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

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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.