Dr. Kathryn Vaillancourt – McGill University
Kathryn Vaillancourt, Jennie Yang, Gary G. Chen, Volodymyr Yerko, Jean-François Théroux, Zahia Aouabed, Alberto Lopez, Kimberly C. Thibeault, Erin S. Calipari, Benoit Labonté, Naguib Mechawar, Carl Ernst, Corina Nagy, Thierry Forné, Eric J. Nestler, Deborah C. Mash & Gustavo Turecki
Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster. Molecular Psychiatry. 2020 Oct 12. https://doi.org/10.1038/s41380-020-00909-x
Methylation could mediate addiction-related neurobiological changes in humans
Epigenetic modification is a process through which expression of genes can be modified in a heritable fashion but without any change in the DNA sequence encoding this gene. One well-known mechanism of epigenetic modification is through DNA methylation. Although DNA methylation has been studied as a biological mediator of cocaine addiction in animals, this study by Kathryn Vaillancourt and colleagues is the first to investigate cocaine-related methylation changes in humans.
Using brain tissue from patients who donated their brain after death, the researchers provide the first evidence that methylation might mediate addiction-related neurobiological changes in humans. They identified over 100 regions of the genome that were differentially methylated in a specific brain region of humans with a history of cocaine dependence. Among them, a region of a gene called IRX2 was less methylated in the cocaine group. This region was also less methylated in a mouse model of chronic cocaine self-administration. IRX2 encodes a neurodevelopmental transcription factor, which is an element that regulates the expression of other genes during development.
Furthermore, Kathryn Vaillancourt and colleagues identified a novel cocaine-sensitive regulatory element within the IRX2 gene, and showed that it has an important impact on local gene expression by regulating the three-dimensional structure of DNA. This gene had not previously been associated with drug dependence, and it represents a novel avenue of exploration into cocaine neurobiology and therapeutic research.
Dr. Kathryn Vaillancourt
This work was done during Kathryn Vaillancourt’s Ph.D. in the laboratory of Dr. Gustavo Turecki at McGill University. Dr. Vaillancourt oversaw the experimental design and scientific direction of the project. She generated most of the data, guided bioinformatic analysis, and analysed and interpreted the data from all follow up experiments. Dr. Vaillancourt also wrote the manuscript and generated all figures in the publication.
Source of funding
This work was supported by a Canadian Institute of Health Research Doctoral Fellowship awarded to Kathryn Vaillancourt, National Institute of Drug Abuse Grants, and grants from the Whitehall Foundation, the Edward Mallinckrodt Jr., Foundation, and the Brain and Behavior Research Foundation.