Applying new technologies to dissect RNA dynamics in response to cellular stress

Illuminating the role of RNA in response to cellular stress is fundamental in understanding how cells rapidly adapt to environmental challenges.

Cellular stress also underpins many human diseases including neurodegeneration, diabetes and cancer and is associated with chemotherapeutic resistance. Therefore, elucidating the molecular mechanisms controlling the stress response is crucial. Our preliminary work has used RNA-seq and metabolic labelling-coupled sequencing (SLAM-seq) to measure genome-wide RNA decay in response to stress in human cells.

This has revealed a specific role for RNA degradation in controlling key components of the stress response, including regulators of extracellular vesicles (EVs) and cell communication pathways.

This project will use a multi-disciplinary approach including molecular biology, biotechnology and bioinformatics to develop and apply new techniques to address the hypothesis that RNA regulatory machines are crucial in controlling EV biology and subsequent survival in response to stress, in human cells.

We have 3 main objectives: 1) To understand how defects in RNA turnover affect the secretory pathway and EV content. 2) To develop a novel molecular approach to allow direct assessment of EV-derived RNA dynamics. 3) To assess how EV-derived RNA is regulated under normal conditions and how regulation changes in response to stress.

The project will lead to a new understanding of the fundamental mechanisms regulating RNA fate and function in response to stress and reveal novel regulators of the stress response. Moreover, in the new age of RNA therapeutics, understanding how both endogenous and exogenous RNA is regulated under sub-optimal conditions, such as those in a disease state, is crucial in maximising the biotechnological and therapeutic potential of RNA.