Investigating Phase Separations as a Mechanism of Genome Compartmentalization Through In-vivo Experiments

通过体内实验研究相分离作为基因组区室化的机制

基本信息

批准号：
2210541
负责人：
Alexandra Zidovska
金额：
$ 90万
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：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2210541&HistoricalAwards=false
关键词：
Investigating Phase Separations Mechanism Genome

项目摘要

The human genome consists of two meters of DNA stored inside the cell nucleus barely 10 micrometers in diameter. The DNA molecule is packed in a structure known as chromatin, whose organization inside the cell nucleus directly affects the genome’s function, which in turn is critical for the proper function of the cell. Hence, elucidating the principles underlying chromatin organization is fundamental to understanding the genome in health and disease, as well as designing new active and smart materials. Yet, the physical principles behind the genome’s organization remain elusive. The goal of this project is to generate a mechanistic picture of chromatin organization inside live human cells by combining quantitative experimental approaches and theory from relevant areas of physics. As a part of this project, the PI will develop educational and outreach components with focus on recruitment and retention of women in physics across different education and career stages. This project will also provide novel educational and training opportunities for undergraduate and graduate students, who will receive training in advanced optical microscopy techniques, small angle X-ray scattering, image processing, and data analysis as well as polymer physics, biophysics, and statistical mechanics. The structure, organization and dynamics of chromatin inside the cell nucleus control all aspects of DNA biology. Chromatin fiber is hierarchically folded with increasing length scale into loops, topologically associated domains, A and B compartments (transcriptionally active and inactive genomic parts) and finally chromosome territories. Moreover, chromatin is heterogeneously distributed across the nucleus into two types of compartments: euchromatin, less dense and predominantly transcriptionally active regions, and heterochromatin, denser regions containing mainly silenced genes. Despite this detailed picture of the genome organization, its underlying physical principles remain unknown. Moreover, the genome is immersed in a solvent, the nucleoplasm, which was shown to organize itself, by undergoing liquid-liquid phase separations, and forming functional liquid condensates. How to reconcile the genomic and nucleoplasmic spatial organization remains an open question. The overall goal of this project is to reveal the physical principles behind the genome’s organization using state-of-the-art in-vivo experimental approaches and data analytics, which will directly inform development of new models and theories. By combining the latest quantitative techniques from polymer physics, soft condensed matter physics, biophysics and cell biology, this project will investigate the mechanism/s behind the genome compartmentalization and elucidate the physical laws underlying such organization. These measurements will provide fundamental insights into phase separation as the guiding physical principle for compartmentalization of the 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.

人类基因组由储存在直径仅 10 微米的细胞核内的两米长 DNA 组成，DNA 分子包装在一种称为染色质的结构中，染色质在细胞核内的组织直接影响基因组的功能，而这对于基因组的功能至关重要。因此，阐明染色质组织的基本原理对于了解健康和疾病中的基因组以及设计新的活性和智能材料至关重要。然而，基因组组织背后的物理原理仍然存在。该项目的目标是通过结合物理学相关领域的定量实验方法和理论来生成活体人类细胞内染色质组织的机制图作为该项目的一部分，PI 将重点开发教育和推广部分。该项目还将为本科生和研究生提供新颖的教育和培训机会，让他们接受先进光学显微镜技术、小角度 X 射线散射、图像处理方面的培训。，以及数据分析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，如聚合物物理学、生物物理学和统计力学。此外，染色质在细胞核中异质分布，分为两种类型的区室：常染色质、密度较低且主要是转录活性的区域。尽管有基因组组织的详细图片，但其基本物理原理仍然未知，此外，基因组浸入溶剂（核质）中，通过液-液过程自行组织。如何协调基因组和核质空间组织仍然是一个悬而未决的问题，该项目的总体目标是揭示基因组组织背后的物理原理。该项目将采用最先进的体内实验方法和数据分析，通过结合聚合物物理学、软凝聚态物理学、生物物理学和细胞生物学的最新定量技术，直接为新模型和理论的开发提供信息。研究基因组划分背后的机制并阐明这种组织背后的物理定律。这些测量将为相分离作为基因组划分的指导物理原理提供基本见解。该奖项反映了 NSF 的法定使命，并被认为是值得的。支持通过使用基金会的智力优点和更广泛的影响审查标准进行评估。

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）

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：
2022-01
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.

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

DOI：
10.1103/physrevlett.131.048401
发表时间：
2023-07
期刊：
Physical Review Letters
影响因子：
8.6
作者：
Eshghi, Iraj;Zidovska, Alexandra;Grosberg, Alexander Y.
通讯作者：
Grosberg, Alexander Y.

Model chromatin flows: numerical analysis of linear and nonlinear hydrodynamics inside a sphere

染色质流动模型：球体内线性和非线性流体动力学的数值分析

DOI：
10.1140/epje/s10189-023-00327-1
发表时间：
2023-08
期刊：
The European Physical Journal E
影响因子：
0
作者：
Eshghi, Iraj;Zidovska, Alexandra;Grosberg, Alexander Y.
通讯作者：
Grosberg, Alexander Y.

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.