期刊论文详细信息
Neurobiology of Disease
Genome-wide approaches reveal EGR1-controlled regulatory networks associated with neurodegeneration
Martina Lefterova1  Nicholas F. Fitz2  Emilie L. Castranio3  Jonathan Schug3  Radosveta Koldamova4  Iliya Lefterov4  Alexis Carter4  Faith A. Davenport5  Andrea A. Cronican6 
[1] Corresponding authors at Department of Environmental and Occupational Health, University of Pittsburgh, BRIDG Building, 100 Technology Dr., Pittsburgh, PA 15219, USA.;Functional Genomics Core, Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA;Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA;;Department of Environmental &Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA;Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA;
关键词: Alzheimer's disease;    Animal model;    ChIP-seq;    Brain;    Egr1;    Histone modifications;   
DOI  :  
来源: DOAJ
【 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.

【 授权许可】

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