Exploring the RNA world to design and test novel therapeutic approaches

When Martin Sauvageau, PhD, isn’t developing therapeutic approaches for liver, pancreatic, and neurodegenerative diseases, you may find him at home in his kitchen cooking up classical French recipes or Asian cuisine. Or, more leisurely, considering the parallels between RNA cellular networks and how a city works architecturally. However, in the lab at the Institute of Clinical Research in Montreal (IRCM), he’s on a mission, researching the mysteries of long non-coding RNAs (lncRNA).

Prof. Sauvageau, Research Director at the IRCM, completed his doctoral studies at the Institute for Immunology (IRIC) and Cancer at Université de Montréal working on leukemic stem cells and epigenetic regulators. He was studying how these complexes effect the epigenetic program of leukemic stem cells and how they effect cancer stem cells. “I found in the papers that were coming out, that some of these complexes actually interact a lot with RNA,” says Prof. Sauvageau. “There was this new type of RNA that was being discovered, lncRNAs, so that piqued my interest, and it was really an open field with so many questions to be asked, that I decided to go and do a postdoc studying these novel types of RNAs.”

At the time, one of the leading labs at Harvard University was working on lncRNAs, so Prof. Sauvageau decided to pursue his post doc there. His project was to determine if lncRNAs had any importance in development in an in vivo context. “For this, I generated about 20 different knockout strains, knocking out different lncRNAs in mouse models, and looked at how this affected their embryonic development and their health generally, after birth,” he says. “We found a bunch of different important phenotypes, indicating that these novel RNAs could be actually quite important for development and for health.”

Prof. Sauvageau also started as a research associate at the Beth Israel Institute continuing to work on cancer-related RNAs. He then began to apply for positions and attained his first at the IRCM. “Right now I'm affiliated with both the University of Montreal and the McGill Biochemistry Department, and our lab is focusing on understanding how these types of RNAs work and how they affect cellular processes involved in disease.”

A history of collaboration

The IRCM and McGill shared research collaboration was established in the early 1960s. Knowledge is transmitted back and forth between the two on a regular basis. “Scientists, like several of my colleagues, interact and collaborate with other McGill researchers. The IRCM has 38 investigators and most of them are in fundamental science, for instance studying metabolic, neurodegenerative and immunological diseases. Other types of things that our lab studies include how RNAs interact with chromatin and DNA,” Prof. Sauvageau explains.

About seventy percent of the human genome is transcribed and most of these RNAs are non-coding, so they don’t produce proteins. The long noncoding RNAs Prof. Sauvageau is working on were identified about 15 years ago. “Since the mid 2000s, we’ve identified tens of thousands of these RNAs being produced by our genome. For most of them we still have no clue about what they do in the cells. We do know that some have important roles in different cellular processes.”

In different mutations found in various diseases many are in the non-coding portions of our genome and several overlap with these long non-coding RNAs, which could be involved in the development of disease.

“That’s what our lab is interested in studying,” Prof. Sauvageau explains. “First, we study the cellular and physiological roles of these lncRNAs. Second, is understanding the molecular mechanism of how these RNAs work in the cell and what type of pathways they regulate and where they are involved in the different pathways that we know; what kind of molecules they interact with, the structure of these RNAs, the motifs that aid their function. The third aspect of our lab is using our knowledge on RNA to rationally design and test novel RNA therapeutic approaches.”

The IRCM is currently working on targets that are messenger RNAs, but the goal is that with time, studying lncRNAs may become useful in diagnostics or therapeutic targets. “For now, we collaborate with several labs in developing these therapeutic approaches, for liver diseases, pancreas, the brain and neurodegenerative diseases.”

Another facet of this field is that if we take RNAs that code for proteins, we have a lexicon to interpret how the sequence of the mRNA will generate a sequence of amino acids which form the proteins. “We can recognize the words that are protein domains. We know the sentences for many of them, and now with different tools we know the structure of many of these proteins. So, we have a whole language around these protein encoding genes that allow us to study them and to predict their potential function.” However, for lncRNAs, we don't yet have such a lexicon.

One of the goals of Prof. Sauvageau’s lab is to decipher the lexicon and grammar of these RNAs. Specifically, the lab focuses on colorectal cancer and breast cancer. “And then we're also interested in developmental diseases, and so we have one RNA which is involved in a rare disease that affects newborns, that affects the development of the lungs.”

Meanwhile, back in the busy Sauvageau kitchen, the most pressing concern is the choice between stir-fried Pad Thai or Kufteh Berenji.

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