Regulatory roles of the epitranscriptome and RNA structurome during vertebrate development

PROJECT SUMMARY/ABSTRACT
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.

Grant Number: 5R35GM146883-04
NIH Institute/Center: NIH
Principal Investigator: Jean-Denis Beaudoin