Chromatin Structure and Dynamics from Nanometer to Micrometer Length Scales

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，多达一米长的DNA可以被包装成一个只有一微米的致密聚集体。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。染色质呈现出真正的层次结构，其中最小长度尺度的修饰会影响更长距离的结构和动力学。重要的是，对潜在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。该项目将由首席研究员和研究生共同进行。除了接受项目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，并参加旨在向当地社区提供染色质在我们日常生活中所起作用的了解的项目。因此，这项工作将为年轻学生提供一个参与未来科学事业的机会。这项工作有望回答有关从小尺度分子相互作用中出现大规模生物行为的重要生物物理学问题。提出的染色质综合模型将把一维一级结构和动力学与三维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，涉及多个长度尺度，它将结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配置之间的自由能差。该模型开发的指导原则将是获得跨越长度和时间尺度范围的能力，这是理解染色质结构和动力学所必需的。预计，当完成时，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获得的关于遗传机制如何被外部挑战改变的见解。该项目的一个重要方面将是研究组蛋白和DNA修饰（如乙酰化）在高阶染色质结构上的作用。更一般地说，这个项目设想的三维分子模型将是同类中的第一个，并将成为研究细胞DNA的重要工具。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。

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.