MATHIEU LUPIEN RESEARCH LABORATORY
Our genome consists of 6 billion “letters” of DNA sequence that form “words” of different nature, such as "nouns" (genes), "verbs" (promoters) and "adjectives" (enhancers) [1, 2]. These need to be organized into “sentences” to give rise to any particular “story”. Muscle, brain, bone and all other cells each emerge from unique "stories". The order of the letters does not typically change across different cell types. The key to generate muscle versus brain or other cell types is to fold our genome differently in each cell to re-align words and thereby create distinct sentences giving rise to unique stories. In the process, some words are masked and therefore no longer part of the story. This folding process is guided by epigenetic events, literally events above (epi) our genome (genetics), that act like post-it notes to bookmark the regions of our genome that need to be read and those that are to be masked in any particular cell type.

Disease development commonly stems from changes in the story of normal cells. Mutations or genetic variations will change the letters or words of a normal story to promote cancer development. Genetic profiling has identified a large collection of mutations and genetic predispositions to cancer. However, the words they target and thereby the underlying biological mechanisms affected in cancer are for the most part unknown.

One research project led by the Lupien Lab consists of delineating the functional consequence of mutations and genetic predispositions in cancer by identifying the words they target and determining the story of cancer cells. This is possible by mapping epigenetic events that discriminate the different words of the human genome. Epigenetic events correspond to the cosmetic changes applied to the human genome. They are chemical modifications that regulate word masking and genome "folding". Different epigenetic events can discriminate out nouns from verbs and adjectives that are readable or masked across the genome. Based on this, the Lupien Lab recently mapped a series of epigenetic events found on the genome of cancer cells to demonstrate that genetic predispositions to breast and prostate cancers were preferentially found in adjectives (enhancers) [1, 2]. These genetic alterations can modulate the function of these adjectives, changing their degree, thereby affecting expression of target oncogenes or tumor suppressor genes (the nouns) to promote cancer development. For instance a normal sentence such as “express more gene A” would be changed in cancer to “express less gene A”. We are currently applying this methodology to reveal the functional nature of mutations that accumulate in tumors throughout their development or as they acquire resistance to drug treatment.