Collaborative Research: DMS/NIGMS2: Discovering the Principles of Active Self-Organization in the Differentiating Genome Using Multi-Scale Modeling and In-Vivo Experiments

在细胞内，DNA以染色质的功能形式存在，并驻留在细胞核内。染色质的结构、组织和动力学控制着DNA生物学的各个方面。虽然DNA的化学结构和基因编码规则已经很好地理解了，但管理DNA在细胞核内堆积的物理原理仍然是一个悬而未决的问题。在干细胞特化的细胞分化过程中，染色质经历了复杂的重排：在干细胞中，DNA的所有部分都可以进行基因表达等处理。然而，在分化时，专门化细胞功能所不需要的DNA部分被浓缩，而细胞活跃使用的DNA部分仍然可用，使细胞的分子机制能够到达相关的遗传信息。了解导致这种分化基因组重组的物理机制对现代生物学和人类医学的许多进展至关重要，但由于这一过程涉及的长度和时间尺度非常广泛，因此一直受到限制。这项研究的目标是通过将最先进的活细胞实验与一套关于细胞核内染色质的多尺度数学和计算模型相结合来揭示这些复杂的机制。这个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模型的培训。这个合作项目将结合高分辨率的活细胞成像实验和数学和计算模型，阐明染色质动力学和分化细胞核重组背后的物理原理。为了表征分化过程中基因组组织的变化，将在分化前后的活细胞中进行实验。这些实验将指导发展一种新的粗粒度计算模型，用于研究不同环境中的染色质动力学，以及能够捕捉这个问题中广泛的时间和长度尺度的第一原理连续统理论。实验和数学建模工作将与发现支配分化基因组重组的基本物理原理的总体目标紧密结合。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Inside cells, the DNA exists in the functional form known as chromatin and resides inside the cell nucleus. Chromatin structure, organization and dynamics control all aspects of DNA biology. While the chemical structure of DNA and the rules by which genes are encoded are well understood, the physical principles governing the packing of DNA inside the cell nucleus remain an open question. During cell differentiation, the process by which stem cells become specialized, chromatin undergoes a complex rearrangement: In stem cells, all parts of DNA are accessible for processing such as gene expression. However, upon differentiation parts of the DNA that are not needed for the function of the specialized cell are condensed, whereas DNA parts actively used by the cell remain accessible, enabling the molecular machinery of the cell to reach the relevant genetic information. Understanding physical mechanisms that give rise to this reorganization of the differentiating genome is critical for many advances in modern biology and human medicine, but has been limited due to the very wide range of length and time scales involved in this process. The goal of this research is to uncover these complex mechanisms by integrating state-of-the-art live cell experiments with a suite of multiscale mathematical and computational models of the chromatin inside the nucleus. This project will also provide novel educational opportunities for graduate and undergraduate students, who will receive training in advanced imaging techniques and analysis, cell biology, polymer dynamics, fluid mechanics, as well as mathematical and computational modeling.This collaborative project will combine high-resolution live cell imaging experiments with mathematical and computational models to elucidate physical principles underlying chromatin dynamics and reorganization in the differentiating cell nucleus. In order to characterize the changes in genomic organization occurring during differentiation, experiments will be performed in live cells before and after differentiation. These experiments will guide the development of a novel coarse-grained computational model for chromatin dynamics in heterogeneous environments and of first-principles continuum theories capable of capturing the wide range of time and length scales in this problem. Experiments and mathematical modeling efforts will be closely integrated with the overarching goal of discovering the fundamental physical principles governing the reorganization of the differentiating genome.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.