Role of Tet1 and 5-hydroxymethylcytosine in cocaine action
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Li Shen
PROVIDER: E-GEOD-63749 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Here we show that Tet1 is down-regulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration which enhances behavioral responses to cocaine. Through genome-wide 5hmC profiling, we identified 5hmC changes selectively clustered in both enhancer and coding regions of genes with several annotated neural functions. By coupling with mRNA sequencing, we found cocaine-induced alterations in 5hmC correlate positively with alternative splicing. We also demonstrated that 5hmC alteration at certain genes lasts up to a month after cocaine exposure. RNA Nac samples were collected at various time points after 7 daily cocaoine ip administration for 5hmC and transcriptome analysis
2015-02-23 | E-GEOD-63748 | biostudies-arrayexpress
Project description:Here we show that Tet1 is down-regulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration which enhances behavioral responses to cocaine. Through genome-wide 5hmC profiling, we identified 5hmC changes selectively clustered in both enhancer and coding regions of genes with several annotated neural functions. By coupling with mRNA sequencing, we found cocaine-induced alterations in 5hmC correlate positively with alternative splicing. We also demonstrated that 5hmC alteration at certain genes lasts up to a month after cocaine exposure. DNA Nac samples were collected at various time points after 7 daily cocaoine ip administration for 5hmC and transcriptome analysis
2015-02-23 | E-GEOD-63747 | biostudies-arrayexpress
Project description:Genetic association studies, pharmacological investigations and analysis of mice-lacking individual genes have made it clear that Cocaine administration and Withdrawal have a profound impact on multiple neurotransmitter systems. The GABAergic medium spiny neurons of the nucleus accumbens (NAc) exhibit changes in the expression of genes encoding receptors for glutamate and in the signaling pathways triggered by dopamine binding to G-protein-coupled dopamine receptors. Deep sequence analysis provides a sensitive, quantitative and global analysis of the effects of Cocaine on the NAc transcriptome. RNA prepared from the NAc of adult male mice receiving daily injections of Saline or Cocaine, or Cocaine followed by a period of Withdrawal, was used for high-throughput sequence analysis. Changes were validated by quantitative polymerase chain reaction or Western blot. On the basis of pathway analysis, a preponderance of the genes affected by Cocaine and Withdrawal was involved in the cadherin, heterotrimeric G-protein and Wnt signaling pathways. Distinct subsets of cadherins and protocadherins exhibited a sustained increase or decrease in expression. Sustained down-regulation of several heterotrimeric G-protein β- and γ-subunits was observed. In addition to altered expression of receptors for small molecule neurotransmitters, neuropeptides and endocannabinoids, changes in the expression of plasma membrane transporters and vesicular neurotransmitter transporters were also observed. The effects of chronic Cocaine and Withdrawal on the expression of genes essential to cholinergic, glutamatergic, GABAergic, peptidergic and endocannabinoid signaling are as profound as their effects on dopaminergic transmission. Simultaneous targeting of multiple Withdrawal-specific changes in gene expression may facilitate development of new therapeutic approaches that are better able to prevent relapse. High-throughput sequence analysis of RNA prepared from the nucleus accumbens of adult male mice receiving daily injections of Saline or Cocaine, or Cocaine followed by a period of Withdrawal. Nucleus accumbens libraries were sequenced in nine lanes (three technical replicates per sample) on an Illumina GAIIx using a 37-cycle paired-end sequencing protocol. Replicates were analyzed for intra-sample disparity and read data from all three lanes were then merged into one composite data file per sample; intra-sample coefficient of determination, R2 ≥ 0.98. The composite file was used for subsequent analyses.
2013-01-10 | E-GEOD-43410 | biostudies-arrayexpress
Project description:Despite addiction being one of the most prevalent and debilitating disorders worldwide, effective treatments are lacking. Repeated cocaine exposure induces maladaptive transcriptional regulation within the brainâ??s reward circuitry, such as the nucleus accumbens (NAc), and epigenetic mechanisms, such as histone acetylation or methylation on Lys (K) residues, have been linked to these lasting actions of cocaine. However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains unexplored in addiction models and poorly understood in brain in general. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, as well as in the NAc of cocaine-addicted humans. PRMT6 downregulation occurs selectively in NAc medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we demonstrate that reduced H3R2me2a binding at gene targets in NAc after repeated cocaine is strongly correlated with increased binding of H3K4me3, and identify Src kinase signaling inhibitor 1 (Srcin1 or p140Cap) as a key gene for these chromatin modifications. Cocaine induction of Srcin1 in NAc, which is associated with reduced Src signaling, decreases cocaine reward, the motivation to self administer cocaine, and cocaine-induced changes in NAc MSN dendritic spines. These results suggest that this suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a downregulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of new treatments for cocaine addiction. H3R2me2A ChIP-seq of mouse. Cocaine vs Saline, 3 biological replicates.
