Base de dados : MEDLINE
Pesquisa : D13.444.735.790.552.625 [Categoria DeCS]
Referências encontradas : 901 [refinar]
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  1 / 901 MEDLINE  
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[PMID]:29377933
[Au] Autor:Sato'o Y; Hisatsune J; Yu L; Sakuma T; Yamamoto T; Sugai M
[Ad] Endereço:Department of Bacteriology, Hiroshima University, Graduate school of Biomedical and Health Sciences, Hiroshima, Hiroshima, Japan.
[Ti] Título:Tailor-made gene silencing of Staphylococcus aureus clinical isolates by CRISPR interference.
[So] Source:PLoS One;13(1):e0185987, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Preparing the genetically modified organisms have required much time and labor, making it the rate-limiting step but CRISPR/Cas9 technology appearance has changed this difficulty. Although reports on CRISPR/Cas9 technology such as genome editing and CRISPR interference (CRISPRi) in eukaryotes increased, those in prokaryotes especially in Staphylococci were limited. Thus, its potential in the bacteriology remains unexplored. This is attributed to ecological difference between eukaryotes and prokaryotes. Here, we constructed a novel CRISPRi plasmid vector, pBACi for Staphylococcus aureus. The transformation efficiency of S. aureus was ~104 CFU/µg DNA using a vector extracted from dcm negative, which encoded one of DNA modification genes, E. coli. Further, pBACi was introduced into various clinical isolates including that not accepting the conventional temperature-sensitive vector. dcas9 in the vector was expressed throughout the growth phases of S. aureus and this vector decreased various gene mRNA expressions based on the crRNA targeting sequences and altered the knockdown strains' phenotypes. The targeted genes included various virulence and antibiotic resistant genes. Bioinformatics suggest this vector can be introduced into wide range of low-GC Gram-positive bacteria. Because this new CRISPR/Cas9-based vector can easily prepare knockdown strains, we believe the novel vector will facilitate the characterization of the function of genes from S. aureus and other Gram-positive bacteria.
[Mh] Termos MeSH primário: Técnicas de Silenciamento de Genes/métodos
Vetores Genéticos/síntese química
Staphylococcus aureus/genética
[Mh] Termos MeSH secundário: Proteínas de Bactérias/genética
Sistemas CRISPR-Cas/genética
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
Escherichia coli/genética
Edição de Genes
Inativação Gênica
Vetores Genéticos/genética
Genoma Bacteriano
Plasmídeos/genética
RNA Guia/genética
Infecções Estafilocócicas/genética
Staphylococcus aureus/patogenicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (RNA, Guide)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180130
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185987


  2 / 901 MEDLINE  
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[PMID]:28462777
[Au] Autor:Lee K; Mackley VA; Rao A; Chong AT; Dewitt MA; Corn JE; Murthy N
[Ad] Endereço:GenEdit Inc, Berkeley, United States.
[Ti] Título:Synthetically modified guide RNA and donor DNA are a versatile platform for CRISPR-Cas9 engineering.
[So] Source:Elife;6, 2017 05 02.
[Is] ISSN:2050-084X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chemical modification of the gRNA and donor DNA has great potential for improving the gene editing efficiency of Cas9 and Cpf1, but has not been investigated extensively. In this report, we demonstrate that the gRNAs of Cas9 and Cpf1, and donor DNA can be chemically modified at their terminal positions without losing activity. Moreover, we show that 5' fluorescently labeled donor DNA can be used as a marker to enrich HDR edited cells by a factor of two through cell sorting. In addition, we demonstrate that the gRNA and donor DNA can be directly conjugated together into one molecule, and show that this gRNA-donor DNA conjugate is three times better at transfecting cells and inducing HDR, with cationic polymers, than unconjugated gRNA and donor DNA. The tolerance of the gRNA and donor DNA to chemical modifications has the potential to enable new strategies for genome engineering.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas
DNA/química
DNA/genética
Edição de Genes/métodos
RNA Guia/química
RNA Guia/genética
[Mh] Termos MeSH secundário: Proteínas de Bactérias/metabolismo
Endonucleases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (RNA, Guide); 9007-49-2 (DNA); EC 3.1.- (Cas9 endonuclease Streptococcus pyogenes); EC 3.1.- (Cpf1 nuclease, Acidaminococcus); EC 3.1.- (Endonucleases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180211
[Lr] Data última revisão:
180211
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  3 / 901 MEDLINE  
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[PMID]:29339069
[Au] Autor:Liu H; Sui T; Liu D; Liu T; Chen M; Deng J; Xu Y; Li Z
[Ad] Endereço:Jilin Provincial Key Laboratory of Animal Embryo Engineering, Jilin University, Changchun 130062, China.
