Article

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

ABSTRACT

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.

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    • "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. "
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    • "Kingetal.(2013)haveobservedthatatopoisomeraseone inhibitor(topotecan),dose-dependentlyreducedtheexpression ofverylonggenesinmouseandhumanneurons.Further, theseauthorsnotedthatasignificantpercentageofthe reducedexpressiongeneswereautismspectrumdisorder(ASD) candidategenes.Aspartofthisanalysis(Zhouetal.,2011) tabulatedfromseveralsourcesalistof974ASDcandidates. "
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    • "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). "
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