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.

该项目的核心目的是开发能够描述DNA在细胞核中的结构，动力学以及最终功能的计算模型。在细胞中，只有一米的DNA可以包装到仅测量千分尺的致密骨料中。该聚集体由称为染色质的DNA蛋白复合物组成，其结构对于基因调节至关重要。染色质表现出真正的分层结构，其中最小长度尺度的修改会影响更长的距离的结构和动力学。重要的是，基础DNA的放松管制或“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，但其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，并有可能阐明各种遗传疾病的起源和传播。该项目将由主要研究人员和研究生进行。除了接受有关项目的建模和研究方面的高级培训外，这些学生还将接受沟通培训，并将参加构想的计划，以使当地社区了解染色质在我们的日常生活中的作用。因此，这项工作将提供一个机会，使年轻学生从事未来的科学职业。这项工作有望回答有关小型分子相互作用大规模生物学行为的重要生物物理问题。提出的染色质的综合模型将将一维主要结构和动力学联系到三维二级和三级结构和运动。它将依赖于与多个长度尺度有关的现有实验数据，并且将融入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性染色质构型之间的自由能差。模型开发的指导原理将是获得跨越理解染色质结构和动态所必需的长度和时间尺度范围的能力。预计，完成后，提出的模型将产生前所未有的基因组观点，并导致迄今为止对遗传机制如何因外部挑战的改变而无法实现的见解。该项目的一个重要方面是检查组蛋白和DNA修饰（例如乙酰化）对高阶染色质结构的作用。更一般而言，该项目中设想的三维分子模型将是其中的第一个模型，并将成为研究细胞DNA的重要工具。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的智力优点和更广泛的影响审查标准通过评估来进行评估的。