Specialized Ribosomes: A New Frontier in Gene Regulation, Organismal Biology, & Evolution

Abstract

The central dogma of molecular biology has for decades served as an explanation for the flow of genetic information within a biological system. In so far as the normal flow of biological information from mRNA to protein, the ribosome has been perceived to decode the genome with essentially machine‐like precision; serving as an integral but largely passive participant in the synthesis of all effector proteins across all kingdoms of life. Our research has changed this view, by demonstrating that not all of the millions of ribosomes within each cell are the same and that ribosome heterogeneity provides a novel means to diversify the proteins that can be produced in specific cells, tissues, and organisms. I will present our work centered on providing a roadmap for the absolute quantification of ribosome composition at a single cell level and during cellular differentiation that has identified subsets of ribosomes that are heterogeneous for core ribosomal proteins and interacting proteins. To further address the functional role of ribosome heterogeneity in translational control of the mammalian genome, we employed CRISPR/Cas9 to endogenously tag and purify heterogeneous ribosome populations to characterize specific preferences in transcripts translated by distinct ribosome subtypes. This led to the identification of subpools of transcripts, critical for key cellular processes including cell signaling, metabolism, growth, proliferation and survival, which are selectively translated by specific types of ribosomes. I will further present recent findings on the mechanisms by which ribosome‐mediated control of gene expression is encoded by structured RNA regulons within 5′UTRs. Together, these studies reveal a critical link between ribosome heterogeneity and specialized translational control of the mammalian genome, which adds an important layer of control to the post‐transcriptional circuitry of gene regulation and mammalian development.