CAREER: Physics of Chromatin: Micromechanics of Active Chromatin Dynamics in Interphase

职业：染色质物理学：间期活性染色质动力学的微观力学

基本信息

批准号：
1554880
负责人：
Alexandra Zidovska
金额：
$ 80万
依托单位：
New York University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1554880&HistoricalAwards=false
关键词：
CAREER Physics Chromatin Micromechanics Active

项目摘要

The DNA molecule in our cells is wrapped in a structure known as chromatin. Understanding how chromatin changes in time presents a fundamental question and is currently a frontier in both polymer physics as well as cell biology. To a physicist, chromatin is an exquisite example of a confined polymer that is subject to the basic laws of physics. To a biologist, chromatin controls gene expression, and physically packages DNA in a way that facilitates its replication and segregation. This project will lead to a mechanistic picture of active chromatin dynamics in live cells by integrating quantitative experimental approaches and theory from different areas of physics. As a part of this research program, the PI will develop a science outreach component targeting high school girls from underrepresented groups. In addition, this research program will provide training opportunities for undergraduate and graduate students, who will be trained in advanced optical microscopy techniques, small angle X-ray scattering, image processing, data analysis and polymer physics and statistical mechanics approaches pertinent to active systems far from equilibrium.The sequence of the human genome has been known for two decades, but its dynamic organization in three dimensions remains elusive. Methods like fluorescence in situ hybridization (FISH) or chromosome conformation capture (HiC) provided insights into how the chromatin is organized inside the cell nucleus. Methods like chromatin immunoprecipitation combined with sequencing (ChIP-Seq) helped us to map specific molecular players to the specific genomic loci within the context of specifics functions, usually transcriptional regulation. While FISH and HiC methods give us a 3D picture of the genome organization, it is a static picture, i.e. a snapshot of the human genome in a given time; they do not inform on the dynamic reorganization of the genome inside the nucleus. Similarly, Chip-Seq provides us with a snapshot of detailed 1D localization information of proteins of interest. The missing link in our current understanding is the connection between the 1D genomic information and the 3D topology of the cell nucleus in real time. The overall goal of this research program is to generate this missing link, i.e. to develop a real-time imaging of spatiotemporal dynamics of the human genome and understand the underlying physical laws. This research focuses on elucidating physics underlying nonequilibrium soft matter. Specifically, it presents development of an experimental and intellectual framework for understanding the dynamic behavior of chromatin in live cells. Chromatin presents an active polymer living in a confinement of the cell nucleus that is very different from the soft matter traditionally studied. It undergoes dynamic rearrangements, dissipates energy and exhibits self-organization far from thermodynamic equilibrium. Understanding of the mechanism/s beyond the active dynamics and elucidating the physical laws that such dynamics follows, will teach us new physics and its role in nuclear physiology.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Cluster in the Division of Molecular and Cellular Biosciences.

我们的细胞中的DNA分子被包裹在称为染色质的结构中。了解染色质在时间上的变化如何提出一个基本问题，目前是聚合物物理和细胞生物学的前沿。对于物理学家来说，染色质是受到基本物理定律的约束聚合物的精致例子。对于生物学家，染色质控制基因表达，并以促进其复制和隔离的方式对DNA进行物理包装。该项目将通过整合来自不同物理领域的定量实验方法和理论，从而导致活细胞中活性染色质动力学的机械图。作为该研究计划的一部分，PI将开发科学外展成分，以来自代表性不足的群体的高中女生。此外，该研究计划将为本科生和研究生提供培训机会，他们将接受高级光学显微镜技术，小角度X射线散射，图像处理，数据分析和聚合物物理学以及与活性系统相关的远离平衡的活性系统的方法。诸如荧光原位杂交（FISH）或染色体构象捕获（HIC）之类的方法为您提供了有关染色质在细胞核内如何组织的见解。诸如染色质免疫沉淀与测序（CHIP-SEQ）相结合的方法有助于我们将特定的分子参与者映射到特定的基因组基因局基因局基因局基因局基因局，通常是转录调节。尽管鱼类和HIC方法为我们提供了基因组组织的3D图片，但它是静态图片，即在给定时间内的人类基因组的快照。他们没有告知原子核内基因组的动态重组。同样，Chip-Seq为我们提供了有关感兴趣蛋白质的详细一维本地化信息的快照。我们当前理解中缺少的联系是实时的一维基因组信息与细胞核的3D拓扑之间的联系。该研究计划的总体目标是生成这种缺失的链接，即开发人类基因组时空动态的实时成像并了解潜在的物理定律。这项研究的重点是阐明非平衡软物质的物理学。具体而言，它提出了一个实验和智力框架的开发，以理解活细胞中染色质的动态行为。染色质表现出一种活性聚合物，生活在细胞核的限制中，与传统研究的软物质大不相同。它进行动态重排，消散能量并表现出远离热力学平衡的自组织。了解超出主动动力学的机制，并阐明这种动态所遵循的物理定律，将教给我们新的物理学及其在核生理学中的作用。该项目由生命系统计划在物理学和细胞群中共同支持分子和细胞生物科学的分工。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Symmetry-based classification of forces driving chromatin dynamics

基于对称性的染色质动力学驱动力分类

DOI：
10.1039/d2sm00840h
发表时间：
2022
期刊：
Soft Matter
影响因子：
3.4
作者：
Eshghi, Iraj;Zidovska, Alexandra;Grosberg, Alexander Y.
通讯作者：
Grosberg, Alexander Y.

Structural and Dynamical Signatures of Local DNA Damage in Live Cells

DOI：
10.1016/j.bpj.2019.10.042
发表时间：
2020-05-05
期刊：
BIOPHYSICAL JOURNAL
影响因子：
3.4
作者：
Eaton, Jonah A.;Zidovska, Alexandra
通讯作者：
Zidovska, Alexandra

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.

Mechanical stress affects dynamics and rheology of the human genome

机械应力影响人类基因组的动力学和流变学