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在人类纹状体中，酪氨酸羟化酶基因的甲基化因可卡因成瘾而失调。

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

作者信息

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

机构信息

McGill Group for Suicide Studies, Douglas Hospital Research Center, Verdun, QC, Canada.

Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.

出版信息

iScience. 2021 Sep 25;24(10):103169. doi: 10.1016/j.isci.2021.103169. eCollection 2021 Oct 22.

DOI:10.1016/j.isci.2021.103169
PMID:34693223
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8517202/
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.

摘要

可卡因成瘾是一种由大脑持久变化引起的慢性复发性疾病。动物研究已确定纹状体DNA甲基化与可卡因相关的改变；然而，甲基化如何与人类可卡因成瘾相关尚不清楚。我们使用来自一组可卡因成瘾个体和健康对照（每组n = 25）的人类死后大脑生成了伏隔核的甲基化组图谱。我们发现酪氨酸羟化酶基因体内的一组CpG存在高甲基化，该基因含有早期生长反应1（EGR1）转录因子的推定结合位点，在可卡因成瘾个体的尾状核中该位点也发生了高甲基化。我们重复了这一发现，并发现它对纹状体神经元核具有特异性。此外，该位点表现出增强子活性，其被甲基化减弱并被EGR1过表达增强。这些结果表明，可卡因成瘾会改变多巴胺能信号基因的表观遗传调控。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/af31313a9a3c/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/beb53b02d32d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/86d2bf86c775/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/8296379ba6e5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/ecf020aee317/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/416ed7d844c8/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/af31313a9a3c/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/beb53b02d32d/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/86d2bf86c775/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/8296379ba6e5/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/ecf020aee317/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/416ed7d844c8/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9de0/8517202/af31313a9a3c/gr5.jpg

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