The Three-Dimensional Genome and Epigenetics basis of Cancer: From Genes and Beyond
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.
In addition to genetic alterations (research theme 1), changes in the readability of “words” can alter stories to promote cancer development. This occurs through epigenetic events that will affect how the genome is folded or how particular "words" are masked.
A second research project in The Lupien Lab consists of mapping the epigenetic events discriminating the nature of “words” across cancer cell genomes. Through this approach the “stories” specific to cancer cells can be identified. This approach was recently applied in colorectal cancer where significant differences in the maps of epigenetic events specific to enhancers  (the adjectives) could be detected between normal colorectal crypt and cancer cells. This is also used to identify the mechanisms that promote cancer progression. Recent work from the Lupien Lab compared epigenetic maps from breast cancer cells responsive or resistant to hormonal (endocrine) therapy . Results revealed significant differences in all types of “words” that were masked and readable between drug-responsive and resistant breast cancer cells. This revealed a “story” specific to hormonal therapy-resistant breast cancer cells indicative of the activation of the Notch pathway. In agreement, drugs against the Notch pathway could block the growth of hormonal therapy-resistant breast cancer cells. On-going research is expanding this work to clinical samples.
For more information, please visit the Lupien Lab website.