Sirtuins as rewiring points to evolve new responses to low NAD+ stress in yeast

Sirtuins 作为重连点，在酵母中进化出对低 NAD 应激的新反应

• 批准号: 1952281
• 负责人: Laura Rusche
• 金额: $ 75万
• 依托单位: SUNY at Buffalo
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1952281&HistoricalAwards=false
• 关键词: Sirtuins; rewiring; points; evolve; new

This project investigates how new traits are created through changes in the set of genes that are activated upon stress. It will uncover basic principles of molecular evolution that explain how organisms adapt to environmental changes in the short term and how species adapt to environmental changes in the long term. The project focuses on a molecule called nicotinamide adenine dinucleotide, or NAD+, which is required to extract energy from nutrients. NAD+ levels in cells fluctuate with metabolic conditions, and these fluctuations are sensed by a widespread family of proteins called sirtuins. When NAD+ levels are insufficient, sirtuins allow particular genes to become active, which produces a response that allows the organism to adjust to the low NAD+. This project examines the hypothesis that new responses to low NAD+ stress can arise when new genes come under the control of sirtuins. In addition to advancing the understanding of molecular evolutionary processes, this project will enhance the scientific infrastructure by training the next generation of scientists in three ways. First, the experiments will be conducted by two PhD students. Through their work, the students will learn analytical, laboratory, and computational skills. Second, the project will provide summer research opportunities for four undergraduates. These undergraduates will be introduced to experimental science and discover whether a research career is a good fit. Third, the project will enhance undergraduate education in genetics at the University at Buffalo. The PI will develop interactive teaching modules for an undergraduate genetics course. These activities will increase student engagement and academic success by helping them appreciate the relevance of genetics to their lives and careers. Although scientists have long studied how deacetylation by sirtuins modulates cellular processes, there has been little consideration of the evolutionary implications of changes in sirtuin targets. This project addresses the issue by investigating how the yeast sirtuin-containing complex SUM1C contributes to phenotypic variation and adaptive evolution. SUM1C is composed of a sirtuin deacetylase and a DNA-binding protein that targets the deacetylase to particular genomic locations. The central hypothesis is that SUM1C serves as a rewiring point that allows yeast species to evolve distinct responses to low NAD+ stress by bringing new genes under the control of an NAD+-dependent deacetylase. This project will identify SUM1C target genes in eight phylogenetically distributed yeast species using a combination of RNA-Seq and ChIP-Seq. These data will be used to (i) investigate how SUM1C tunes transcriptional output to intracellular [NAD+] and (ii) determine the functional consequences of changes in the set of SUM1C targets. In so doing, this work will provide new insights into how sirtuin deacetylases, which are broadly conserved across the tree of life, contribute to phenotypic variation in the short term and adaptive evolution in the long-term.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.

该项目研究了如何通过在压力下激活的基因组的变化来创造新的特征。它将揭示分子进化的基本原理，解释生物如何在短期内适应环境变化，以及物种如何在长期内适应环境变化。该项目的重点是一种名为烟酰胺腺嘌呤二核苷酸（NAD+）的分子，它是从营养物质中提取能量所必需的。细胞中的NAD+水平随着代谢条件而波动，这些波动被称为sirtuins的广泛蛋白质家族所感知。当NAD+水平不足时，sirtuins允许特定的基因变得活跃，从而产生一种反应，使生物体能够适应低NAD+。该项目研究了当新基因受到sirtuins的控制时，对低NAD+应激的新反应可能出现的假设。除了促进对分子进化过程的理解外，该项目还将通过三种方式培训下一代科学家来加强科学基础设施。首先，实验将由两名博士生进行。通过他们的工作，学生将学习分析，实验室和计算技能。第二，该项目将为四名本科生提供暑期研究机会。这些本科生将被介绍给实验科学，并发现研究生涯是否是一个很好的适合。第三，该项目将加强布法罗大学的遗传学本科教育。PI将为本科遗传学课程开发交互式教学模块。这些活动将通过帮助学生理解遗传学与他们的生活和职业的相关性来提高学生的参与度和学术成就。 尽管科学家们长期以来一直在研究去乙酰化是如何通过sirtuins调节细胞过程的，但很少考虑sirtuin靶标变化的进化意义。该项目通过研究酵母sirtuin复合物SUM 1C如何有助于表型变异和适应性进化来解决这个问题。SUM 1C由去乙酰化酶和将去乙酰化酶靶向特定基因组位置的DNA结合蛋白组成。中心假设是SUM 1C作为一个重新布线点，允许酵母物种通过在NAD+依赖性脱乙酰酶的控制下引入新基因来进化对低NAD+胁迫的不同反应。该项目将使用RNA-Seq和ChIP-Seq的组合在8种遗传分布的酵母物种中鉴定SUM 1C靶基因。这些数据将用于（i）研究SUM 1C如何将转录输出调节到细胞内[NAD+]，以及（ii）确定SUM 1C靶标组变化的功能后果。在这样做，这项工作将提供新的见解sirtuin脱乙酰酶，这是广泛保存在整个生命之树，有助于在短期内的表型变异和长期的适应性进化。这一奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。