Dr. Benoit Chabot is a molecular biologist with a passion for fundamental research. Over 23 years, he has become an expert in the alternative splicing of pre-messenger RNAs – the process responsible for protein diversity in humans and, largely, the complexity of life.
He was one of the first scientists to show how the process of alternative splicing is directed and to anticipate how defects in the protein-building factory within cells contribute to cancer and other diseases.
“When I started in this field, alternative splicing was an anecdote,” he recalls. “There were not enough examples for people to believe that this (process) happens in almost all of our cells.” Scientists now have evidence that 95% of human genes use alternative splicing to create protein diversity.
Dr. Chabot’s pioneering work in this field has helped to define how cells regulate the complex, protein-building process. “We’re trying to understand the fundamental rules of splicing decisions,” he explains.
He and his colleagues were first to show how SR proteins regulate alternative splicing. Today, Dr. Chabot is one of the world’s leading experts on the rules and regulators that control the molecular factories that construct proteins in our cells.
How does alternative splicing work?
Using alternative splicing, protein-building factories can build more than 100,000 proteins from only 20,000 to 25,000 genes in human DNA.
Here’s how it works. Construct three five-letter words from the following string of letters: HOUGHOFISTRSTSE.
During the word-building process, your brain selects certain letters and discards others to form “house”, “ghost” and “first”.
“The act of splicing removes bits and pieces of genetic material after a gene is transcribed to make a functional template,” explains Dr. Chabot. “Alternative splicing creates a blueprint that will dictate what kind of protein will be made. The basic process of splicing is the same, but the rules or codes governing that process differ in different types of cells or when a cell is challenged with stresses.”
For example, in the thymus, mRNA transcribes the hormone calcitonin from the same gene that brain cells use to make CGRP, a compound with completely different properties.
To complicate matters, the protein-building machinery is connected to signalling pathways that monitor the cell’s condition. “Every time it reproduces a gene, before it decides to splice the template in a certain way, it senses the cellular environment and reacts to it,” explains Dr. Chabot.
For example, depending on cellular conditions, pre-mRNA regulators can alternatively splice the pre-mRNA transcript from a gene called BCL-X to make a template for two different proteins: one kills the cell; the other helps it to survive more efficiently.
Why study alternative splicing?
“About 60% of all mutations known to cause disease in humans affect splicing,” says Dr. Chabot.
Cancer, muscular dystrophy and a host of other diseases have evidence of defective splicing; however, scientists don’t know whether these disruptions are the cause or simply a marker of the disease.
Understanding how diseases affect splicing and how to reverse the damage is another major focus of functional genomic research at the Université de Sherbrooke.
“We are trying to find ways to evaluate the impact of changes in splicing decisions on diseased cells,” he explains.
Dr. Chabot and his collaborators are working on developing molecular tools that will intervene to reprogram splicing decisions. In the last 5 years, his laboratory has documented changes in alternative splicing that occur in breast and ovarian cancers.
“We found a collection of events that differ in those tissues,” he says. “Once we identify those that are functionally relevant, we can use our tools to try to modulate them.”
Dr. Chabot hopes that this research will identify sets of signature splicing events that will act as strong markers to diagnose phenotypes of breast or ovarian cancer that respond well or not at all to certain types of treatment.
Through his quiet leadership, Dr. Chabot has championed this field of research in Canada. “Twenty-three years ago, I was alone in Canada working on this. Nobody had really done anything with alternative splicing. When I arrived at Université de Sherbrooke, only a few people were interested in RNA research. Now, this institution is considered an RNA hub and alternative splicing is one of our strengths,” he says.
“We’ve come a long way. We now have a platform that performs splicing analysis for scientists at my institution, in Canada and throughout the world. A truly impressive collection of people has contributed to building this unit that addresses functional and regulatory aspects of alternative splicing,” he states. “To witness that progress has been very satisfying.”