2016-08-08 | E-GEOD-85310 | biostudies-arrayexpress
Project description:We cataloged miRNA expression in the nucleus accumbens and at striatal synapses in control and chronically cocaine-treated mice. We identified cocaine-responsive miRNAs, synaptically-enriched and depleted miRNA families, and confirmed cocaine-induced changes in protein expression for several predicted synaptic target genes. Analysis of small RNA from Mus musculus nucleus accumbens (NAc) and postsynaptic densities (PSD) with and without chronic cocaine treatment.
2011-05-13 | E-GEOD-29261 | biostudies-arrayexpress
Project description:Many of the long-term effects of cocaine on the brain's reward circuitry have been shown to be mediated by alterations in gene expression. Several chromatin modifications, including histone acetylation and methylation, have been implicated in this regulation, but the effect of other histone modifications remains poorly understood. Poly(ADP-ribose) polymerase-1 (PARP-1), a ubiquitous and abundant nuclear protein, catalyzes the synthesis of a negatively charged polymer called poly(ADP-ribose) or PAR on histones and other substrate proteins and forms transcriptional regulatory complexes with several other chromatin proteins. Here, we identify an essential role for PARP-1 in cocaine-induced molecular, neural, and behavioral plasticity. Repeated cocaine administration, including self-administration, increased global levels of PARP-1 and its mark PAR in mouse nucleus accumbens (NAc), a key brain reward region. Using PARP-1 inhibitors and viral-mediated gene transfer, we established that PARP-1induction in NAc mediates enhanced behavioral responses to cocaine, including increased self-administration of the drug. Using chromatin immunoprecipitation sequencing, we demonstrated a global, genome-wide enrichment of PARP-1 in NAc of cocaine-exposed mice and identified several PARP-1 target genes that could contribute to the lasting effects of cocaine. Specifically, we identified sidekick-1-important for synaptic connections during development-as a critical PARP-1 target gene involved in cocaine's behavioral effects as well as in its ability to induce dendritic spines on NAc neurons. These findings establish the involvement of PARP-1 and PARylation in the long-term actions of cocaine. c57bl/6 mice were given IP injections of chronic cocaine 20mg/kg once per day for 7 days and sacrificed 30 minutes after the final dose of cocaine. Control animals were given saline for 7 days and sacrificed 30 minutes after the final dose of saline. Nucleus accumbens (NAc) tissue was collected and then PARP-1 ChIP-seq was performed. Three sequencing replicates were performed on each group.
2014-02-20 | E-GEOD-55136 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-02-27 | E-GEOD-66350 | biostudies-arrayexpress
Project description:The aim of the study was to investigate whether environmental factors like S-adenosylmethionine (SAM) via affecting epigenome could alter cocaine-induced gene expression and locomotor sensitization in mice. Using mouse nucleus accumbens (NAc) tissue, whole-genome gene expression profiling revealed that repeated SAM treatment affected a limited number of genes, but significantly modified cocaine-induced gene expression by blunting nonspecifically the cocaine response. At the gene level, we discovered that SAM modulated cocaine-induced DNA methylation by inhibiting both promoter-associated CpG-island hyper- and hypomethylation in the NAc but not in the reference tissue cerebellum. Total RNA was extracted from the mouse nucleus accumbens (NAc) tissue. Two tissues were combined to a sample, 4 samples per group used. RNA quality and quantity were assessed using the Nano-Drop -1000 spectrophotometer and the Agilent 2100 Bioanalyzer.
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Project description:DNA methylation profiling of nucleus Accumbens of rats that self administered cocaine, were subjected to 30 withdrawal days, were treated with aCSF, RG108 or SAM and were subjected to extinction tests. The groups consist of: 1. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days, were injected in the nucleus accumbens with aCSF and were subjected to an extinction test for assessment of cue-induced cocaine-seeking behavior (aCSF) 2. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days, were injected in the nucleus accumbens with RG108 and were subjected to an extinction test for assessment of cue-induced cocaine-seeking behavior (RG108) 3. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days, were injected in the nucleus accumbens with SAM and were subjected to an extinction test for assessment of cue-induced cocaine-seeking behavior (SAM)
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Project description:Gene expression profiling of nucleus Accumbens of rats that self administered cocaine and were subjected to 1 or 30 withdrawal days with or without extinction tests. The groups consist of 1. Saline rats (Sal.) 2. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 1 day (1W) 3. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 1 day and to an extinction test for assessment of cue-induced cocaine-seeking behavior (1C) 4. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days (30W) 5. Rats that self-administered cocaine for 10 days and that were subjected to a withdrawal period of 30 days and to an extinction test for assessment of cue-induced cocaine-seeking behavior (30C)
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