Probing heterochromatin growth and memory dynamics in live single cells

探究活单细胞中的异染色质生长和记忆动态

• 批准号: 2113319
• 负责人: BASSEM AL-SADY
• 金额: $ 124.25万
• 依托单位: University of California-San Francisco
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2113319&HistoricalAwards=false
• 关键词: Probing; heterochromatin; growth; memory; dynamics

Each cell of an organism contains the same genetic information, yet development of unique cell types requires that only part of this information be accessible in any given cell. This selective access is governed by structures inside the cell nucleus that assemble along large stretches of a chromosome, grow to variable extents depending on the cell type and then repress the underlying information. If this process is repeated every cell division, this repression is heritable. It remains unclear how these structures, known as heterochromatin, (i) grow along the chromosome, and (ii) “remember” their sites of assembly and growth over cell divisions. This research project aims to resolve these questions, and thereby help lay the foundation to build or manipulate genetic information-controlling heterochromatin structures to drive cells to adopt new fates and perform new functions. The project will also educate diverse undergraduate and graduate students in different scientific fields, including genetics, biophysics, cell biology, and biotechnology, through research training and teaching opportunities. While the genetic requirements for gene silencing by heterochromatin have been long studied, the rules governing heterochromatin growth (spreading) along the chromosome in cells remain opaque. Neither it is understood why certain heterochromatin elements epigenetically maintain themselves across cell divisions while others do not. In this project, the single-celled fission yeast model system is employed to investigate the mechanisms of spreading and maintenance of heterochromatin. The research will combine the ability to visualize and quantify spreading in real-time in single fission yeast cells with Langevin dynamics modeling to distinguish different models of how heterochromatin spreads along the chromosome within the cell cycle. To understand how heterochromatin formed by spreading is remembered across cell divisions, hysteresis measurements with fission yeast cells containing heterochromatin spreading reporters will be used to assess the degree of memory within a given heterochromatin domain. The power of yeast genetics, single cell imaging and modeling combined is expected to yield new insights into the molecular origins of epigenetic memory.This research is funded by the Genetic Mechanisms program in the Division of Molecular and Cellular Biosciences in the Directorate of Biological Sciences.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.

生物体的每个细胞都含有相同的遗传信息，然而，独特细胞类型的发展要求在任何给定的细胞中只能获得部分遗传信息。这种选择性通路是由细胞核内的结构控制的，这些结构沿着染色体的大延伸组装，根据细胞类型生长到不同的程度，然后抑制潜在的信息。如果每次细胞分裂都重复这个过程，这种抑制是可遗传的。目前尚不清楚这些被称为异染色质的结构是如何(1)沿着染色体生长的，以及(2)在细胞分裂过程中“记住”它们的组装和生长位置的。本研究项目旨在解决这些问题，从而为构建或操纵遗传信息控制异染色质结构以驱动细胞接受新的命运和执行新的功能奠定基础。该项目还将通过研究培训和教学机会，培养不同科学领域的本科生和研究生，包括遗传学、生物物理学、细胞生物学和生物技术。虽然异染色质对基因沉默的遗传要求已经研究了很长时间，但控制细胞中异染色质沿染色体生长（扩散）的规则仍然不清楚。也不明白为什么某些异染色质元素在细胞分裂过程中表观遗传地维持自己，而另一些却没有。本项目采用单细胞分裂酵母模型系统研究异染色质扩散和维持的机制。该研究将结合在单个分裂酵母细胞中实时可视化和量化扩散的能力与朗格万动力学建模，以区分异染色质如何在细胞周期内沿染色体扩散的不同模型。为了了解通过扩散形成的异染色质是如何在细胞分裂中被记忆的，将使用含有异染色质扩散报告者的裂变酵母细胞的滞后测量来评估给定异染色质结构域内的记忆程度。酵母遗传学、单细胞成像和建模相结合的力量有望对表观遗传记忆的分子起源产生新的见解。这项研究由生物科学理事会分子和细胞生物科学部的遗传机制项目资助。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。