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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.

人类基因组由两米长的DNA组成，储存在直径仅10微米的细胞核中。DNA分子被包裹在一种被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，而基因组的功能反过来又对细胞的正常功能至关重要。因此，阐明染色质组织的基本原理对于理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难以捉摸。该项目的目标是通过结合定量实验方法和相关物理领域的理论，生成活的人类细胞内染色质组织的机制图。作为该项目的一部分，PI将制定教育和外联内容，重点是在不同教育和职业阶段招聘和留住物理学领域的女性。该项目还将为本科生和研究生提供新的教育和培训机会，他们将接受先进光学显微镜技术、小角度x射线散射、图像处理和数据分析以及聚合物物理学、生物物理学和统计力学方面的培训。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。染色质纤维在层次上折叠成环、拓扑相关结构域、A和B区室（转录活性和非活性基因组部分），最后是染色体区域。此外，染色质在细胞核中分布不均，分为两种类型的室室：常染色质，密度较低且主要转录活跃的区域；异染色质，密度较大的区域，主要包含沉默基因。尽管对基因组组织有了详细的了解，但其潜在的物理原理仍然未知。此外，基因组浸泡在溶剂核质中，核质通过液-液相分离来组织自己，并形成功能性液体凝聚物。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利用最先进的体内实验方法和数据分析揭示基因组组织背后的物理原理，这将直接为新模型和理论的发展提供信息。本项目将结合高分子物理学、软凝聚态物理、生物物理学和细胞生物学的最新定量技术，研究基因组区隔背后的机制，阐明这种组织背后的物理规律。这些测量将为相分离提供基本的见解，作为基因组区隔化的指导物理原理。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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
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.

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.

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