No abstract

TET enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We demonstrate that TET1 is downregulated in nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhances behavioral responses to cocaine. We then identify 5hmC induction in both putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which is induced similarly upon TET1 knockdown alone, correlates with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. Additionally, 5hmC alterations at certain loci persist for at least one month after cocaine exposure. Together, these findings reveal a novel epigenetic mechanism of cocaine action, and provide new insight into how 5hmC regulates transcription in brain in vivo.