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

基本信息

批准号：
2153432
负责人：
Alexandra Zidovska
金额：
$ 69.42万
依托单位：
New York University
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=2153432&HistoricalAwards=false
关键词：
Collaborative Research DMS NIGMS2 Discovering

项目摘要

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，并驻留在细胞核内。染色质结构、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的规则已广为人知，但控制 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。在细胞分化过程中，即干细胞变得特化的过程中，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处理，例如基因表达。然而，在分化时，特化细胞功能不需要的 DNA 部分会被浓缩，而细胞主动使用的 DNA 部分仍然可以访问，从而使细胞的分子机制能够获取相关的遗传信息。了解引起分化基因组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，但由于这一过程涉及的长度和时间尺度范围非常广泛，因此受到限制。这项研究的目标是通过将最先进的活细胞实验与细胞核内染色质的一套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颖的教育机会，他们将接受先进成像技术和分析、细胞生物学、聚合物动力学、流体力学以及数学和计算建模方面的培训。该合作项目将结合高分辨率利用数学和计算模型进行活细胞成像实验，以阐明染色质动力学和分化细胞核重组的物理原理。为了表征分化过程中基因组组织发生的变化，将在分化前后的活细胞中进行实验。这些实验将指导异质环境中染色质动力学的新型粗粒度计算模型的开发，以及能够捕获该问题中广泛的时间和长度尺度的第一原理连续统理论的开发。实验和数学建模工作将与发现控制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价值和更广泛的影响进行评估，被认为值得支持审查标准。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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：
2022-12
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.

Activity-Driven Phase Transition Causes Coherent Flows of Chromatin

活动驱动的相变导致染色质的相干流动