[Ti] Título:Multiple homologous genes knockout (KO) by CRISPR/Cas9 system in rabbit.
[So] Source:Gene;647:261-267, 2018 Mar 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The CRISPR/Cas9 system is a highly efficient and convenient genome editing tool, which has been widely used for single or multiple gene mutation in a variety of organisms. Disruption of multiple homologous genes, which have similar DNA sequences and gene function, is required for the study of the desired phenotype. In this study, to test whether the CRISPR/Cas9 system works on the mutation of multiple homologous genes, a single guide RNA (sgRNA) targeting three fucosyltransferases encoding genes (FUT1, FUT2 and SEC1) was designed. As expected, triple gene mutation of FUT1, FUT2 and SEC1 could be achieved simultaneously via a sgRNA mediated CRISPR/Cas9 system. Besides, significantly reduced serum fucosyltransferases enzymes activity was also determined in those triple gene mutation rabbits. Thus, we provide the first evidence that multiple homologous genes knockout (KO) could be achieved efficiently by a sgRNA mediated CRISPR/Cas9 system in mammals, which could facilitate the genotype to phenotype studies of homologous genes in future.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas/genética
Mutação/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sequência de Bases
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética
Fucosiltransferases/genética
Técnicas de Inativação de Genes/métodos
Fenótipo
RNA Guia/genética
Coelhos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Guide); EC 2.4.1.- (Fucosyltransferases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE


  4 / 901 MEDLINE  
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[PMID]:29211736
[Au] Autor:Adikusuma F; Pfitzner C; Thomas PQ
[Ad] Endereço:School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
[Ti] Título:Versatile single-step-assembly CRISPR/Cas9 vectors for dual gRNA expression.
[So] Source:PLoS One;12(12):e0187236, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CRISPR/Cas9 technology enables efficient, rapid and cost-effective targeted genomic modification in a wide variety of cellular contexts including cultured cells. Some applications such as generation of double knock-outs, large deletions and paired-nickase cleavage require simultaneous expression of two gRNAs. Although single plasmids that enable multiplex expression of gRNAs have been developed, these require multiple rounds of cloning and/or PCR for generation of the desired construct. Here, we describe a series of vectors that enable generation of customized dual-gRNA expression constructs via an easy one-step golden gate cloning reaction using two annealed oligonucleotide inserts with different overhangs. Through nucleofection of mouse embryonic stem cells, we demonstrate highly efficient cleavage of the target loci using the dual-guide plasmids, which are available as Cas9-nuclease or Cas9-nickase expression constructs, with or without selection markers. These vectors are a valuable addition to the CRISPR/Cas9 toolbox and will be made available to all interested researchers via the Addgene plasmid repository.
[Mh] Termos MeSH primário: Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
RNA Guia/genética
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Clonagem Molecular
Células-Tronco Embrionárias/metabolismo
Vetores Genéticos
Camundongos
Plasmídeos
Reação em Cadeia da Polimerase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Guide)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180110
[Lr] Data última revisão:
180110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187236


  5 / 901 MEDLINE  
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[PMID]:29176845
[Au] Autor:Basila M; Kelley ML; Smith AVB
[Ad] Endereço:Dharmacon, a Horizon Discovery Group company, Lafayette, Colorado, United States of America.
[Ti] Título:Minimal 2'-O-methyl phosphorothioate linkage modification pattern of synthetic guide RNAs for increased stability and efficient CRISPR-Cas9 gene editing avoiding cellular toxicity.
