Thursday, October 31, 2024
10/31/2024
Project Summary Translational control is critical for a variety of cellular processes such as homeostasis and differentiation. Dysregulation of translation has been implicated in many human diseases, including cancer. Stem cells are characterized by low global protein synthesis rates, despite high levels of ribosome biogenesis, suggesting that stem cells actively repress translation. Indeed, precise translational control has been shown to be essential for maintaining pluripotency, as perturbations that increased translation rates induced differentiation in various types of stem cells. Although there are several examples of how translation is regulated, the molecular mechanisms that modulate translation, particularly in stem cells, are largely unknown. To achieve a comprehensive understanding of translational control, I propose to systematically investigate the regulatory pathways that mediate translation in stem cells and across cell types. I will begin by developing a genome-scale genetic screening platform that combines CRISPR screening with polysome profiling to identify genetic perturbations that alter translation. Compared to previous approaches that relied on reporter protein expression, the proposed screening approach measures presence of ribosomes on mRNA, which more directly and accurately quantifies translation rates. This screening approach is also more versatile and can be adapted for studying other modes of translation by exchanging the reporter gene in the vector. I will then apply this screening approach to systematically discover genes that regulate global translation levels in stem cells and fibroblasts and investigate associated mechanisms. Finally, I will focus on genes that are selectively translated using ribosome profiling and characterize the pathways that mediate selective mRNA translation. Together, my proposed work establishes a framework for systematic exploration of translational control networks and, in concert with its application in other contexts, will contribute to a comprehensive understanding of the processes controlling translation that are relevant in development and disease.
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