Adolescent Binge Ethanol Dysregulation of H3K36me3 Leads to Cryptic Transcription and Lasting Memory Deficits

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PROJECT SUMMARY The prefrontal cortex (PFC) undergoes significant changes during adolescence, and alcohol exposure during this time is particularly damaging. Consuming alcohol, especially in binges, has been shown to negatively impact the adolescent brain, resulting in brain structural changes and lasting deficits in attention, visuospatial skills, and memory. The underlying mechanisms of these deficits are largely unknown; however, histone epigenetic regulation of gene expression provides an attractive mechanism for driving long-term behavioral and cognitive changes following binge ethanol. Through interaction with environmental stimuli, such as alcohol, epigenetic alterations can determine downstream gene expression, which in turn affects behavioral outcomes. The proposed study will investigate whether histone epigenetic alterations are the mechanism behind the persistent memory deficits of adolescents exposed to binge levels of ethanol. Specifically, the study will focus on tri-methylated histone 3, lysine 36 (H3K36me3). H3K36me3 has been shown to be affected by adolescent binge ethanol, and also plays significant roles in transcription regulation and memory function. These functional roles may provide a mechanism for how dysregulation of H3K36me3 by adolescent binge ethanol could underlie long-term memory deficits. Additionally, H3K36me3 is an under-studied mark, and further investigation of its role in memory function and cryptic transcription will provide valuable data for others involved in behavioral epigenetic research. Through this proposal, we intend to determine how H3K36me3-regulated loci and gene expression patterns within the PFC are altered after adolescent binge ethanol. By overlaying chromatin immunoprecipitation (ChIP) sequencing with RNA sequencing data, we will determine how ethanol- induced dysregulation of H3K36me3 affects gene expression, and at which loci these changes are occurring. We also plan to manipulate H3K36me3 levels within the PFC to determine if altering this epigenetic mark can change the behavioral outcomes of adolescent binge ethanol. These studies therefore have the potential to expand the knowledge of how epigenetic alterations can induce lasting behavioral changes. The success of these epigenetic and genomic studies will identify novel genes that might contribute to the persistent memory deficits associated with adolescent binge ethanol, which could ultimately lead to pharmaceutical targets to reverse cognitive deficits associated with adolescent binge drinking. Additionally, this study will facilitate my training in molecular techniques, bioinformatics analyses, and animal behavior models. In addition to the critical thinking, scientific writing, and professional development skills that I will be trained in, this research will prepare me to become a successful independent researcher studying how environmental influences, such as alcohol consumption, is encoded into the epigenome and how this can cause lasting impacts to behavior.