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

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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.