Essential Role of the Histone Methyltransferase G9a in Cocaine-induced Plasticity

By I. Maze, H. Covington, D. Dietz, Q. LaPlant, W. Renthal, S. Russo, Maxwell Mechanic, E. Mouzon, R. Neve, S. Haggarty and 7 more. Science, 2010

648 citations recorded by the source corpus.

Cocaine Addiction and Histone Methylation Long-lasting behavioral syndromes associated with chronic cocaine exposure may result from dysregulation of the global transcriptional machinery. Maze et al. (p. 213) observed that histone lysine methylation in the nucleus accumbens plays a critical role in mediating the regulation of gene expression in response to repeated cocaine self-administration. Chronic cocaine was linked to overall reductions in dimethylation of lysine 9 of histone 3 (H3K9) in this brain region. Repressing H3K9 after chronic cocaine administration facilitated reward-related changes in behavior. The authors identifed the methyltransferase G9a as an essential mediator and an important regulator of dendritic spine plasticity. Downregulation of G9a was linked to the transcription factor ΔFosB. Cocaine suppression of histone methylation in the nucleus accumbens mediates the drug’s ability to enhance reward. Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. In mice, we identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor ∆FosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/5eb17291b15b3d0d661c215158337dd22a6edc89

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Nora D. Volkow
2. E. Nestler
3. R. Malenka
4. S. Russo
5. M. Morales
6. Alfred J. Robison
7. G. Koob
8. S. Hyman

In Molecular Biology

1. Nora D. Volkow
2. R. Malenka
3. E. Nestler
4. S. Russo
5. Alfred J. Robison
6. M. Morales
7. Li Shen
8. Xiaochuan Liu

In Pharmacology

1. E. Nestler
2. Nora D. Volkow
3. R. Malenka

Citations in the corpus

• The Brain on Drugs: From Reward to Addiction. (2015, background): “, 2010), and DFosB is implicated in their generation (Maze et al., 2010).”
• Transcriptional and Epigenetic Mechanisms of Addiction (2011, background): “: it is both necessary and sufficient for cocaine-induced increases in the dendritic spine number of NAc MSN”
• The Addicted Synapse: Mechanisms of Synaptic and Structural Plasticity in Nucleus Accumbens (2010, background): “Furthermore, Ras-GRF1 appears to mediate expression of ΔFosB [78], which as noted earlier promotes spinogenesis on NAc MSNs [6,7] Interestingly, chronic cocaine was recently shown to reduce levels of GTP-bound RhoA, presumably leading to decreases in downstream actin severing molecules such as LIMK ”
• ngs.plot: Quick mining and visualization of next-generation sequencing data by integrating genomic databases (2014, background): “H3K9me2 is a histone mark that displays dispersive enrichment patterns and is often associated with gene silencing [44].”