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

doi:10.1016/j.isci.2021.103169

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

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12 Scopus citations

Abstract

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.

Original language	English
Article number	103169
Journal	iScience
Volume	24
Issue number	10
DOIs	https://doi.org/10.1016/j.isci.2021.103169
State	Published - 22 Oct 2021

Keywords

drugs
molecular mechanism of gene regulation
molecular neuroscience

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Vaillancourt, K., Chen, G. G., Fiori, L., Maussion, G., Yerko, V., Théroux, J. F., Ernst, C., Labonté, B., Calipari, E., Nestler, E. J., Nagy, C., Mechawar, N., Mash, D. C., & Turecki, G. (2021). Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum. iScience, 24(10), Article 103169. https://doi.org/10.1016/j.isci.2021.103169

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title = "Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum",

abstract = "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.",

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AU - Yerko, Volodymyr

AU - Théroux, Jean François

AU - Ernst, Carl

AU - Labonté, Benoit

AU - Calipari, Erin

AU - Nestler, Eric J.

AU - Nagy, Corina

AU - Mechawar, Naguib

AU - Mash, Deborah C.

AU - Turecki, Gustavo

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AB - 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.

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

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