to gain the ability to span the range of length and time scales that are necessary to understand chromatin structure and dynamics. It is anticipated that, when completed, the proposed model will yield an unprecedented view of the genome and lead to hitherto unavailable insights into how genetic mechanisms are altered by external challenges. An important aspect of the project will be to examine the role of histone and DNA modifications, such as acetylations, on higher-order chromatin structures. More generally, the three-dimensional, molecular models envisaged in this project will be the first of their kind, and will become an important tool for studies of cellular DNA.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.

该项目的中心目标是开发能够描述细胞核中DNA的结构、动力学和最终功能的计算模型。在细胞中，多达一米的DNA可以被包装成一个只有一微米大小的致密聚集体。这种聚集体由称为染色质的DNA蛋白质复合物组成，其结构对基因调控至关重要。染色质具有真正的层次结构，其中最小长度尺度的修饰影响更长距离的结构和动力学。重要的是，潜在DNA的失调或“误读”与包括癌症在内的许多疾病有关。尽管染色质具有固有的功能，但它在细胞核中的结构在很大程度上仍然是一个谜。这项工作将寻求解决这种结构，并可能揭示各种遗传疾病的起源和传播。该项目将由首席研究员和研究生进行。除了接受关于该项目的建模和研究方面的高级培训外，这些学生还将接受通信培训，并将参加旨在为当地社区提供染色质在我们日常生活中所起作用的理解的计划。因此，这项工作将提供一个机会，让年轻的学生在未来的科学生涯。这项工作有望回答重要的生物物理学问题的出现，从小规模的分子相互作用的大规模生物行为。所提出的染色质综合模型将把一维的一级结构和动力学与三维的二级和三级结构和运动联系起来。它将依赖于现有的实验数据有关的多个长度尺度，它将耦合自上而下和自下而上的建模设计方法。为此，将采用一种策略，其中使用先进的采样技术来提取不同实验提出的染色质构型之间的自由能差异。模型开发的指导原则是获得跨越理解染色质结构和动力学所需的长度和时间尺度范围的能力。预计完成后，所提出的模型将产生前所未有的基因组视图，并导致迄今为止无法深入了解遗传机制如何被外部挑战改变。该项目的一个重要方面将是研究组蛋白和DNA修饰的作用，如乙酰化，对高阶染色质结构。更广泛地说，该项目中设想的三维分子模型将是同类项目中的第一个，并将成为细胞DNA研究的重要工具。该奖项反映了NSF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。