[So] Source:PLoS One;12(11):e0188593, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Since its initial application in mammalian cells, CRISPR-Cas9 has rapidly become a preferred method for genome engineering experiments. The Cas9 nuclease is targeted to genomic DNA using guide RNAs (gRNA), either as the native dual RNA system consisting of a DNA-targeting CRISPR RNA (crRNA) and a trans-activating crRNA (tracrRNA), or as a chimeric single guide RNA (sgRNA). Entirely DNA-free CRISPR-Cas9 systems using either Cas9 protein or Cas9 mRNA and chemically synthesized gRNAs allow for transient expression of CRISPR-Cas9 components, thereby reducing the potential for off-targeting, which is a significant advantage in therapeutic applications. In addition, the use of synthetic gRNA allows for the incorporation of chemical modifications for enhanced properties including improved stability. Previous studies have demonstrated the utility of chemically modified gRNAs, but have focused on one pattern with multiple modifications in co-electroporation with Cas9 mRNA or multiple modifications and patterns with Cas9 plasmid lipid co-transfections. Here we present gene editing results using a series of chemically modified synthetic sgRNA molecules and chemically modified crRNA:tracrRNA molecules in both electroporation and lipid transfection assessing indel formation and/or phenotypic gene knockout. We show that while modifications are required for co-electroporation with Cas9 mRNA, some modification patterns of the gRNA are toxic to cells compared to the unmodified gRNA and most modification patterns do not significantly improve gene editing efficiency. We also present modification patterns of the gRNA that can modestly improve Cas9 gene editing efficiency when co-transfected with Cas9 mRNA or Cas9 protein (> 1.5-fold difference). These results indicate that for certain applications, including those relevant to primary cells, the incorporation of some, but not all chemical modification patterns on synthetic crRNA:tracrRNA or sgRNA can be beneficial to CRISPR-Cas9 gene editing.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas/genética
Edição de Genes
Organotiofosfatos/toxicidade
RNA Guia/metabolismo
[Mh] Termos MeSH secundário: Morte Celular/efeitos dos fármacos
Eletroporação
Seres Humanos
Células K562
Lipídeos/química
Fenótipo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipids); 0 (Organothiophosphates); 0 (RNA, Guide); 0 (RNA, Messenger)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188593


  6 / 901 MEDLINE  
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[PMID]:29036168
[Au] Autor:Abadi S; Yan WX; Amar D; Mayrose I
[Ad] Endereço:Department of Molecular Biology and Ecology of Plants, Tel Aviv University, Tel Aviv, Israel.
[Ti] Título:A machine learning approach for predicting CRISPR-Cas9 cleavage efficiencies and patterns underlying its mechanism of action.
[So] Source:PLoS Comput Biol;13(10):e1005807, 2017 Oct.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The adaptation of the CRISPR-Cas9 system as a genome editing technique has generated much excitement in recent years owing to its ability to manipulate targeted genes and genomic regions that are complementary to a programmed single guide RNA (sgRNA). However, the efficacy of a specific sgRNA is not uniquely defined by exact sequence homology to the target site, thus unintended off-targets might additionally be cleaved. Current methods for sgRNA design are mainly concerned with predicting off-targets for a given sgRNA using basic sequence features and employ elementary rules for ranking possible sgRNAs. Here, we introduce CRISTA (CRISPR Target Assessment), a novel algorithm within the machine learning framework that determines the propensity of a genomic site to be cleaved by a given sgRNA. We show that the predictions made with CRISTA are more accurate than other available methodologies. We further demonstrate that the occurrence of bulges is not a rare phenomenon and should be accounted for in the prediction process. Beyond predicting cleavage efficiencies, the learning process provides inferences regarding patterns that underlie the mechanism of action of the CRISPR-Cas9 system. We discover that attributes that describe the spatial structure and rigidity of the entire genomic site as well as those surrounding the PAM region are a major component of the prediction capabilities.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas/genética
Biologia Computacional/métodos
Edição de Genes/métodos
Aprendizado de Máquina
[Mh] Termos MeSH secundário: Algoritmos
Seres Humanos
RNA Guia/genética
Curva ROC
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Guide)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005807


  7 / 901 MEDLINE  
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[PMID]:29016691
[Au] Autor:Zhou W; Wan Y; Guo R; Deng M; Deng K; Wang Z; Zhang Y; Wang F
[Ad] Endereço:Jiangsu Livestock Embryo Engineering Laboratory, Nanjing Agricultural University, Nanjing, Jiangsu, PR, China.
