Post-transcriptional regulation of cell plasticity

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SUMMARY Cell plasticity is the ability of cells to change their phenotypes without genetic mutations in response to environmental cues. This cellular behavior is crucial for the development and progress of complex diseases, such as immune responses and cancer. Changes in cellular transcription programs have long been considered a major factor in defining the fate of cells during cell-type switching. However, the role that post-transcriptional mechanisms can play in regulating cell fate, specifically in response to rapid changes in the environmental cues, is a black box. A long-term goal of my laboratory is to identify the post-transcriptional mechanisms that regulate protein synthesis and understand their contribution to cellular plasticity. Here, we focus on two areas of post- transcriptional gene regulation: mRNA modifications and translational control. While there has been impressive progress towards understanding the role of RNA modifications and translational regulation in controlling cellular homeostasis, there is a significant gap in our knowledge of how these processes can rapidly affect cellular plasticity in response to the changes in environmental cues. The eukaryotic initiation factor 3 (eIF3) has emerged as a master player in translation regulation by promoting or suppressing the translation of a subset of mRNAs. However, how this key initiation factor controls cell plasticity is a mystery. Our data indicate that eIF3 is critically important for morphological transition in the yeast Candida albicans. In Theme 1, we will address the role of eIF3 in controlling cell plasticity in C. albicans by answering two key questions: 1) What are the composition and the interactome of eIF3 in different cell types of C. albicans? and 2) What is the role of C. albicans eIF3 in regulating mRNA translation during the yeast-to-hyphae transition? Our second area of research (Theme 2) is focused on understanding how RNA modifications regulate cell plasticity in C. albicans. Our work demonstrates that mRNAs are differentially methylated in different cell types in C. albicans, and inhibiting the mRNA methylation impairs cell plasticity in this organism. By combining novel genetic tools and reagents that we have recently developed with biochemical assays, proteomics, and next-generation sequencing we will answer two key questions: 3) What is the mechanism of m6A deposition in mRNA during cell-type switching in C. albicans? and 4) How do m6A mRNA modifications contribute to cell-type switching in C. albicans? Our findings will provide significant insights into the mechanisms of post-transcriptional control of cell plasticity at the mRNA or translation level and will aid in understanding how dysregulation of these processes contributes to human disease.