Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum
Kathryn Vaillancourt,
Gang G. Chen,
Laura Fiori,
Gilles Maussion,
Volodymyr Yerko,
Jean-François Théroux,
Carl Ernst,
Benoit Labonté,
Erin Calipari,
Eric J. Nestler,
Corina Nagy,
Naguib Mechawar,
Deborah C. Mash,
Gustavo Turecki
Affiliations
Kathryn Vaillancourt
McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
Gang G. Chen
McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada
Laura Fiori
McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada
Gilles Maussion
Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, QC, Canada
Volodymyr Yerko
McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada
Jean-François Théroux
McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada
Carl Ernst
Department of Psychiatry, McGill University, Montreal, QC, Canada
Benoit Labonté
Centre de Recherche Cervo, Université Laval, Québec, QC, Canada
Erin Calipari
Departments of Pharmacology, Molecular Physiology and Biophysics, Psychiatry and Behavioral Sciences; Vanderbilt Center for Addiction Research; Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA
Eric J. Nestler
Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Corina Nagy
McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada; Department of Psychiatry, McGill University, Montreal, QC, Canada
Naguib Mechawar
McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada; Department of Psychiatry, McGill University, Montreal, QC, Canada
Deborah C. Mash
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
Gustavo Turecki
McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University, Montreal, QC, Canada; Corresponding author
Summary: Cocaine dependence is a chronic, relapsing disorder caused by lasting changes in the brain. Animal studies have identified cocaine-related alterations in striatal DNA methylation; however, it is unclear how methylation is related to cocaine dependence in humans. We generated methylomic profiles of the nucleus accumbens using human postmortem brains from a cohort of individuals with cocaine dependence and healthy controls (n = 25 per group). We found hypermethylation in a cluster of CpGs within the gene body of tyrosine hydroxylase (TH), containing a putative binding site for the early growth response 1 (EGR1) transcription factor, which is hypermethylated in the caudate nucleus of cocaine-dependent individuals. We replicated this finding and found it to be specific to striatal neuronal nuclei. Furthermore, this locus demonstrates enhancer activity which is attenuated by methylation and enhanced by EGR1 overexpression. These results suggest that cocaine dependence alters the epigenetic regulation of dopaminergic signaling genes.
