Genome-wide approaches reveal EGR1-controlled regulatory networks associated with neurodegeneration

摘要

Early growth response gene 1 (Egr1) is a member of the immediate early gene (IEG) family of transcription factors and plays a role in memory formation. To identify EGR1 target genes in brain of Alzheimer's disease (AD) model mice - APP23, we applied chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq). Functional annotation of genes associated with EGR1 binding revealed a set of related networks including synaptic vesicle transport, clathrin-mediated endocytosis (CME), intracellular membrane fusion and transmission of signals elicited by Ca2+ influx. EGR1 binding is associated with significant enrichment of activating chromatin marks and appears enriched near genes that are up-regulated in the brains of APP23 mice. Among the putative EGR1 targets identified and validated in this study are genes related to synaptic plasticity and transport of proteins, such as Arc, Grin1, Syn2, Vamp2 and Stx6, and genes implicated in AD such as Picalm, Psen2 and App. We also demonstrate a potential regulatory link between EGR1 and its newly identified targets in vivo, since conditions that up-regulate Egr1 levels in brain, such as a spatial memory test, also lead to increased expression of the targets. On the other hand, protein levels of EGR1 and ARC, SYN2, STX6 and PICALM are significantly lower in the brain of adult APP mice than in age-matched wild type animals. The results of this study suggest that EGR1 regulates the expression of genes involved in CME, vesicular transport and synaptic transmission that may be critical for AD pathogenesis.