Grant: Project Grant

Recent technological advances have led to a number of important discoveries. Amongst these is the realization that the better part of our genome is read at one time or another to produce RNA molecules that do not encode proteins. Given that the biological function of most of these "non-coding RNA" transcripts is unknown, they currently fall into different categories based mainly on their size and the site from which they are produced in the genome. The "long non-coding RNAs" (lncRNAs) are one such class of molecules. The biological relevance of many lncRNAs has been demonstrated, with family members even considered as promising therapeutic or prognostic tools. Yet, how they regulate gene expression is very poorly understood. In this project, we suggest using four lncRNAs as discovery tools to identify and characterize new mechanisms used by this family of molecules to control gene expression. These lncRNAs are encoded within the HOXA gene cluster and have been linked to human cancers. We previous showed that one of them, HOTAIRM1, regulates the expression of HOXA genes both by regulating what binds and shapes the DNA encoding them. Our preliminary data indicates that HOTAIRM1 regulates many other genes across the genome. To better understand their biological function, we will first identify new gene targets genome-wide. We will investigate how they regulate genome folding and spatial organization using state-of-the-art technologies that yield three-dimensional maps of our genome at very high resolution. This information will then be used to characterize the molecular mechanisms used by the HOXA-encoded lncRNAs to regulate gene expression, and test our hypothesis that given lncRNAs can use different molecular mechanisms to modulate gene expression depending on the DNA context and/or target gene.