Specialized post-transcriptional mechanisms of gene expression in quiescence

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Abstract Specialized post-transcriptional mechanisms of gene expression in quiescence Vision Quiescence (G0) is an assortment of reversible, cell-cycle arrested phases that permits cells to avoid death due to harsh conditions. G0 is critical in immunity and cancer, promoting inflammation and adaptations for disease persistence; however, G0 is poorly understood despite its medical significance. Our studies uncovered powerful RNA regulators and modifications in G0 cells, revealing inhibition of conventional translation and its replacement by non-canonical mechanisms to enable specific gene expression for G0 roles and survival. Based on our data, G0 cells are perpetuated by specialized post-transcriptional mechanisms that elicit specific gene expression, which maintains the transient arrested state, enables G0 survival in stress conditions, and retains the ability of G0 cells to re-enter the cell cycle and persist disease. This permits important G0 functions: drug and immune survival in malignancies like leukemia, immune cell extravasation, tissue regeneration, and development. The goal of our study is to investigate the distinct post-transcriptional mechanisms and gene expression in G0 leukemic cells, to understand G0 roles and persistence in disease. Premise The key finding of our studies is that conventional translation is inhibited by G0 signals and replaced by non-canonical factors that enable specific expression of genes that are critical for survival. Significantly, such non-canonical factors alter translation start site selection, expanding the proteome by creating new frames (PNAS 2014). We identified noncoding RNAs, associated RNA-protein complexes (RNPs), and non- canonical translation factors that mediate select expression of few immune and cell state regulators in G0 (Molecular Cell 2016). Our data reveal signaling changes that modify RNPs in G0 to enable specific gene expression, which allowed targeting of drug resistant G0 in disease (Genome Biol. 2020). Our studies indicate important layers of undiscovered regulation: modification of ribosomes, mRNAs and RNPs and associated non-canonical translation (Science 2020, Nat. Commun. 2020, Science Adv. 2022). Characterization of G0 post-transcriptional changes, will reveal hidden mechanisms that drive G0 survival for disease persistence. Directions in the next 5 years First, profiling, purifications, depletions, mutations, and biochemical analyses of snoRNAs and ribosomes, will map snoRNPs and ribosome modifications, providing insights on changes to the translation machinery underlying gene expression in G0 survival. Second, modifications on mRNAs, associated RNPs, non-canonical translation factors, translated targets and unique start sites in G0 will be identified to uncover the G0 translatome, expanded at the translation frame. Finally, these will be verified in vivo and in patient samples, to uncover post-transcriptional mechanisms that impact G0 roles and persistence. Impact These studies will uncover new insights into G0 post-transcriptional mechanisms, provide a map of ribosome and RNA modifications, and translation frames, and their impact on G0 roles and survival in disease.