Transcriptional Regulation of Alcohol Sensitivity and Tolerance

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––– PROJECT SUMMARY ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– Resistance to the initial negative, intoxicating effects of alcohol, is a risk factor in the development of alcohol use disorder. Another hallmark and driver of AUD is tolerance, which develops after repeat exposures. Such repeat alcohol exposures also lead to expression changes in numerous genes, yet many transcriptional mechanisms that enact these changes and mediate tolerance and its close relative, dependence, remain to be elucidated. Transcriptional mechanisms encoding stable changes in gene expression include the modification of chromatin. One of the lesser studied chromatin-modifying mechanisms is histone methylation, especially histone demethylating enzymes (HDMs). The goal of this application is to understand the neural, molecular, and genetic mechanisms of Kdm3 HDM-mediated regulation of initial sensitivity and of acquired tolerance to alcohol. This is based on our published findings that Drosophila knock out of Kdm3 causes increased initial sensitivity, and reduced tolerance to repeat ethanol exposure. First, we will determine the neurons and conserved neurotransmitter systems that require Kdm3 for normal alcohol responses. Second, we will determine Kdm3-dependent changes in open chromatin induced by alcohol exposure. This will include an analysis of transcription factors that have binding sites overrepresented in regions of ethanol-induced changes in chromatin accessibility. Third, we will investigate putative Kdm3-target genes by asking which of them mediate Kdm3’s effects on alcohol-induced behavior. The premise for each of our aims is supported by extensive published and preliminary data. Together, the proposed experiments will illuminate mechanisms of Kdm3-mediated chromatin modifications and gene regulation that mediate alcohol sensitivity and tolerance. The proposed experiments are highly responsive to the NIAAA Notice of Special Interest NOT-AA-21-029 “Genetics of Alcohol Sensitivity and Tolerance” and will provide an “enhanced understanding of genetic, genomic, and epigenetic factors contributing to biological processes for individual variation in sensitivity and the development of tolerance” (NOT-AA-21-029).