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Cocaine dynamically regulates heterochromatin and repetitive element unsilencing in nucleus accumbens.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2011 Feb 15; Vol. 108 (7), pp. 3035-40. Date of Electronic Publication: 2011 Feb 07. - Publication Year :
- 2011
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Abstract
- Repeated cocaine exposure induces persistent alterations in genome-wide transcriptional regulatory networks, chromatin remodeling activity and, ultimately, gene expression profiles in the brain's reward circuitry. Virtually all previous investigations have centered on drug-mediated effects occurring throughout active euchromatic regions of the genome, with very little known concerning the impact of cocaine exposure on the regulation and maintenance of heterochromatin in adult brain. Here, we report that cocaine dramatically and dynamically alters heterochromatic histone H3 lysine 9 trimethylation (H3K9me3) in the nucleus accumbens (NAc), a key brain reward region. Furthermore, we demonstrate that repeated cocaine exposure causes persistent decreases in heterochromatization in this brain region, suggesting a potential role for heterochromatic regulation in the long-term actions of cocaine. To identify precise genomic loci affected by these alterations, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-Seq) was performed on NAc. ChIP-Seq analyses confirmed the existence of the H3K9me3 mark mainly within intergenic regions of the genome and identified specific patterns of cocaine-induced H3K9me3 regulation at repetitive genomic sequences. Cocaine-mediated decreases in H3K9me3 enrichment at specific genomic repeats [e.g., long interspersed nuclear element (LINE)-1 repeats] were further confirmed by the increased expression of LINE-1 retrotransposon-associated repetitive elements in NAc. Such increases likely reflect global patterns of genomic destabilization in this brain region after repeated cocaine administration and open the door for future investigations into the epigenetic and genetic basis of drug addiction.
- Subjects :
- Analysis of Variance
Animals
Base Sequence
Blotting, Western
Chromatin Immunoprecipitation
DNA Primers genetics
Heterochromatin drug effects
Immunohistochemistry
Long Interspersed Nucleotide Elements genetics
Lysine metabolism
Methylation drug effects
Mice
Models, Statistical
Molecular Sequence Data
Nucleus Accumbens drug effects
Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Reward
Sequence Analysis, DNA
Cocaine toxicity
Cocaine-Related Disorders metabolism
Gene Regulatory Networks drug effects
Genomic Instability drug effects
Heterochromatin metabolism
Histones metabolism
Nucleus Accumbens metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 108
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 21300862
- Full Text :
- https://doi.org/10.1073/pnas.1015483108