Dissecting the roles of pervasive short ORFs in meiosis

University Of California Berkeley, Berkeley CA

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Abstract

? DESCRIPTION (provided by applicant): Informed studies of gene expression have allowed us to decipher fundamental elements of how cells work and to develop targeted treatments for disease, but these studies have depended on rigid assumptions for how genomic blueprints should be interpreted. Until recently, it was not possible to experimentally determine which genomic regions encode proteins, and computational approaches for systematic identification of such regions have historically been limited to Open Reading Frames (ORFs) that were above 100 codons. Recent experimental data, including my own, challenge this choice with evidence for pervasive, regulated translation of shorter ORFs (sORFs). A small number of sORF-encoded peptides have been found to have important and specific cellular roles, but these examples were investigated in an ad hoc manner and the functions of the thousands of sORFs recently identified as translated in large-scale studies remain unexplored. I propose that cellular and molecular significance for sORFs can be unraveled through integrated, complementary, and highly parallel functional screening in cells undergoing meiosis, the conserved process of cellular differentiation that produces gametes. I identified over 2500 sORFs that undergo regulated translation in meiotic budding yeast cells, all of which are currently functionally mysterious. The goal of this proposal is to define roles for these new factors, with a broader goal of informing on the types of biological function that can be mediated by the short translated regions that we now know to be prevalent in eukaryotic cells. Meiosis is a system that is well suited to multilayered and systematic discovery of in vivo sORF function, as it consists of many precisely timed and benchmarked stages, driven by intricate and layered control of gene expression. Proper meiotic progression is important for fertility and health, and meiotic errors result in disorders, such as Down's Syndrome, through mechanisms that we do not yet understand. I anticipate that determining function for the set of meiotic sORFs will illuminate new molecular aspects of this important biological process by defining roles for a large, active portion of the genome that has been overlooked. By integrating layered genomic, functional, and computational data, these approaches leverage our knowledge of the many defined stages of meiosis to uncover specific function for a large new class of cellular factors. Further, my findings will enable distillation of general principles in peptide function and genome coding. This work has the potential to change the way that we think about eukaryotic signaling and gene function, with broad importance for our understanding of the fundamental mechanisms underlying normal and disease states.