Role of Tet1 and 5-hydroxymethylcytosine in cocaine action
| Autor: | Keith E. Szulwach, Chun Zhong, Li Shen, Guo Li Ming, David Estey, Yujing Li, Benjamin M. Laitman, Gustavo Turecki, Ning-Yi Shao, Ja Wook Koo, Hongjun Song, Kym F. Faull, Victoria Stockman, Patrizia Casaccia, Jimmy Huynh, Michael E. Cahill, Peng Jin, Deveroux Ferguson, Efrain Ribeiro, Vincent Vialou, Thuc Le, Pamela J. Kennedy, Guoping Fan, Eric J. Nestler, Thomas Couroussé, Isaac Mensah, Jian Feng, Benoit Labonté |
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| Rok vydání: | 2015 |
| Předmět: |
Male
Drug Abuse (NIDA Only) Behavioral epigenetics Down-Regulation Gene Expression Pharmacology Biology Nucleus accumbens Epigenetics of cocaine addiction Inbred C57BL Nucleus Accumbens Epigenesis Genetic chemistry.chemical_compound Cytosine Mice Genetic Cocaine Proto-Oncogene Proteins Genetics Psychology Animals Enhancer 5-Hydroxymethylcytosine Behavior Gene knockdown Neurology & Neurosurgery Behavior Animal Animal General Neuroscience Substance Abuse Neurosciences Brain Disorders DNA-Binding Proteins Mice Inbred C57BL DNA demethylation chemistry 5-Methylcytosine Cognitive Sciences Brain stimulation reward Neuroscience Biotechnology Epigenesis |
| Zdroj: | Nature neuroscience, vol 18, iss 4 |
| ISSN: | 1546-1726 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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