[Ti] Título:Generation of beta-lactoglobulin knock-out goats using CRISPR/Cas9.
[So] Source:PLoS One;12(10):e0186056, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Goat's milk, considered a substitute for cow's milk, has a high nutritional value. However, goat's milk contains various allergens, predominantly ß-lactoglobulin (BLG). In this study, we employed the CRISPR/Cas9 system to target the BLG locus in goat fibroblasts for sgRNA optimization and generate BLG knock-out goats through co-injection of Cas9 mRNA and small guide RNAs (sgRNAs) into goat embryos at the one-cell stage. We firstly tested sgRNA editing efficiencies in goat fibroblast cells, and approximately 8.00%-9.09% of the cells were modified in single sgRNA-guided targeting experiment. Among the kids, the genome-targeting efficiencies of single sgRNA were 12.5% (10 ng/µL sg1) and 0% (10 ng/µL sg2) and efficiencies of dual sgRNAs were 25.0% (25 ng/µL sg2+sg3 group) and 28.6% (50 ng/µL sg2+sg3 group). Relative expression of BLG in BLG knock-out goat mammary glands significantly (p < 0.01) decreased as well as other milk protein coding genes, such as CSN1S1, CSN1S2, CSN2, CSN3 and LALBA (p < 0.05). As expected, BLG protein had been abolished in the milk of the BLG knock-out goat. In addition, most of the targeted kids were chimeric (3/4), and their various body tissues were edited simultaneously. Our study thus provides a basis for optimizing the quality of goat milk, which can be applied to biomedical and agricultural research.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas
Deleção de Genes
Edição de Genes
Lactoglobulinas/genética
Leite/química
[Mh] Termos MeSH secundário: Alérgenos/genética
Animais
Animais Geneticamente Modificados
Complexo do Signalossomo COP9
Quimerismo
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
Transferência Embrionária/métodos
Embrião de Mamíferos
Feminino
Fibroblastos/citologia
Fibroblastos/metabolismo
Expressão Gênica
Loci Gênicos
Cabras
Lactação/fisiologia
Lactoglobulinas/deficiência
Masculino
Microinjeções
Proteínas Nucleares/genética
Proteínas Nucleares/metabolismo
Cultura Primária de Células
Proteínas Quinases/genética
Proteínas Quinases/metabolismo
Subunidades Proteicas/genética
Subunidades Proteicas/metabolismo
RNA Guia/genética
RNA Guia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Allergens); 0 (Lactoglobulins); 0 (Nuclear Proteins); 0 (Protein Subunits); 0 (RNA, Guide); EC 2.7.- (Protein Kinases); EC 3.4.19.12 (COP9 Signalosome Complex)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186056


  8 / 901 MEDLINE  
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[PMID]:28985510
[Au] Autor:Montalbano A; Canver MC; Sanjana NE
[Ad] Endereço:New York Genome Center, New York, NY, USA; Department of Biology, New York University, New York, NY, USA.
[Ti] Título:High-Throughput Approaches to Pinpoint Function within the Noncoding Genome.
[So] Source:Mol Cell;68(1):44-59, 2017 Oct 05.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas nuclease system is a powerful tool for genome editing, and its simple programmability has enabled high-throughput genetic and epigenetic studies. These high-throughput approaches offer investigators a toolkit for functional interrogation of not only protein-coding genes but also noncoding DNA. Historically, noncoding DNA has lacked the detailed characterization that has been applied to protein-coding genes in large part because there has not been a robust set of methodologies for perturbing these regions. Although the majority of high-throughput CRISPR screens have focused on the coding genome to date, an increasing number of CRISPR screens targeting noncoding genomic regions continue to emerge. Here, we review high-throughput CRISPR-based approaches to uncover and understand functional elements within the noncoding genome and discuss practical aspects of noncoding library design and screen analysis.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
DNA Intergênico/genética
Endonucleases/genética
Edição de Genes/métodos
Genoma
[Mh] Termos MeSH secundário: Animais
DNA Intergênico/metabolismo
Endonucleases/metabolismo
Células Eucarióticas/citologia
Células Eucarióticas/metabolismo
Engenharia Genética
Biblioteca Genômica
Ensaios de Triagem em Larga Escala
Seres Humanos
RNA Guia/genética
RNA Guia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (DNA, Intergenic); 0 (RNA, Guide); EC 3.1.- (Endonucleases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


  9 / 901 MEDLINE  
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[PMID]:28985508
[Au] Autor:Hess GT; Tycko J; Yao D; Bassik MC
[Ad] Endereço:Department of Genetics and Stanford University Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford, CA, USA.
