Grant: Project Grant

Recent technological advances have led to the important realization that the better part of our genome is read to produce RNA molecules that do not encode proteins. The "long non-coding RNAs" (lncRNAs) are one such class of molecules with demonstrated biological significance. Many were found to function as regulators of various biological processes. They also play essential roles in cancer biology, where abnormal lncRNA expression profiles are found in virtually all cancers. Their impact on cancer is broad, ranging from the control of cell proliferation to cell invasion and drug resistance. In fact, lncRNAs are promising high precision tools for cancer diagnosis, prognosis, and therapy. Yet, how they regulate gene expression is very poorly understood. In this project, we suggest investigating how lncRNAs may use strategies that combine different mechanisms to orchestrate gene regulation in a cell context-dependent fashion, as well as their own regulation. We will mainly use the HOTAIRM1 lncRNA as discovery tool although part of our analysis will be genome wide. Like many other lncRNAs, HOTAIRM1 is often misexpressed in cancer, but can act as oncogene or tumour suppressor depending on cancer type. It is also found both in the cell nucleus and cytoplasm, allowing for discovery of strategies involving coordinated regulation across cellular compartments. We will first characterize the proteins and RNAs associated with HOTAIRM1 to understand how they might be regulated and regulate gene expression when this lncRNA is present. We will then identify and characterize lncRNA-regulated genes controlled epigenetically and through genome folding using state-of-the-art technologies that yield three-dimensional maps of our genome to characterize molecular mechanisms regulating transcription. Finally, we will examine how HOTAIRM1-interacting proteins and translation can control its abundance in different cell contexts to better understand how HOTAIRM1 levels can be regulated.