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

TitleMethylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum.
Publication TypeJournal Article
Year of Publication2021
AuthorsVaillancourt K, Chen GG, Fiori L, Maussion G, Yerko V, Théroux J-F, Ernst C, Labonte B, Calipari E, Nestler EJ, Nagy C, Mechawar N, Mash DC, Turecki G
JournaliScience
Volume24
Issue10
Pagination103169
Date Published2021 Oct 22
ISSN2589-0042
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 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.

DOI10.1016/j.isci.2021.103169
Alternate JournaliScience
PubMed ID34693223
PubMed Central IDPMC8517202
Grant ListP01 DA047233 / DA / NIDA NIH HHS / United States
R01 DA007359 / DA / NIDA NIH HHS / United States