RNA structure ensemble dynamics in living cells

Introduction

Ribonucleic acid (RNA) is a jack-of-all-trades. It orchestrates and contributes to a multitude of essential cellular processes, both under physiological and pathological conditions. Among these are transcriptional and post-transcriptional regulation of gene expression, splicing, and translation control.

RNA Structure and Dynamics

Many of the functions of RNA rely on its ability to fold into stable secondary structures. However, RNA structures are far from being static. Indeed, for a given RNA, multiple alternative structural conformations can coexist as part of a heterogeneous and dynamic ensemble.

Crucial to the regulatory functions of RNA structures is their ability to dynamically redistribute the relative abundance of specific conformations within the ensemble, in response to environmental cues. Despite its ascertained importance, the study of RNA structural dynamics in living cells has largely remained elusive.

Project Goals

The goal of this ambitious proposal is to provide a deeper understanding of the mechanistic aspects underlying RNA structural dynamics in living cells, and thereby to comprehend the regulation and mechanism of action of RNAs. In other words:

• How are changes in the structure of an RNA triggered?
• How do these changes reflect on the cell’s phenotype?

Methodology

By combining cutting-edge experimental and computational methods, many of which were developed in my lab, my team will:

1. Explore how RNA secondary structure ensembles dynamically change in response to environmental cues.
2. Investigate how RNA post-transcriptional modifications and editing contribute to and control RNA secondary structure ensemble dynamics.
3. Characterize RNA secondary structure ensemble dynamics at transcription, and their contribution to splicing regulation.

Significance

By dissecting the role of RNA secondary structure ensemble dynamics in fine-tuning gene expression, the pioneering research proposed here will fill an important gap in our understanding of the mechanisms of gene regulation in cells.