Role of Tet1 and 5-hydroxymethylcytosine in cocaine action

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.

The effect of morphine upon DNA methylation in ten regions of the rat brain

“…TET1 has been demonstrated to be down-regulated in response to cocaine administration, leading to locus-specific decreases in 5-hmc. 39 Whilst other studies have reported no change in global 5-hmc content in response to heroin and cocaine exposure 19,20,39 , they have focussed upon a single region (nucleus accumbens) or utilized homogenized brain tissue and therefore could not exclude the possibility of localized changes in 5-hmc in specific regions of the brain. The limitations of such approaches were addressed in the current study.…”

Genome-wide DNA hydroxymethylation identifies potassium channels in the nucleus accumbens as discriminators of methamphetamine addiction and abstinence

“…Here we show that compulsive METH taking is associated with large-scale changes in DNA hydroxymethylation in the rat NAc, consistent with a potential role for DNA hydroxymethylation processes in addiction. 43 Genes that were affected in the METH-addicted rats included those that participate in calcium signaling, among others. In contrast, nonaddicted rats exhibited increased expression of mRNAs that code for several K+ channels in NAc, but not in the PFC and dorsal striatum.…”

5-Hydroxymethylcytosine (5hmC) and Ten-eleven translocation 1–3 (TET1–3) proteins in the dorsal root ganglia of mouse: Expression and dynamic regulation in neuropathic pain

“…Previous studies have demonstrated that 5hmC correlates positively with gene expression in neurons of the CNS and in olfactory neurons (Khare et al 2012; Colquitt et al 2013; Perera et al 2015), and that some neurological disease states show dynamic regulation of 5hmC (Feng et al 2015). Microarray and RNA sequencing (RNA-Seq) experiments in animal models of neuropathic pain have shown that hundreds of genes are dynamically upregulated by injury and that such changes contribute to the development of neuropathic pain (Costigan et al 2002; Scholz and Woolf 2007; LaCroix-Fralish et al 2011).…”

“…One novel epi-genetic mark that has been intensely studied in the central nervous system (CNS) is 5-hydroxymethylcytosine (5hmC), which is produced by hydroxylation of 5-methylcytosine (5mC) through the action of the Ten-eleven translocation hydroxylases (TET1–3) (Pastor et al 2013). 5hmC has been implicated in many neuronal processes, including learning, memory, synaptic transmission, and disease states such as cocaine addiction (Szulwach et al 2011; Kaas et al 2013; Feng et al 2015). Genome-wide studies have revealed that 5hmC correlates positively with gene expression in neurons, in contrast to its progenitor, 5mC, which generally acts to silence gene expression (Xu et al 2011; Denk and McMahon 2012; Colquitt et al 2013).…”