In this proposal, we examine for the first time an epigenetic mechanism called nucleosome remodeling and how it regulates coordinate gene expression required for cocaine-induced memory formation. The nucleosome is the repeating unit of chromatin and fundamental to the compaction of genomic DNA. Nucleosome remodeling complexes modify chromatin structure and regulate expression by repositioning nucleosomes at the promoters of genes. Recent human exome sequencing studies have identified subunits of the polymorphic BAF complexes (mammalian SWI/SNF nucleosome remodeling complex) that are frequently mutated in sporadic mental retardation and sporadic autism. Moreover, de novo mutations in various subunits of neuron-specific Brg1- associated factor (nBAF) nucleosome remodeling complex have been implicated in Coffin-Siris and Nicolaides-Baraitser syndromes, both of which are associated with intellectual disability. Together, these studies suggest that nBAF function is necessary for normal cognitive function. Although an important topic in other fields (e.g. yeast genetics and cancer), nucleosome remodeling has received little attention in neuroscience. However, a major discovery was the identification of the first neuron-specific BAF complex, which was subsequently found to regulate gene expression required for the conversion of precursor cells into terminally differentiated neurons. Importantly, the nBAF complex has a subunit, BAF53b, which participates in making nBAF neuron- specific. This subunit is both neuron and nBAF complex specific, making it an ideal target for investigating the potential contributions of nBAF to synaptic physiology and behavior. Building on this point, we propose to test the hypothesis that BAF53b, after playing a key role in neuronal fate decisions during development, continues to regulate gene expression and does so in a manner critical to adult memory processes as well as cocaine-induced memory formation. We propose three specific aims to test this hypothesis.
In Specific Aim 1, we will use genetically modified mice to examine the role of BAF53b in long-term memory.
In Specific Aim 2, we will use next generation sequencing, RNA seq, and chromosomal conformation capture 3C to determine what gene expression profiles are being regulated by BAF53b and chromatin looping during memory consolidation.
In Specific Aim 3, we will determine how cocaine regulates coordinate gene expression via BAF53b-dependent nucleosome remodeling and chromatin looping during cocaine-induced memory formation. Together, the work under these specific aims will elucidate the contributions of BAF53b and the nBAF complex in general, to memory processes, and more specifically to cocaine-induced memory formation as a precursor event to persistent drug-seeking behavior.
It is becoming increasingly important to examine how gene expression is controlled by epigenetic mechanisms to understand human disorders including substance use disorders. In this proposal, we examine for the first time an epigenetic mechanism called nucleosome remodeling and how it regulates coordinate gene expression required for cocaine-induced memory formation.
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