Gene expression is considered a key step for long-term memory processes. Until recently, the analysis of transcription in learning and memory has focused on transcription factors. However, as transcription is not occurring on naked DNA, but rather in the context of chromatin, it has become increasingly appreciated that chromatin regulation is critical for gene expression required for long-term memory processes. Chromatin is the protein complex that condenses and organizes genomic DNA, allowing six feet of genomic information to be compacted into a six micron nucleus. The repeating unit of chromatin is called a nucleosome, which consists of pairs of the core histone proteins H2A, H2B, H3, and H4. Histone modification, nucleosome remodeling, and DNA methylation are the three main mechanisms by which chromatin structure is regulated in order to access DNA and express specific gene profiles that subserve specific cellular functions. Histone modification refers to th post-translational modification of histone proteins including, but not limited to, histone acetylation, methylation, and phosphorylation. These histone modifications provide recruitment signals for non-histone proteins involved in transcriptional activation and silencing, and they alter nucleosome-nucleosome interactions. Nucleosome remodeling is carried out by ATP-dependent enzymatic complexes, which use the energy of ATP hydrolysis to disrupt nucleosome-DNA contacts, move nucleosomes along DNA, and remove or exchange nucleosomes. Histone modifying enzymes and nucleosome remodeling complexes work hand-in- hand to orchestrate gene expression for cellular function. However, to date, not a single study has examined the role of nucleosome remodeling in regulating gene expression required for long-term memory processes. Nucleosome remodeling complexes are critical for proper gene expression and are central to mechanisms of development, cancer, and human disease, including mental retardation. A major discovery in understanding the role of nucleosome remodeling in neurons was the identification of a neuron-specific nucleosome remodeling complex (nBAF). The defining feature of nBAF is the subunit BAF53b, which is critical for this complex to be recruited to promoters of specific genes. Importantly, loss of BAF53b results in aberrant gene expression and significantly impairs activity-dependent dendritic outgrowth, synapse formation, and axonal development. The focus of this research proposal is to understand the function of this unique neuron-specific nucleosome remodeling complex with regard to long-term memory formation (Aim 1 and 2) and the regulation of gene expression (Aim 3). Considering the fundamental role nucleosome remodeling complexes have in maintaining and regulating chromatin structure, it is not surprising that mutations in components of these complexes give rise to severe developmental disorders, cancer, and cognitive disorders. Findings from the proposal may lead to the discovery of novel drug targets for cognitive disorders such as like Alzheimer's disease (Fischer, et al., 2007) or addiction (Malvaez et al., 2010).
This project will examine the role of nucleosome remodeling in learning and memory. Nucleosome remodeling is one of the most important mechanisms regulating gene expression and has a central role in development, cancer, and human disease including mental retardation. However, its role in neuronal function is barely understood and it has never been examined with regard to learning and memory, which is the focus of this proposal.
|Vogel-Ciernia, Annie; Wood, Marcelo A (2014) Neuron-specific chromatin remodeling: a missing link in epigenetic mechanisms underlying synaptic plasticity, memory, and intellectual disability disorders. Neuropharmacology 80:18-27|