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，细胞生长和分裂都是紧密协调的，以建立一个动态平衡的细胞大小。大小控制优化了单细胞物种在不同环境条件下的适合性，对于多细胞生物中适当的器官发育和维护至关重要。在人类中，控制细胞生长、分裂或大小的网络中断与许多疾病有关，包括癌症、代谢综合征和心肌病。在萌芽酵母中，大小受营养物质的调节。细胞生长快，营养丰富，体积大，营养贫乏，生长缓慢，体积小。PI将使用最先进的定量成像方法、遗传操作和数学建模的独特组合来构建芽期酵母细胞大小动态平衡的系统级框架。这些研究将回答一个长期存在的问题：细胞如何知道它们何时足够大，可以分裂？将本文提出的方法应用于其他重要的细胞状态转变，将为在私营部门开发用于组织内工程和药物发现的新产品或新工艺奠定基础。拟议的项目提供生物学、遗传工程、物理、计算和数学方面的高度跨学科研究生培训。作为CBIS本科生研究计划、以少数族裔为主的BCBP暑期实习计划和CBIS高中学者计划的一部分，罗耶集团招收了大量本科生。参加这些项目的学生将体验到他们所掌握的知识在现实生活中的应用。这项研究涉及的一系列独特而广泛的技能将有助于他们为科学和技术这个日益跨学科的词做好准备。作为RPI生物化学和生物物理学研究生项目的主任，PI将在生物物理周期间组织对东北地区四年制大学的外联活动，并每年向公众开放。假设激活导致分裂承诺的G1/S调节子的转录因子，差异和动态地整合营养信号来协调生长和分裂，从而实现对细胞大小的适应性营养调节。该项目有三个具体的目标：i)以超分辨率绘制G1/S转录激活子核组织与大小和营养的函数图，ii)测量和模拟营养依赖的启动动力学，以及iii)定义上游信号通路和营养调节细胞大小的靶标。尽管在发芽酵母中确实发现了数百个与大小控制有关的基因，但这个复杂的遗传网络如何影响启动机制来控制大小仍然是一个谜。PI将超越大小控制网络的定性遗传特征，转向对该网络如何动态处理信息的定量理解。PI将使用的策略将对复杂的生物状态转换、承诺分裂提供全面、定量的评估。起始因子浓度和超分辨率定位的测量将确定营养控制细胞大小的关键参数。数学模型将作为检验假说的概念框架，并将向包括人类在内的高等生物体的细胞分裂的物理原理提供信息。最后，研究结果将揭示细胞间异质性或生物噪声对细胞生长的影响，以及对分裂和大小稳态的承诺动态。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稳健的细胞决策奠定基础。该项目由物理和细胞动力学与功能部的生命系统物理学项目以及分子和细胞生物科学部的系统和合成生物学项目共同支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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

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

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.