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Nat Neurosci. 2015 Apr;18(4):536-44. doi: 10.1038/nn.3976. Epub 2015 Mar 16.

Role of Tet1 and 5-hydroxymethylcytosine in cocaine action.

Author information

1
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
3
1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Institut National de la Santé et de la Recherhe Médicale (INSERM) U1130, CNRS UMR8246, UPMC UM18, Neuroscience Paris Seine, Paris, France.
4
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
5
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
6
Institut National de la Santé et de la Recherhe Médicale (INSERM) U1130, CNRS UMR8246, UPMC UM18, Neuroscience Paris Seine, Paris, France.
7
The McGill Group for Suicide Studies, Douglas Hospital Research Centre, McGill University, Montreal, Canada.
8
Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Abstract

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.

Comment in

PMID:
25774451
PMCID:
PMC4617315
DOI:
10.1038/nn.3976
[Indexed for MEDLINE]
Free PMC Article

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