Collaborative Research URoL: Epigenetics2: Epigenetic pathways to regulate homeostatic resilience: Model-based discovery of rules across diverse mammals

合作研究 URoL：表观遗传学2：调节稳态恢复力的表观遗传途径：基于模型的不同哺乳动物规则发现

• 批准号: 2022012
• 负责人: Diane Genereux
• 金额: $ 66.98万
• 依托单位: Broad Institute, Inc.
• 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: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2022012&HistoricalAwards=false
• 关键词: Collaborative; Research; URoL; Epigenetics2; Epigenetic

This project will examine biological rules that govern how different species respond, at the cellular level, to changes in their environment, and why some species are more robust than others. All species encounter environmental variation, but some tolerate extremes that would be dangerous to most other species. Fruit bats withstand dramatic changes in blood glucose between feeding and flying, camels tolerate high body temperatures in hot desert environments, and deep-diving mammals survive with little oxygen during long dives. The goal of this project is to understand how diverse species cope with extremes by measuring how their cells respond in the lab to changing culture conditions that mimic real-world variation. This will provide a foundation for developing mathematical models to understand the genetic components of this tolerance, and why the response differs between species. This project will provide active learning and research opportunities for middle school, undergraduate and graduate students, including many from historically underserved populations. It will develop sixth grade curricular enrichment in biology and computer coding, provide opportunities for undergraduate students to participate in laboratory research, and support graduate students and postdoctoral researchers. Through cross-institutional collaborations, it will establish mentoring relationships between students at different levels. This project will also develop and disseminate outreach materials for the general public.Most mammals lie somewhere between the extremes of strict and flexible homeostasis, meaning that they tolerate fluctuations in cellular biochemical conditions to varying degrees. Some species tolerate extreme variation in cellular conditions, often for environmental factors that are specific to each organism. Conversely, variation in cellular conditions is poorly tolerated by many other species, including humans. This project will apply a common-garden framework to cultured cells from diverse mammals to uncover epigenetic responses that render cells of diverse species robust to variation in the internal milieu. RNA-seq, ATAC-seq, and cellular morphology and physiology data will be used to assay the responses of cells from different species when exposed to a panel of variable oxygen, glucose, and temperature conditions. By analyzing these datasets using new comparative computational approaches and an evolutionary framework, the project will identify genes involved in strictly homeostatic versus flexible cellular phenotypes. These genes will be modeled as “agents” in an agent-based modeling approach to distinguish between a "driver" hypothesis, with robustness coordinated by a few epigenotypes of large effect, or an alternate "small-impact" hypothesis, with robustness arising from many epigenotypes of individually small effect, and between the possibility of few versus many evolutionary paths to a given robustness phenotype. This cross-disciplinary collaboration will pioneer a new strategy to discover the nature — and limits — of cellular buffering abilities that underlie extreme phenotypes and reveal the "rules" whereby mammalian cells cope with environmental variation.This project is funded by the Understanding the Rules of Life: Epigenetics Program, administered as part of NSF's Ten Big Ideas through the Division of Emerging Frontiers in the Directorate for 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.

该项目将研究生物学规则，这些规则决定了不同物种在细胞水平上对环境变化的反应，以及为什么有些物种比其他物种更健壮。所有物种都会遇到环境变化，但有些物种能忍受对大多数其他物种来说是危险的极端环境。果蝠在进食和飞行之间能承受血糖的剧烈变化，骆驼能在炎热的沙漠环境中忍受高体温，深潜哺乳动物在长时间潜水时几乎没有氧气。该项目的目标是通过测量不同物种的细胞在实验室中如何应对模拟现实世界变化的培养条件来了解它们如何科普极端情况。这将为开发数学模型提供基础，以了解这种耐受性的遗传成分，以及为什么物种之间的反应不同。该项目将为中学生、本科生和研究生提供积极的学习和研究机会，其中包括许多来自历史上服务不足的人口。它将开发生物学和计算机编码的六年级课程，为本科生提供参与实验室研究的机会，并支持研究生和博士后研究人员。通过跨机构合作，它将在不同层次的学生之间建立指导关系。该项目还将为公众编写和分发宣传材料。大多数哺乳动物处于严格和灵活的体内平衡的极端之间，这意味着它们在不同程度上容忍细胞生物化学条件的波动。一些物种容忍细胞条件的极端变化，通常是针对每个生物体的环境因素。相反，许多其他物种（包括人类）对细胞条件的变化耐受性较差。该项目将应用一个共同的花园框架来培养来自不同哺乳动物的细胞，以揭示表观遗传反应，使不同物种的细胞对内部环境的变化保持稳健。RNA-seq、ATAC-seq以及细胞形态学和生理学数据将用于测定不同物种的细胞在暴露于一组可变氧气、葡萄糖和温度条件时的反应。通过使用新的比较计算方法和进化框架分析这些数据集，该项目将确定参与严格稳态与灵活细胞表型的基因。这些基因将被建模为“代理人”，在代理人为基础的建模方法，以区分“驱动器”的假设，与鲁棒性协调的几个表观基因型的大的影响，或一个替代的“小影响”的假设，与鲁棒性产生的许多表观基因型的个别小的影响，和之间的可能性，少数与许多进化路径到一个给定的鲁棒性表型。这一跨学科合作将开创一种新的策略，以发现极端表型背后的细胞缓冲能力的本质和局限性，并揭示哺乳动物细胞科普环境变化的“规则”。表观遗传学项目，作为NSF十大创意的一部分，通过生物科学理事会新兴前沿部门进行管理。该奖项反映了NSF的基金会的使命是履行其法定使命，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。