TITLE: The epigenetic role of EGR1 during postnatal brain development and in neuronal activity Project Summary/Abstract Early growth response gene-1 (Egr1) is a critical transcription factor involved in many important biological processes, including neuronal plasticity and memory formation. With a rapid increase in expression during the first few weeks after birth, Egr1 controls the selection, maturation and functional integration of newborn neurons. The regulation of Egr1-mediated gene expression has been shown to be under methylation control. However, Egr1 target sites and their epigenetic regulation in the nervous system remains largely unknown. The investigators have recently identified a large number of genomic loci with their cell-type specific methylation patterns established during postnatal frontal cortex development. For both human and mouse, these loci enrich for transcription factor binding motifs, in particular for Egr1. The CpG dinucleotides within these predicted EGR1 binding sites become hypo-methylated in mature neurons but remain heavily methylated in glia. In this study, the investigators propose to systematically investigate Egr1-mediated epigenetic regulatory networks underlying the postnatal brain development. The central hypothesis is that, Egr1 is a key mediator for gene-environment interactions shaping brain methylome during early postnatal development, and plays an essential role in the establishment of cell-type specific DNA methylation patterns and in the epigenetic control of activity-induced methylation changes.
In Aim 1, the investigators will determine the methylation profiles of EGR1 binding sites during postnatal brain development.
In Aim 2, the investigators will determine DNA demethylation mechanism underlying the postnatal brain development. Gain- or loss-of-function methods will be used to manipulate Egr1 and Tet enzymes expression to test the hypothesis that increased Egr1 and Tet enzymes expression is prerequisites for the establishment of the cell-type specifically methylation patterns on its target sites during development. In addition, the investigators will examine whether high basal Egr1 expression is required to maintain the hypo-methylation states of its binding sites. Given the critical role of Egr1 in brain development and function, the investigators anticipate that these studies will provide important new insights into the key epigenetic mechanisms that underlie postnatal brain development and neuronal activity.
PublicHealthRelevanceStatement: ThisproposalisaimingattheunderstandingofepigeneticroleofEgr1duringpostnatalbrain developmentandneuronalactivity.WewilldeterminethefunctionaldownstreamtargetgenenetworkofEgr1 andrevealtheepigeneticbasisofEgr1-mediatedgeneregulation.Ourstudywillfacilitatethetranslationof recentadvancesonepigenomicstudiestopracticalapplicationsinneurologicaldiseases.
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