Regulatory roles of the epitranscriptome and RNA structurome during vertebrate development

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PROJECT SUMMARY/ABSTRACT (as submitted in original application) In all animals, the maternal-to-zygotic transition allows the transfer of information required for a single zygote to develop into a mature organism. After fertilization, the maternal program, composed of maternally-inherited mRNAs and proteins, drives cellular development and is replaced by the zygotic program. Because this transition occurs primarily in a transcriptionally silent embryo, it relies heavily on post-transcriptional regulation. Failure to properly regulate maternally-inherited mRNAs generally leads to developmental arrest or abnormalities. Recent studies have shown that maternal mRNAs are decorated with RNA modifications, collectively known as the ‘epitranscriptome’, that correlate with different mRNA fates. Moreover, we and others performed global analyses of mRNA structure dynamics during the maternal-to-zygotic transition and identified numerous regions that are structurally remodeled during this fundamental process, many of which impact mRNA decay. These studies suggest that RNA modifications and dynamic RNA structures are emerging as key regulators of gene expression during the maternal-to-zygotic transition. However, the detailed landscape of the epitranscriptome and dynamic RNA structures, and their roles in gene regulation during the maternal-to-zygotic transition remain poorly understood. Furthermore, RNA modifications and structures affect one another to regulate RNA functions, but little is known about how they interact to control gene expression during vertebrate development. The primary goal of my lab is to understand how the epitranscriptome and RNA structures mediate gene regulatory networks, separately and cooperatively, during vertebrate development and how their dysfunction promotes developmental defects or diseases. Here, we hypothesize that RNA modifications and structures interact with trans-factors to participate in the post-transcriptional regulatory landscape driving vertebrate development. To test this hypothesis, we will combine zebrafish —an in vivo model of vertebrate development— and its genetic toolbox with innovative multi-omics approaches. Over the next five years, we will inspect the native transcriptome to generate global, yet detailed, maps of the epitranscriptome during the maternal-to-zygotic transition, and study how specific RNA modifications impact gene expression. We will also decipher the RNA folds formed by dynamic regions of the transcriptome and analyze their effect on RNA regulation. We will identify trans-factors interacting with RNA modifications and structures of interest and study the consequences of their loss-of-function on gene expression and vertebrate development. Finally, we will examine how RNA modifications and structures cooperate to modulate post-transcriptional regulation. Successful completion of these investigations will greatly increase the existing knowledge of how RNA modifications and structures orchestrate post-transcriptional regulation, and will expand our understanding of the molecular mechanisms shaping vertebrate development.