Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum

iScience

Gang G. Chen¹  Naguib Mechawar²  Corina Nagy³  Erin Calipari⁴  Volodymyr Yerko⁵  Benoit Labonté⁶  Eric J. Nestler⁷  Gilles Maussion⁸  Carl Ernst⁸  Laura Fiori⁸  Jean-François Théroux⁸  Gustavo Turecki⁸  Kathryn Vaillancourt⁸  Deborah C. Mash⁹ 

[1] Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada;Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA;Vanderbilt Center for Addiction Research;Centre de Recherche Cervo, Université Laval, Québec, QC, Canada;Department of Neurology and Neurosurgery, Montreal Neurological Institute, Montreal, QC, Canada;Department of Psychiatry, McGill University, Montreal, QC, Canada;Departments of Pharmacology, Molecular Physiology and Biophysics, Psychiatry and Behavioral Sciences;McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada;Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA;

关键词: drugs;    molecular mechanism of gene regulation;    molecular neuroscience;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown