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An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior

Jung, Yonwoo; Hsieh, Lawrence S.; Lee, Angela M.; Zhou, Zhifeng; Coman, Daniel; Heath, Christopher J.; Hyder, Fahmeed; Mineur, Yann S; Yuan, Qiaoping; Goldman, David; Bordey, Angelique and Picciotto, Marina R (2016). An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior. Nature Neuroscience, 19(7) pp. 905–914.

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Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2lmRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior.

Item Type: Journal Item
ISSN: 1097-6256
Keywords: Developmental disorders; Epigenetics and behaviour; Histone post-translational modifications; Molecular neuroscience; Neuronal development
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Research Group: Health and Wellbeing PRA (Priority Research Area)
Item ID: 46478
Depositing User: ORO Import
Date Deposited: 01 Jun 2016 11:04
Last Modified: 23 Jan 2020 21:19
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