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

合作研究：DMS/NIGMS2：利用多尺度建模和体内实验发现分化基因组中主动自组织的原理

• 批准号: 2153520
• 负责人: David Saintillan
• 金额: $ 50.58万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2153520&HistoricalAwards=false
• 关键词: Collaborative; Research; DMS; NIGMS2; Discovering

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.

在细胞内部，DNA以称为染色质的功能形式存在，并存在于细胞核内。染色质结构，组织和动力学控制DNA生物学的各个方面。虽然对DNA的化学结构和基因编码的规则有充分的理解，但控制DNA在细胞核内的物理原理仍然是一个悬而未决的问题。在细胞分化过程中，干细胞变得专门的过程，染色质经历复杂的重排：在干细胞中，DNA的所有部分都可以用于处理基因表达等处理。然而，在DNA的分化部分中，专门细胞功能不需要的DNA部分被凝结，而细胞积极使用的DNA部分仍然可以访问，从而使细胞的分子机械能够达到相关的遗传信息。了解引起分化基因组的重组的物理机制对于现代生物学和人类医学的许多进步至关重要，但是由于此过程中涉及的长度和时间尺度非常广泛，因此受到限制。这项研究的目的是通过将最先进的活细胞实验与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。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，流体机制以及数学和计算建模的培训。该协作项目将结合高分辨率实时成像模型与数学和计算模型，以隔离核心构建核对核心的隔离组合，并将其分化为综合构图。为了表征分化过程中发生的基因组组织的变化，将在分化前后在活细胞中进行实验。这些实验将指导在异质环境中的染色质动力学和第一原理连续理论的新型粗粒计算模型的开发。实验和数学建模工作将与总体目标紧密融合，即在划分区分基因组的重新组织的基本物理原理上，这奖反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的评估审查审查标准来通过评估来通过评估来获得支持的。

项目成果

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.