Elucidation of the PRC2 interactome in early human neural development

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Project Summary My research investigates the mechanisms by which epigenetic modifiers regulate the developing mammalian brain. The mammalian brain contains well over 1010 neurons, which synapse together to perform multiple functions including but not limited to sensation, cognition, and conscious thought. These vast numbers of cells all originate from a relatively small pool of neural progenitors, which divide and differentiate in response to spatiotemporal clues during embryonic development. The correct development and function of these cells requires exquisitely accurate gene expression control that is mediated by both transcription factors and epigenetic modifiers. While mutations in transcription factors are well characterized for causing neurodevelopmental defects, little is known about the mechanisms by which epigenetic modifier mutations cause neurodevelopmental defects. This project will begin filling this gap by analyzing the Polycomb Repressive Complex 2 (PRC2) complex, an epigenetic modifier that methylates lysine 27 of histone H3 (H3K27me3), regulates RNA polymerase II transcription, and is necessary for neural progenitor formation and function. Specifically, my project will investigate the regulation of PRC2 function and gene targeting within neural progenitor cells as they proliferate and differentiate to neuronal fates. Using immunoprecipitation-mass spectrometry, we recently identified a novel interaction between a PRC2 component and a key neurogenesis determinant, which likely has a never-discovered function in gene regulation. We will use multidisciplinary approaches to establish the mechanistic details of this interaction and to elucidate how these interactions affect PRC2 function. To achieve this goal, we will first biochemically identify the protein domains or amino acids required for this molecular interaction. Next, we will determine how this neurogenesis determinant affects PRC2 binding to gene targets and influences transcription activities. Finally, we will delineate the effect of this interaction on the self-renewal and differentiation capacity of neural progenitors. Our findings will reveal the molecular mechanism by which a crucial neurogenesis determinant interacts with PRC2 to program gene expression required for early neurogenesis. My research uses multiple tools to elucidate mechanisms by which epigenetic modifiers regulate early neural development. The long-term goal of my studies is to define the cross-talk between chromatin modifiers and transcriptional circuitry in regulating gene expression in developmental contexts and to determine how dysfunction in this cross-talk contributes to human birth defects and diseases.