Analysis of the Molecular Machinery Regulating Gene Expression during Vertebrate Development

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The maternal to zygotic transition is a fundamental transfer of information conserved among all animals and characterized by a profound change of the transcriptional landscape. Post-transcriptional regulation mediates this drastic change in gene expression through regulatory elements embedded in maternal mRNAs. RNA structure is detrimental to RNA function and regulatory element activity. Coordination of essential biological processes relies on specific RNA structures such as RNA G-quadruplexes-mediated translation in cancer. Therefore, this proposal will address two central questions in biology: what are the components of the code regulating early embryogenesis and what is the role and molecular function of individual components in vertebrate development. New approaches will be used to understand this vital transition. First, high throughput experiments will be performed to identify mRNA elements that regulate mRNA abundance and translation (Aim 1), and to solve their RNA structure (Aim 2). Then, a combination of biochemical and functional approaches will be used to discover the readers of those regulatory elements (Aim 3). Finally, mutants of those readers will be generated and their molecular mechanism and role studied during vertebrate development (Aim 3). Since the interaction between RNA structures and readers are master regulators of key biological phenomenon (e.g. GAIT system in inflammation and roquin in autoimmunity), the novel gene expression regulatory networks uncover in this proposal will likely be conserved in human and impact human development and health. To accomplish this proposal, Dr. Beaudoin will continue his training as Postdoctoral fellow in the Genetics Department at Yale University, where he will enjoy both state-of-the-art facilities and the interaction with his mentors and other scientific leaders in the field. With this K99 Award, Dr. Beaudoin's goals are to get close mentoring from several scientific experts (mentors and collaborators) in mRNA regulation, developmental biology, machine learning and CRISPR/Cas9-mediated functional screens. Furthermore, Dr. Beaudoin plans to expand his previous teaching and mentoring experience by participating in structured courses and workshops. This will allow him to learn innovative and effective ways to teach biology and progress to become a well- rounded scientist and mentor. Dr. Beaudoin existing expertise and the scientific and training plans of this proposal will allow him to reaching his long-term career goal: to establish a research program to understand the role of RNA structures and RNA helicases in vertebrate development. Defective RNA helicases have been associated to dozens of human diseases (e.g. infertility, neurological disorders, cancers and aging). Therefore, their molecular characterization in a relevant vertebrate model will provide invaluable insights to develop new human therapeutic approaches. Dr. Beaudoin is fully committed to obtain an appointment as a tenure track junior faculty in academia. It is fully expected that Dr. Beaudoin will be competitive for such group leader appointments at the completion of his K99/R00 Award tailored to enhance his scientific and mentoring skills.