TY - JOUR
T1 - Methylation of the tyrosine hydroxylase gene is dysregulated by cocaine dependence in the human striatum
AU - Vaillancourt, Kathryn
AU - Chen, Gang G.
AU - Fiori, Laura
AU - Maussion, Gilles
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
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/10/22
Y1 - 2021/10/22
N2 - 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.
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.
KW - drugs
KW - molecular mechanism of gene regulation
KW - molecular neuroscience
UR - https://www.scopus.com/pages/publications/85123074084
UR - https://www.scopus.com/pages/publications/85123074084#tab=citedBy
U2 - 10.1016/j.isci.2021.103169
DO - 10.1016/j.isci.2021.103169
M3 - Article
AN - SCOPUS:85123074084
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 10
M1 - 103169
ER -