Zhou Z, Yuan Q, Mash DC, Goldman D. Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol. Proceedings of the National Academy of Sciences USA 108: 6626

Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20849, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2011; 108(16):6626-31. DOI: 10.1073/pnas.1018514108
Source: PubMed


The hippocampus is a key brain region involved in both short- and long-term memory processes and may play critical roles in drug-associated learning and addiction. Using whole genome sequencing of mRNA transcripts (RNA-Seq) and immunoprecipitation-enriched genomic DNA (ChIP-Seq) coupled with histone H3 lysine 4 trimethylation (H3K4me3), we found extensive hippocampal gene expression changes common to both cocaine-addicted and alcoholic individuals that may reflect neuronal adaptations common to both addictions. However, we also observed functional changes that were related only to long-term cocaine exposure, particularly the inhibition of mitochondrial inner membrane functions related to oxidative phosphorylation and energy metabolism, which has also been observed previously in neurodegenerative diseases. Cocaine- and alcohol-related histone H3K4me3 changes highly overlapped, but greater effects were detected under cocaine exposure. There was no direct correlation, however, between either cocaine- or alcohol-related histone H3k4me3 and gene expression changes at an individual gene level, indicating that transcriptional regulation as well as drug-related gene expression changes are outcomes of a complex gene-regulatory process that includes multifaceted histone modifications.

  • Source
    • "Additionally, cocaine (either non-contingent or contingent exposure) was found to alter the expression of p21 in the ventral sector of the rodent hippocampus. These findings can be aligned with human data suggesting a potential relationship between CDK-related proteins and cocaine-induced behaviors (Zhou et al., 2011;Gelernter et al., 2014), further advocating the potential importance of cell cycle related proteins in responses to drugs of abuse. Furthermore, hippocampal sector-specific cocaineinduced increases in p21 expression correlated to alterations in histone acetylation of the promoter region. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study investigated the functional role of cyclin-dependent kinase inhibitor 1a (Cdkn1a or p21) in cocaine-induced response using a knockout mouse model. Acute locomotor activity following cocaine administration (15 mg/kg, i.p.) was decreased in p21(-/-) mice, whereas cocaine-induced place preference was enhanced. Interestingly, κ-opioid-induced place aversion was also significantly enhanced. Concentration-dependent analysis of locomotor activity in response to cocaine demonstrated a rightward shift in the p21(-/-) mice. Additionally, pretreatment with a serotonin antagonist did not alter cocaine-induced CPP in this model, consistent with the involvement of dopaminergic signaling. Cocaine exposure increased p21 expression exclusively in the ventral sector of the hippocampus of rodents following either contingent or non-contingent drug administration. Increased p21 expression was accompanied by increased histone acetylation of the p21 promoter region in rats. Finally, increased neurogenesis in the dorsal hippocampus of p21(-/-) mice was also observed. These results show that functional loss of p21 altered the acute locomotor response to cocaine and the conditioned responses to either rewarding or aversive stimuli. Collectively, these findings demonstrate a previously unreported involvement of p21 in modulating responses to cocaine and in motivated behaviors.
    Full-text · Article · Jan 2016 · Journal of Pharmacology and Experimental Therapeutics
  • Source
    • "Kingetal.(2013)haveobservedthatatopoisomeraseone inhibitor(topotecan),dose-dependentlyreducedtheexpression ofverylonggenesinmouseandhumanneurons.Further, theseauthorsnotedthatasignificantpercentageofthe reducedexpressiongeneswereautismspectrumdisorder(ASD) candidategenes.Aspartofthisanalysis(Zhouetal.,2011) tabulatedfromseveralsourcesalistof974ASDcandidates. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Across species and tissues and especially in the mammalian brain, production of gene isoforms is widespread. While gene expression coordination has been previously described as a scale-free coexpression network, the properties of transcriptome-wide isoform production coordination have been less studied. Here we evaluate the system-level properties of cosplicing in mouse, macaque, and human brain gene expression data using a novel network inference procedure. Genes are represented as vectors/lists of exon counts and distance measures sensitive to exon inclusion rates quantifies differences across samples. For all gene pairs, distance matrices are correlated across samples, resulting in cosplicing or cotranscriptional network matrices. We show that networks including cosplicing information are scale-free and distinct from coexpression. In the networks capturing cosplicing we find a set of novel hubs with unique characteristics distinguishing them from coexpression hubs: heavy representation in neurobiological functional pathways, strong overlap with markers of neurons and neuroglia, long coding lengths, and high number of both exons and annotated transcripts. Further, the cosplicing hubs are enriched in genes associated with autism spectrum disorders. Cosplicing hub homologs across eukaryotes show dramatically increasing intronic lengths but stable coding region lengths. Shared transcription factor binding sites increase coexpression but not cosplicing; the reverse is true for splicing-factor binding sites. Genes with protein-protein interactions have strong coexpression and cosplicing. Additional factors affecting the networks include shared microRNA binding sites, spatial colocalization within the striatum, and sharing a chromosomal folding domain. Cosplicing network patterns remain relatively stable across species.
    Full-text · Article · May 2015 · Frontiers in Genetics
  • Source
    • "One area of intensive research aims at identifying these long-term neuroadaptations such as modifications in gene expression evoked by drugs of abuse. In the brain of alcoholic patients, ethanol has been shown to induce histonerelated and DNA methylation epigenetic changes in several reward regions such as hippocampus, prefrontal cortex and amygdala (Taqi et al. 2011; Zhou et al. 2011; Ponomarev et al. 2012). In neuronal cell line culture, ethanol was shown to induce histone deacetylase (HDAC) expression (Agudelo et al. 2011; Agudelo, Yoo & Nair 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Converging evidence indicates that epigenetic mechanisms are involved in drug addiction, and that enzymes involved in chromatin remodeling may represent interesting targets in addiction treatment. No study has addressed whether histone deacetylase (HDAC) inhibitors (HDACi) can reduce excessive ethanol intake or prevent relapse in alcohol-dependent animals. Here, we assessed the effects of two HDACi, sodium butyrate (NaB) and MS-275, in the operant ethanol self-administration paradigm in dependent and non-dependent rats. To characterize some of the epigenetic mechanisms associated with alcohol dependence and NaB treatment, we measured the levels of histone H3 acetylation in different brain areas of dependent and non-dependent rats, submitted or not to NaB treatment. Our results demonstrated that (1) NaB and MS-275 strongly decreased excessive alcohol intake of dependent rats in the operant ethanol self-administration paradigm but not of non-dependent rats; (2) NaB reduced excessive drinking and prevented the escalation of ethanol intake in the intermittent access to 20% ethanol paradigm; and (3) NaB completely blocked the increase of ethanol consumption induced by an alcohol deprivation, thus demonstrating a preventive effect of NaB on relapse. The mapping of cerebral histone H3 acetylation revealed a hyperacetylation in the amygdala and cortical areas in dependent rats. Interestingly, NaB did not exacerbate the hyperacetylation observed in these regions, but instead restored it, specifically in cortical areas. Altogether, our results clearly demonstrated the efficacy of NaB in preventing excessive ethanol intake and relapse and support the hypothesis that HDACi may have a potential use in alcohol addiction treatment.
    Full-text · Article · Aug 2014 · Addiction Biology
Show more