PINNING DOWN THE GENE REGULATORY NETWORKS THAT GENERATE ALCOHOL TOLERANCE

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Atkinson, NS1 and Ghezzi, A1

1 Waggoner Center for Alcohol & Addiction Research, Department of Neuroscience, The University of Texas at Austin, Austin, Texas, U.S.A.

One of the earliest adaptions of the nervous system to alcohol results in functional tolerance. Functional alcohol tolerance is alcohol-induced alcohol resistance that is not mediated by a change in alcohol metabolism. Gene expression changes important for any alcohol neuroadaptation are difficult to identify because such a very large fraction of the genome (up to ~30%) changes expression following ethanol exposure. Unfortunately, responses important for producing alcohol behaviors can be obscured by this surfeit of changes. To help identify changes important for producing functional tolerance to alcohol, we exploited the fact that two chemically distinct alcohols produce mutual cross tolerance through a related mechanism. This was demonstrated in detail using the Drosophila slo gene as a test case. In flies, the capacity to acquire tolerance to either ethanol or benzyl alcohol has been linked to the slo gene, which encodes BK-type Ca2+-activated K+ channels. Mutations in slo block the acquisition of tolerance, sedation with either drug induces slo expression, and slo induction has been shown to phenocopy tolerance. A survey of the alcohol-induced changes in histone modification and transcription factor binding across the slo transcriptional control region proved to be an effective way to identify DNA regulatory elements that mediated the alcohol response. Based on the success of this approach, we performed a genomic survey to identify all genes and regions that respond similarly to both benzyl alcohol and ethanol. This technique identified a gene network, shown to play important roles in this alcohol response (tested by mutation, RNAi, or transgenic mis-expression). We also developed profiles for alcohol-induced histone H4 acetylation patterns and CREB-binding patterns across the slo promoter region. These profiles were then used in a ChIP-Seq genomic survey to find other genes with similar patterns. This has produced a very well defined signature for at least one class of alcohol-regulated gene. Funded by NIH grant 2R01AA018037-06A1 to N.S.A.

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