The genome provides a fundamental layer of information for cellular transitions in the form of coding and regulatory sequences. One conserved mode of regulation is conferred through RNA structure, which directly dictates RNA function. Recent studies have uncovered key roles for RNA structures in the regulation of many steps of gene expression, including transcription, splicing, translation, localization, and decay. Some RNA structures have been identified as master regulators of essential biological pathways, such as the GAIT elements modulating the inflammatory response and G-quadruplexes mediating translation and regulation in cancer. To perform their regulatory roles, RNA structures generally work in concert with protein factors. These include RNA helicases, conserved enzymes that are specialized in remodeling RNA structures, and whose malfunction in humans can lead to disease.
While the regulatory role of RNA structures in gene expression and cellular functions is unequivocal, many fundamental questions remain regarding the identification of regulatory RNA structural motifs, their molecular mechanisms and their biological outcomes, especially in vivo.
Our lab is spinning up three main areas of research. Read on to learn more!
An additional level of cellular regulation is with complex structures, made of both proteins and RNA termed ribonucleoprotein (RNP) granules. RNP granules are thought to assemble through a process referred to as liquid-liquid phase separation, which is driven by RNA-protein and protein-protein interactions. Recent studies suggest that intermolecular RNA-RNA interactions and RNA structures play a central role in RNP granule formation, composition and function. RNP granule function controls crucial biological processes such as regulation of mRNAs in neurons that underpin synaptic plasticity, and regulation of mRNAs that drive primordial germ cell fate and, ultimately, sperm and oocyte production.
This project rests on the fundamental hypothesis that RNA structure is key to the formation of phase separations. Yet current studies have not combined powerful genome-wide structural analyses with the analysis of different liquid phases in the cell. Combining these approaches, our laboratory addresses two central unanswered questions: Does the microenvironement of RNP granules control RNA folding? What is the role of intermolecular RNA-RNA interactions and RNA structures in regulating RNP granules assembly and function?
Fertilization initiates the first biological transition in animals, where the sperm and oocyte undergo cellular reprogramming to a totipotent state during the maternal-to-zygotic transition. Initially, the maternal program, composed of mRNAs and proteins, drives cellular development until it is replaced by the zygotic program. Since this change occurs in a transcriptionally silent embryo, it relies exclusively on post-transcriptional events, such as mRNA translation and decay.
While stable RNA structures have been shown to regulate mRNA translation, our genome-wide analysis of RNA structure in zebrafish embryos found no translational regulatory activity for mRNA structures at a global level. However, we noticed that mRNAs differ in translation efficiency by >10,000-fold in the early embryo. Moreover, specialized 5’-UTR structures coordinating cap-independent translation of homeobox genes are crucial to pattern the body plan during vertebrate embryogenesis. Therefore, we hypothesize that there is a more refined regulatory code driven by sequence and RNA structure motifs modulating translation during early embryogenesis and that many regulatory elements will be conserved across systems. Our laboratory aims to dissect this universal code by combining massive parallel reporter assays and machine learning approaches with powerful vertebrate models of cellular transitions (e.i. embryonic development and neuronal differentiation).
RNA helicases are key remodelers of RNA structure, and play vital roles in embryonic development, diseases, and cancers. In our previous work, we found that dynamic 3’-UTR structures are conserved and enriched for regulatory activity. Therefore, we hypothesize that RNA helicases are fundamental regulators of gene expression during development through their ability to modify these structures. Our laboratory plans to characterize the role and molecular mechanisms of RNA helicases during vertebrate development using CRISPR technologies and genome-wide approaches (e.i. RNA-seq, Ribo-seq, eCLIP and DMS-seq).