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

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 Ash2l, a component of a histone methyltransferase complex. We therefore examined genome-wide changes in H3K4 tri-methylation, a mark induced by the Ash2l complex associated with increased gene transcription. A significant number of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4 tri-methylation. Knockdown of Ash2l or Mef2c abolishes nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuates nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimics nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a novel target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior.