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

• Published in: iScience Vol. 24; no. 10; p. 103169
• Main Authors: Vaillancourt, Kathryn, Chen, Gang G., Fiori, Laura, Maussion, Gilles, Yerko, Volodymyr, Théroux, Jean-François, Ernst, Carl, Labonté, Benoit, Calipari, Erin, Nestler, Eric J., Nagy, Corina, Mechawar, Naguib, Mash, Deborah C., Turecki, Gustavo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.10.2021; Elsevier
• Subjects: drugs; molecular mechanism of gene regulation; molecular neuroscience; molecular mechanism of gene regulation; drugs; molecular neuroscience
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.103169

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. [Display omitted] •Chronic cocaine dependence alters DNA methylation in human nucleus accumbens•The TH gene contains a binding site for EGR1, a cocaine-induced DNA binding protein•The EGR1 binding site is hypermethylated after chronic cocaine in striatal neurons•This region has enhancer activity that is responsive to EGR1 and methylation levels Drugs; Molecular mechanism of gene regulation; Molecular neuroscience