Physical Mechanisms of Cell State Transitions: Size Homeostasis in Budding Yeast

细胞状态转变的物理机制：出芽酵母的大小稳态

• 批准号: 1806638
• 负责人: Catherine Royer
• 金额: $ 90万
• 依托单位: Rensselaer Polytechnic Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1806638&HistoricalAwards=false
• 关键词: Physical; Mechanisms; Cell; State; Transitions

In all species, cell growth and division are tightly coordinated to establish a homeostatic cell size. Size control optimizes fitness under variable environmental conditions in unicellular species, and is critical for proper organ development and maintenance in multi-cellular organisms. In humans, disruption of the networks that control cell growth, division or size is linked to many diseases, including cancer, metabolic syndrome, and cardiomyopathy. In budding yeast, size is modulated by nutrients. Cells grow fast and are large in rich nutrients and slowly and are small in poor nutrients. The PI will use a unique combination of state-of-the-art quantitative imaging methods, genetic manipulation, and mathematical modeling to construct a systems-level framework for cell size homeostasis in budding yeast. These studies will answer the longstanding question: How do cells know when they are big enough to divide? Application of the approach proposed here to other important cell state transitions will provide the foundation for the development in the private sector of new products or processes for in-tissue engineering and drug discovery. The proposed project provides highly interdisciplinary graduate training in biology, genetic engineering, physics, computation and mathematics. The Royer group hosts a large number of undergraduate students as part of the CBIS Undergraduate Research Program, the BCBP Summer internship program for predominantly minority institutions and the CBIS High School Scholars Program. Students participating in these programs will experience a "real life" application of their knowledge. The uniquely broad set of skills implicated in the research will help to prepare them for the increasingly interdisciplinary word of science and technology. The PI as Director of the RPI Graduate Program in Biochemistry and Biophysics will organize outreach to four-year colleges in the Northeast and to the public annually during Biophysics week.The hypothesis is that the transcription factors which activate the G1/S regulon leading to commitment to division, differentially and dynamically integrate nutrient signals to coordinate growth and division, thereby enabling adaptive nutrient modulation of cell size. This project has three specific objectives: i) Map the G1/S transcriptional activator nuclear organization at super-resolution as a function of size and nutrients, ii) Measure and model nutrient dependent Start dynamics, and iii) Define the upstream signaling pathways and targets for nutrient modulation of cell size. Despite the identification of literally hundreds of genes implicated in size control in budding yeast, it remains a mystery how this complex genetic network impacts the Start machinery to control size. The PI will move beyond the qualitative genetic characterization of the size control network to a quantitative understanding of how this network dynamically processes information. The strategy that will be used by the PI will provide a comprehensive, quantitative assessment of a complex biological state transition, commitment to division. The measurements of Start factor concentration and super-resolution localization will identify the key parameters for nutrient control of cell size. The mathematical models will serve as a conceptual framework for testing hypotheses, and will inform physical principles of cell division in higher organisms, including humans. Finally, the results will reveal the impact of cell-to-cell heterogeneity, or biological noise, on cell growth and the dynamics of commitment to division and size homeostasis. This work will provide the foundation for a rigorous understanding of how evolution has shaped molecular networks to cope with a stochastic environment and how robust cellular decision-making is established. This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Dynamics and Function as well as the Systems and Synthetic Biology Programs in the Division of Molecular and Cellular Biosciences.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.

在所有物种中，细胞的生长和分裂都经过严格协调，以建立稳态细胞的大小。大小控制优化了单细胞物种可变环境条件下的适应性，并且对于多细胞生物的适当器官发育和维护至关重要。在人类中，控制细胞生长，分裂或大小的网络的破坏与许多疾病有关，包括癌症，代谢综合征和心肌病。在萌芽的酵母中，大小是由营养调节的。细胞生长迅速，富含富营养，并且缓慢地且营养不良。 PI将使用最先进的定量成像方法，遗传操纵和数学建模的独特组合来构建用于崭露头角的酵母中细胞大小稳态的系统级框架。这些研究将回答一个长期以来的问题：细胞如何知道它们何时足够大以分裂？此处提出的方法应用于其他重要的细胞状态过渡，将为组织内工程和药物发现的新产品或过程的私营部门的发展提供基础。拟议的项目提供了高度跨学科的生物学，基因工程，物理，计算和数学的研究生培训。 Royer集团作为CBIS本科研究计划，BCBP暑期实习计划和CBIS高中学者计划的BCBP暑期实习计划，拥有大量的本科生。参加这些计划的学生将体验他们知识的“现实生活”。与研究有关的独特广泛技能将有助于为越来越多的科学技术跨学科词做准备。 The PI as Director of the RPI Graduate Program in Biochemistry and Biophysics will organize outreach to four-year colleges in the Northeast and to the public annually during Biophysics week.The hypothesis is that the transcription factors which activate the G1/S regulon leading to commitment to division, differentially and dynamically integrate nutrient signals to coordinate growth and division, thereby enabling adaptive nutrient modulation of cell size.该项目具有三个特定的目标：i）以超分辨率作为大小和养分的函数绘制G1/S转录激活核组织，ii）测量和模型养分依赖性的起始动力学，iii）定义上游信号通路和目标，以确定细胞大小的养分调节。尽管从字面上鉴定了数百个基因与萌芽酵母中的尺寸控制有关，但这种复杂的遗传网络如何影响起始机械控制尺寸仍然是一个谜。 PI将超越大小控制网络的定性遗传表征，以定量了解该网络如何动态处理信息。 PI将使用的策略将对复杂的生物状态过渡，对分裂的承诺进行全面的定量评估。起始因子浓度和超分辨率定位的测量将确定细胞尺寸营养控制的关键参数。数学模型将成为检验假设的概念框架，并将为包括人类在内的较高生物体中细胞分裂的物理原理提供信息。最后，结果将揭示细胞对细胞异质性或生物噪声对细胞生长以及对分裂和大小稳态承诺的动态的影响。这项工作将为严格理解进化如何塑造分子网络以应对随机环境以及如何建立牢固的细胞决策。该项目在物理学和细胞动力学和功能部以及分子和蜂窝生物科学部门的系统和合成生物学计划中的生命系统计划共同支持。该奖项反映了NSF的法定任务，并通过使用该基金会的知识优点和广泛的影响来评估NSF的法定任务。

项目成果

G1/S Transcription Factor Copy Number Is a Growth-Dependent Determinant of Cell Cycle Commitment in Yeast

• DOI: 10.1016/j.cels.2018.04.012
• 发表时间: 2018-05-23
• 期刊: CELL SYSTEMS
• 影响因子: 9.3
• 作者: Dorsey, Savanna;Tollis, Sylvain;Royer, Catherine A.
• 通讯作者: Royer, Catherine A.

G1/S transcription factors assemble in increasing numbers of discrete clusters through G1 phase

• DOI: 10.1083/jcb.202003041
• 发表时间: 2020-09-07
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Black, Labe;Tollis, Sylvain;Royer, Catherine Ann
• 通讯作者: Royer, Catherine Ann