Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens
Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic dimethylation of histone H3 at lysine 9 (H3K9me2), has been implicated recently in mediating neural and behaviora...
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| Format: | Article |
| Language: | en_US |
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Society for Neuroscience
2013
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| Online Access: | http://hdl.handle.net/1721.1/79352 https://orcid.org/0000-0002-3854-5968 |
| _version_ | 1826195875855073280 |
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| author | Sun, Hao Sheng Maze, Ian Dietz, David M. Scobie, Kimberly N. Kennedy, Pamela J. Damez-Werno, Diane Neve, Rachael L. Zachario, Venetia Shen, Li Nestler, Eric J. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Sun, Hao Sheng Maze, Ian Dietz, David M. Scobie, Kimberly N. Kennedy, Pamela J. Damez-Werno, Diane Neve, Rachael L. Zachario, Venetia Shen, Li Nestler, Eric J. |
| author_sort | Sun, Hao Sheng |
| collection | MIT |
| description | Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic dimethylation of histone H3 at lysine 9 (H3K9me2), has been implicated recently in mediating neural and behavioral plasticity in response to chronic cocaine administration. Here, we show that chronic morphine, like cocaine, decreases G9a expression, and global levels of H3K9me2, in mouse nucleus accumbens (NAc), a key brain reward region. In contrast, levels of other histone methyltransferases or demethylases, or of other methylated histone marks, were not affected in NAc by chronic morphine. Through viral-mediated gene transfer and conditional mutagenesis, we found that overexpression of G9a in NAc opposes morphine reward and locomotor sensitization and concomitantly promotes analgesic tolerance and naloxone-precipitated withdrawal, whereas downregulation of G9a in NAc enhances locomotor sensitization and delays the development of analgesic tolerance. We identified downstream targets of G9a by providing a comprehensive chromatin immunoprecipitation followed by massively parallel sequencing analysis of H3K9me2 distribution in NAc in the absence and presence of chronic morphine. These data provide novel insight into the epigenomic regulation of H3K9me2 by chronic morphine and suggest novel chromatin-based mechanisms through which morphine-induced addictive-like behaviors arise. |
| first_indexed | 2024-09-23T10:17:06Z |
| format | Article |
| id | mit-1721.1/79352 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:17:06Z |
| publishDate | 2013 |
| publisher | Society for Neuroscience |
| record_format | dspace |
| spelling | mit-1721.1/793522022-09-30T20:05:53Z Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens Sun, Hao Sheng Maze, Ian Dietz, David M. Scobie, Kimberly N. Kennedy, Pamela J. Damez-Werno, Diane Neve, Rachael L. Zachario, Venetia Shen, Li Nestler, Eric J. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Neve, Rachael L. Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic dimethylation of histone H3 at lysine 9 (H3K9me2), has been implicated recently in mediating neural and behavioral plasticity in response to chronic cocaine administration. Here, we show that chronic morphine, like cocaine, decreases G9a expression, and global levels of H3K9me2, in mouse nucleus accumbens (NAc), a key brain reward region. In contrast, levels of other histone methyltransferases or demethylases, or of other methylated histone marks, were not affected in NAc by chronic morphine. Through viral-mediated gene transfer and conditional mutagenesis, we found that overexpression of G9a in NAc opposes morphine reward and locomotor sensitization and concomitantly promotes analgesic tolerance and naloxone-precipitated withdrawal, whereas downregulation of G9a in NAc enhances locomotor sensitization and delays the development of analgesic tolerance. We identified downstream targets of G9a by providing a comprehensive chromatin immunoprecipitation followed by massively parallel sequencing analysis of H3K9me2 distribution in NAc in the absence and presence of chronic morphine. These data provide novel insight into the epigenomic regulation of H3K9me2 by chronic morphine and suggest novel chromatin-based mechanisms through which morphine-induced addictive-like behaviors arise. 2013-06-20T15:45:21Z 2013-06-20T15:45:21Z 2012-11 2012-10 Article http://purl.org/eprint/type/JournalArticle 0270-6474 1529-2401 http://hdl.handle.net/1721.1/79352 Sun, H., I. Maze, D. M. Dietz, K. N. Scobie, P. J. Kennedy, D. Damez-Werno, R. L. Neve, V. Zachariou, L. Shen, and E. J. Nestler. Morphine Epigenomically Regulates Behavior Through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens. Journal of Neuroscience 32, no. 48 (November 28, 2012): 17454-17464. https://orcid.org/0000-0002-3854-5968 en_US http://dx.doi.org/10.1523/jneurosci.1357-12.2012 Journal of Neuroscience Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Society for Neuroscience SFN |
| spellingShingle | Sun, Hao Sheng Maze, Ian Dietz, David M. Scobie, Kimberly N. Kennedy, Pamela J. Damez-Werno, Diane Neve, Rachael L. Zachario, Venetia Shen, Li Nestler, Eric J. Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens |
| title | Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens |
| title_full | Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens |
| title_fullStr | Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens |
| title_full_unstemmed | Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens |
| title_short | Morphine Epigenomically Regulates Behavior through Alterations in Histone H3 Lysine 9 Dimethylation in the Nucleus Accumbens |
| title_sort | morphine epigenomically regulates behavior through alterations in histone h3 lysine 9 dimethylation in the nucleus accumbens |
| url | http://hdl.handle.net/1721.1/79352 https://orcid.org/0000-0002-3854-5968 |
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