Grant: Canada Research Chairs

In humans, less than 3% of the genomic information encoded in the DNA sequence is used for the generation of RNA biomolecules that are subsequently translated into proteins to mediate various cellular functions (protein-coding genome). However, it is the non-coding genome that holds the lion’s share, ~97% of the human genomic sequence, which has been until recently called ''junk'' DNA and considered to have no functional importance. A new generation of devices called next-generation sequencers, that can read the whole genome sequence in a matter of hours, have revealed that >80% of the non-coding genome is producing RNAs that do not encode for proteins, called non-coding RNAs (ncRNAs). The function of most of them and their role in human health and disease remain largely unknown. A class of these ncRNAs, called SINE RNAs, are produced by highly repetitive sequences in the genome (SINE elements). My research program aims to shed light on the function and role of these SINE RNAs, long regarded as the “dark matter” of our genomes, in various biological contexts. Using an integrative RNA genomics approach, which combines next generation sequencing (NGS), bioinformatics, cell assays and in vivo mouse models, my lab has demonstrated that SINE RNAs have a central role in response to cellular stress and neurotoxicity and developed new methods for sequencing and analyzing their processing and editing. During my second CRC, I aim to further advance these tools and dissect the mechanisms underlying the function of SINE RNAs by addressing: • How SINE RNAs regulate the cellular response to stress in vivo, and, in particular, the response of neural cells of brain tissues such as hippocampus to neurotoxicity. • What regulates SINE RNA stability in these cells. • How we can improve the genomic and bioinformatics tools for their study. Dissecting the role of these RNAs in hippocampal cells during response to cell stress will help us understand their function in the human brain and their importance in aging-associated diseases, such as Alzheimer’s disease, which are connected with impaired response to cellular stress in the hippocampus. To achieve our goals, we are using both standard next-generation sequencing (Illumina) and a novel type of RNA sequencing, called Nanopore sequencing, which enables for the first time direct RNA sequencing for the identification of modifications in RNA sequence that may control the stability and function of SINE RNAs.