Methamphetamine Induces TET1- and TET3-Dependent DNA Hydroxymethylation of Crh and Avp Genes in the Rat Nucleus Accumbens

Abstract

Methamphetamine (METH) addiction is a biopsychosocial disorder that is accompanied by multiple relapses even after prolonged abstinence, suggesting the possibilities of long-lasting maladaptive epigenetic changes in the brain. Here, we show that METH administration produced time-dependent increases in the expression of corticotropin-releasing hormone (Crh/Crf), arginine vasopressin (Avp), and cocaine- and amphetamine-regulated transcript prepropeptide (Cartpt) mRNAs in the rat nucleus accumbens (NAc). Chromatin immunoprecipitation (ChIP) assays revealed that METH increased the abundance of phosphorylated CREB (pCREB) at the promoter of Cartpt but not at Avp or Crh DNA sequences. In contrast, METH produced DNA hypomethylation at sites near the Crh transcription start site (TSS) and at intragenic Avp sequences. METH also increased DNA hydroxymethylation at the Crh TSS and at intragenic Avp sites. In addition, METH increased the protein expression of ten-eleven-translocation enzymes that catalyze DNA hydroxymethylation. Importantly, METH increased TET1 binding at the Crh promoter and increased TET3 binding at Avp intragenic regions. We further tested the role of TET enzymes in METH-induced changes in gene expression by using the TET inhibitor, 1,5-isoquinolinediol (IQD), and found that IQD blocked METH-induced increases in Crh and Avp mRNA expression. Together, these results indicate that METH produced changes in neuropeptide transcription by both activation of the cAMP/CREB pathway and stimulation of TET-dependent DNA hydroxymethylation. These results provide molecular evidence for epigenetic controls of METH-induced changes in the expression of neuropeptides.Electronic supplementary materialThe online version of this article (10.1007/s12035-017-0750-9) contains supplementary material, which is available to authorized users.

DNA Methylation and Hydroxymethylation in Cervical Cancer: Diagnosis, Prognosis and Treatment

“…The Ten-eleven translocation (TET) family oxidize 5-mC to 5-hydroxymethylcytosine (5-hmC) that is further oxidized to 5-formylcytosine and 5-carboxylcytosine. Finally, using thymine-DNA glycosylase (TDG), the carboxyl group from 5formylcytosine and 5-carboxylcytosine are removed to restore unmethylated cytosine pool (Figure 1; Silva et al, 2017;Jayanthi et al, 2018;Zhu et al, 2018). 5-hmC is an intermediate throughout the process (Li et al, 2016).…”

Physiological and Epigenetic Features of Yoyo Dieting and Weight Control

“…Of similar importance are hedonic control centers and reward circuitry within the limbic system, which orchestrate behavioral and biological responses such as food seeking, food reward and food perception behaviors, memory formation and cognition. These brain regions are susceptible to epigenetic reprogramming (Alsiö et al, 2010;Miller et al, 2010;Gupta-Agarwal et al, 2014;Jayanthi et al, 2018), and are likely targets for epigenetic modifications induced by obesity. Future studies should unravel whether an epigenetic memory for obesity exists within these CNS centers, and whether it is functionally linked to the regulation of body weight or weight re-gain after weight loss.…”

“…NK1R upregulation) and the promotion of reward behaviors within a conditioned place preference paradigm (Renthal et al, 2007). Methamphetamine intake promoted hydroxylation and hypomethylation in CpG-rich regions in the promoter and intragenic sequences of the Crh/Crf and Avf genes in the NAc (Jayanthi et al, 2018). The increased expression of both neuropeptide genes is associated with prolonged neuroendocrine responses like hypersecretion of plasma adrenocorticotropine hormone (ACTH) and cortisone after acute amphetamine injections (Bisagno and Cadet, 2014).…”

A Single Prior Injection of Methamphetamine Enhances Methamphetamine Self-Administration (SA) and Blocks SA-Induced Changes in DNA Methylation and mRNA Expression of Potassium Channels in the Rat Nucleus Accumbens

“…We selected to use the 3-week time-point to perform SA experiments after the non-contingent METH injection because of previous studies in which we had documented enhanced changes in gene expression in rats that were euthanized one month after a single injection of METH (10 mg/kg) [40]. Increased expression of stress-related genes was apparent after 2 weeks and remained elevated for one month [72].…”

“…Genomic DNA was isolated from NAc tissues by overnight Proteinase K treatment, phenol-chloroform extraction, ethanol precipitation, and RNase digestion as previously described by Jayanthi et al (2017) [72]. Subsequently, 300 μL fractions of DNA (20 μg) were sheared by ultrasonic treatment using the Diagenode Bioruptor (12 cycles, 30 s "ON", 30 s "OFF") to obtain a fragment size between~200-600 bp.…”