Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2.
Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2.
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DOI：
10.1038/mp.2016.131
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发表时间：
2017-12
影响因子：
11
通讯作者：
Heilig M
中科院分区：
文献类型：
--
作者：
Barbier E;Johnstone AL;Khomtchouk BB;Tapocik JD;Pitcairn C;Rehman F;Augier E;Borich A;Schank JR;Rienas CA;Van Booven DJ;Sun H;Nätt D;Wahlestedt C;Heilig M
表观遗传过程涉及酒精依赖的病理生理学，但介导依赖诱导的神经适应的特定分子机制在很大程度上仍不清楚。在这里，我们发现酒精依赖史持续降低大鼠背内侧前额叶皮质(DmPFC)中Prdm2的表达，Prdm2是一种组蛋白甲基转移酶，它使组蛋白3在赖氨酸9位残基(H3K9me1)上单甲基化。Prdm2基因表达下调与H3K9me1基因表达下降相关，支持Prdm2基因表达水平的改变影响其活性。染色质免疫沉淀和大规模平行DNA测序表明，在依赖大鼠中，参与突触通讯的基因受到H3K9me1的表观遗传调控。在非依赖大鼠中，病毒载体介导的dmPFC中Prdm2基因的敲除导致了类似于酒精依赖病史后观察到的表达变化。Prdm2基因敲除导致酒精自我给药增加，抗厌恶酒精摄入量增加，并增强了应激诱导的重新饮酒行为，这是后依赖大鼠的一种表现。总而言之，这些结果确定了一种新的表观遗传学机制，有助于在依赖史之后发展寻找酒精的行为。
Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.
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影响因子：
4.8
作者：
Finegersh A;Ferguson C;Maxwell S;Mazariegos D;Farrell D;Homanics GE
通讯作者：
Homanics GE
影响因子：
16.2
作者：
Frank, Thomas;Rutherford, Mark A.;Strenzke, Nicola;Neef, Andreas;Pangrsic, Tina;Khimich, Darina;Fetjova, Anna;Gundelfinger, Eckart D.;Liberman, M. Charles;Harke, Benjamin;Bryan, Keith E.;Lee, Amy;Egner, Alexander;Riedel, Dietmar;Moser, Tobias
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Moser, Tobias
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4.5
作者：
Connor CM;Dincer A;Straubhaar J;Galler JR;Houston IB;Akbarian S
通讯作者：
Akbarian S
影响因子：
5.2
作者：
Geli, Janos;Kiss, Nimrod;Larsson, Catharina
通讯作者：
Larsson, Catharina
影响因子：
5.3
作者：
Barbier, Estelle;Tapocik, Jenica D.;Heilig, Markus
通讯作者：
Heilig, Markus