2016 New Investigator Grant
Elizabeth Heller, Ph.D. Assistant Professor, Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania
Neuroepigenetic Remodeling in Transcription and Behavior
Abstract
Gene expression in the brain is one mechanism by which neurons respond to their environment and adapt to chronic stimuli. The epigenome refers to molecular modifications to the DNA and histone proteins that make up the eukaryotic genome; these are regulated in neurons during development and following different types of stimulation. Myriad histone-modifying enzymes and epigenetic modifications are both necessary and sufficient for the formation of memory, depression-like phenotypes, and drug-evoked behavior. However, it has been difficult to examine the precise molecular mechanisms by which epigenetic remodeling leads to changesin gene expression, due to the genome-wide nature of these changes and the promiscuity of the transcriptional apparatus. Advances in this field will allow greater understanding of the mechanisms by which the brain responds and adapts to chronic environmental stimuli. Recently we have developed a novel approach to target epigenetic remodeling only to one specific gene, allowing isolation of the transcriptional mechanisms that result from a given histone or DNA modification. The current proposal focuses on one mechanism of epigenetically regulated gene expression - alternative splicing - in which a given gene expresses only one or a subset of isoforms. In particular, methylation of histone H3 lysine 36 is mechanistically linked to alternative splicing in cell culture systems. The goal of the current proposal is to examine this mechanism in neurons and to test the hypothesis that chromatin-mediated alternative splicing regulates reward-evoked behavior. Several key innovations will be applied in behavioral, analytical and molecular approaches, in order to directly test the relevance of neuronal histone modifications to alternative isoform expression in vivo.