RNA Modifying Enzymes with Prion-Like Properties

We place particular focus on regulators of RNA chemical modifications, or RNA modifying enzymes (RMEs), due to their ability to influence expression of numerous genes simultaneously, through molecularly definable rules. Through a large phenotypic screen, based on transient perturbation of more than seventy RMEs and two-dozen other RBPs, that generated >3.5 million growth data points, we discovered numerous examples of RMEs driving prion-like, heritable growth states. These states influenced fundamental traits such as proliferation, cell size, lifespan, and growth in a variety of stresses. Our goals are to understand the causes and effects of this type of regulation, by connecting long-lasting, heritable changes in RNA regulation to their consequent effects on cell growth across varying environments. 

ResearchSection_graphs_v5_01.jpg
 

Live Fast, Die Young—An Ancient RNA Modifying Enzyme Accelerating Proliferation and Aging

We have studied one particular example of an RME that can promote a prion-like epigenetic state in great detail. This state causes yeast to proliferate, and age, rapidly. Compared to genetically identical "naive" cells, these cells, represented by a state we call [BIG+], are larger in size, have increased protein synthesis, and have an altered response to TOR pathway inhibition. This state thus provides a means by which cells can epigenetically and reversibly adopt different proliferation and aging programs. We are exploring the molecular basis of this state, in particular its effects on protein synthesis, as well as its existence beyond yeast.

ResearchSection_graphs_v3-03.png
 

Stress-Induced Epigenetic States

We are also interested in the ability of molecules—both natural and man-made—and environmental stresses to induce new heritable growth states. We showed the possibility of identifying environmental molecules responsible for inducing prions in yeast (Garcia and Dietrich et al., 2016). We then approached this question from a different angle, executing a large phenotypic screen,  testing many known molecules and discovering examples of new heritable growth states. The goal is now to identify the bases for these long-lived states, whether prion-like, chromatin-altered, or other mechanisms. We are also interested in screening for this behavior in metazoan cells.

ResearchSection_graphs_v3-02.png
 

From Yeast To Humans

We are excited to explore the above phenomenon in human cells, with the near-future goal of testing their importance in disease models. We are motivated by the relative speed at which we can profile emergent epigenetic behavior in model systems like yeast. But in the long-run, we dream that our work will present opportunities to learn more about human disease, and maybe new ways to fight it.

ResearchSection_graphs_v2-04.png