Feng Jian, Shao Ningyi, Szulwach Keith E, Vialou Vincent, Huynh Jimmy, Zhong Chun, Le Thuc, Ferguson Deveroux, Cahill Michael E, Li Yujing, Koo Ja Wook, Ribeiro Efrain, Labonte Benoit, Laitman Benjamin M, Estey David, Stockman Victoria, Kennedy Pamela, Couroussé Thomas, Mensah Isaac, Turecki Gustavo, Faull Kym F, Ming Guo-li, Song Hongjun, Fan Guoping, Casaccia Patrizia, Shen Li, Jin Peng, Nestler Eric J
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
Nat Neurosci. 2015 Apr;18(4):536-44. doi: 10.1038/nn.3976. Epub 2015 Mar 16.
Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which occurred similarly following TET1 knockdown alone, correlated with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. In addition, 5hmC alterations at certain loci persisted for at least 1 month after cocaine exposure. Together, these reveal a previously unknown epigenetic mechanism of cocaine action and provide new insight into how 5hmC regulates transcription in brain in vivo.
10-11易位（TET）酶介导5-甲基胞嘧啶（5mC）向5-羟甲基胞嘧啶（5hmC）的转化，5hmC在大脑中含量丰富，最终实现DNA去甲基化。然而，TET和5hmC对大脑基因转录的影响仍不清楚。我们发现，重复给予可卡因会使小鼠伏隔核（NAc，大脑关键的奖赏结构）中的10-11易位蛋白1（TET1）表达下调，这增强了对可卡因的行为反应。然后我们在药物成瘾中起关键作用的基因的推定增强子和编码区域中鉴定出5hmC的诱导。这种5hmC的诱导在单独敲低TET1后也类似地发生，与这些基因的表达增加以及它们在可卡因给药后的可变剪接相关。此外，可卡因暴露后某些位点的5hmC改变至少持续1个月。这些结果共同揭示了一种先前未知的可卡因作用的表观遗传机制，并为5hmC如何在体内调节大脑中的转录提供了新见解。
