This proposal seeks to understand mechanisms of chromatin biology in memory. Histone methylation- dependent epigenetic mechanisms serve to regulate gene transcription in mature neurons of the adult nervous system. Here, we focus on the SET-domain/PHD-domain-containing protein lysine methyltransferase, G9a/GLP, that catalyses the histone H3 lysine 9 dimethylation (H3K9me2) mark and functions as a molecular linker between histone methylation, chromatin remodeling, and transcription regulation. However, very little is known about the role of G9a/GLP-H3K9me2 interactions in the nervous system or in the context of memory.
AIM 1. Using two of the most innovative approaches in the field of neuroscience as it pertains to epigenetics, we will first selectively sort neuronal chromatin followed by massively parallel sequencing of immunoprecipitates (ChIP-seq) to obtain insight into the H3K9me2 landscape in mature neurons from the hippocampus, entorhinal cortex, and amygdala. We will then define the epigenetic readers recruited to the H3K9me2 methylation marks in a gene promoter-specific manner in mature neurons. The effect of genetically manipulating G9a/GLP activity will also be determined at gene promoter regions and behavioral outcomes will be assessed. This genetic data, together with information gathered on the H3K9me2 landscape, will strongly implicate G9a/GLP as a major regulator of gene transcription in the adult brain during memory consolidation.
AIM 2. Currently, nothing is known about the signaling mechanisms coupled to these molecular processes for any cell-type. Thus, we will determine the signaling pathways coupled to G9a/GLP-H3K9me2 interactions in neuronal cell types recruited by NMDA receptor activation during memory consolidation using pharmacological approaches and laser-capture microdissection technology.
AIM 3. NF-?B (p65) is a non-histone target of protein lysine methyltransferases, and once methylated NF?B can associate with proteins such as G9a/GLP. Here, we will determine how this transcription factor serves as an epigenetic initiator of the G9a/GLP- H3K9me2 interaction in mature neurons during memory consolidation. Through genetic knockdown of p65, blocking peptides, and lysine demethylase inhibitors, we will manipulate the p65-G9a/GLP interaction and assess behavioral outcomes. Together, the research studies proposed will provide the first glimpse into the epigenetic initiators and writers of the H3K9me2 methylation mark in the adult brain. Interestingly, subtelomeric deletion of the human chromosome 9 (9q34), which includes G9a/GLP, is associated with human mental retardation or intellectual disability disorders characterized by major defects in learning and cognition. Thus, this basic scientific study will clearly impact cognitive dysfunction by helping to develop new therapeutic approaches based on manipulating the epigenome to improve learning and memory deficits associated with aging, schizophrenia, depression, and post-traumatic stress disorder.
The epigenetic chromatin remodeling mechanisms involved in memory formation are largely unknown and unexplored. The goal of these studies is to elucidate the role of the histone methytransferase G9a/GLP in the regulation of gene transcription during the consolidation of memory. These studies will provide novel insights into a candidate histone methylation-dependent epigenetic mechanism that may be involved in abnormal regulation of genes underlying traumatic memories associated with post-traumatic stress disorders, phobias, and depression.
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