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Transcriptional regulation of rod photoreceptor homeostasis revealed by in vivo NRL targetome analysis
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نویسنده
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hao h. ,kim d.s. ,klocke b. ,johnson k.r. ,cui k. ,gotoh n. ,zang c. ,gregorski j. ,gieser l. ,peng w. ,fann y. ,seifert m. ,zhao k. ,swaroop a.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 4
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چکیده
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A stringent control of homeostasis is critical for functional maintenance and survival of neurons. in the mammalian retina,the basic motif leucine zipper transcription factor nrl determines rod versus cone photoreceptor cell fate and activates the expression of many rod-specific genes. here,we report an integrated analysis of nrl-centered gene regulatory network by coupling chromatin immunoprecipitation followed by high-throughput sequencing (chip-seq) data from illumina and abi platforms with global expression profiling and in vivo knockdown studies. we identified approximately 300 direct nrl target genes. of these,22 nrl targets are associated with human retinal dystrophies,whereas 95 mapped to regions of as yet uncloned retinal disease loci. in silico analysis of nrl chip-seq peak sequences revealed an enrichment of distinct sets of transcription factor binding sites. specifically,we discovered that genes involved in photoreceptor function include binding sites for both nrl and homeodomain protein crx. evaluation of 26 chip-seq regions validated their enhancer functions in reporter assays. in vivo knockdown of 16 nrl target genes resulted in death or abnormal morphology of rod photoreceptors,suggesting their importance in maintaining retinal function. we also identified histone demethylase kdm5b as a novel secondary node in nrl transcriptional hierarchy. exon array analysis of flow-sorted photoreceptors in which kdm5b was knocked down by shrna indicated its role in regulating rod-expressed genes. our studies identify candidate genes for retinal dystrophies,define cis-regulatory module(s) for photoreceptor-expressed genes and provide a framework for decoding transcriptional regulatory networks that dictate rod homeostasis.
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آدرس
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neurobiology-neurodegeneration and repair laboratory,national eye institute,national institutes of health,bethesda,md,united states,janelia farm research campus,howard hughes medical institute,ashburn,va, United States, neurobiology-neurodegeneration and repair laboratory,national eye institute,national institutes of health,bethesda,md, United States, genomatix gmbh,munich, Germany, information technology and bioinformatics program,national institute of neurological disorders and stroke,national institutes of health,bethesda,md, United States, laboratory of molecular immunology,national heart,lung,and blood institute,national institutes of health,bethesda,md, United States, neurobiology-neurodegeneration and repair laboratory,national eye institute,national institutes of health,bethesda,md, United States, department of physics,the george washington university,washington,d.c.,united states,department of biostatistics and computational biology,dana-farber cancer institute,harvard school of public health,boston,ma, United States, neurobiology-neurodegeneration and repair laboratory,national eye institute,national institutes of health,bethesda,md, United States, neurobiology-neurodegeneration and repair laboratory,national eye institute,national institutes of health,bethesda,md, United States, department of physics,the george washington university,washington,d.c., United States, information technology and bioinformatics program,national institute of neurological disorders and stroke,national institutes of health,bethesda,md, United States, genomatix gmbh,munich, Germany, laboratory of molecular immunology,national heart,lung,and blood institute,national institutes of health,bethesda,md, United States, neurobiology-neurodegeneration and repair laboratory,national eye institute,national institutes of health,bethesda,md, United States
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Authors
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