[Ti] Título:Methods and Applications of CRISPR-Mediated Base Editing in Eukaryotic Genomes.
[So] Source:Mol Cell;68(1):26-43, 2017 Oct 05.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The past several years have seen an explosion in development of applications for the CRISPR-Cas9 system, from efficient genome editing, to high-throughput screening, to recruitment of a range of DNA and chromatin-modifying enzymes. While homology-directed repair (HDR) coupled with Cas9 nuclease cleavage has been used with great success to repair and re-write genomes, recently developed base-editing systems present a useful orthogonal strategy to engineer nucleotide substitutions. Base editing relies on recruitment of cytidine deaminases to introduce changes (rather than double-stranded breaks and donor templates) and offers potential improvements in efficiency while limiting damage and simplifying the delivery of editing machinery. At the same time, these systems enable novel mutagenesis strategies to introduce sequence diversity for engineering and discovery. Here, we review the different base-editing platforms, including their deaminase recruitment strategies and editing outcomes, and compare them to other CRISPR genome-editing technologies. Additionally, we discuss how these systems have been applied in therapeutic, engineering, and research settings. Lastly, we explore future directions of this emerging technology.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
Reparo do DNA
Endonucleases/genética
Edição de Genes/métodos
Genoma
[Mh] Termos MeSH secundário: Animais
Evolução Molecular Direcionada
Endonucleases/metabolismo
Células Eucarióticas/citologia
Células Eucarióticas/metabolismo
Engenharia Genética
Seres Humanos
Mutagênese
Nucleotídeos/genética
Nucleotídeos/metabolismo
RNA Guia/genética
RNA Guia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Nucleotides); 0 (RNA, Guide); EC 3.1.- (Endonucleases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


  10 / 901 MEDLINE  
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[PMID]:28985507
[Au] Autor:Chen YC; Farzadfard F; Gharaei N; Chen WCW; Cao J; Lu TK
[Ad] Endereço:Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
[Ti] Título:Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity.
[So] Source:Mol Cell;68(1):247-257.e5, 2017 Oct 05.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The genome-wide perturbation of transcriptional networks with CRISPR-Cas technology has primarily involved systematic and targeted gene modulation. Here, we developed PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a screening platform that uses randomized CRISPR-Cas transcription factors (crisprTFs) to globally perturb transcriptional networks. By applying PRISM to a yeast model of Parkinson's disease (PD), we identified guide RNAs (gRNAs) that modulate transcriptional networks and protect cells from alpha-synuclein (αSyn) toxicity. One gRNA identified in this screen outperformed the most protective suppressors of αSyn toxicity reported previously, highlighting PRISM's ability to identify modulators of important phenotypes. Gene expression profiling revealed genes differentially modulated by this strong protective gRNA that rescued yeast from αSyn toxicity when overexpressed. Human homologs of top-ranked hits protected against αSyn-induced cell death in a human neuronal PD model. Thus, high-throughput and unbiased perturbation of transcriptional networks via randomized crisprTFs can reveal complex biological phenotypes and effective disease modulators.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas
Redes Reguladoras de Genes
RNA Guia/genética
Fatores de Transcrição/genética
Transcrição Genética
alfa-Sinucleína/genética
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
Perfilação da Expressão Gênica
Regulação da Expressão Gênica
Ensaios de Triagem em Larga Escala
Seres Humanos
Modelos Biológicos
Neurônios/metabolismo
Neurônios/patologia
Doença de Parkinson/genética
Doença de Parkinson/metabolismo
Doença de Parkinson/patologia
Fenótipo
RNA Guia/metabolismo
Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/metabolismo
Fatores de Transcrição/metabolismo
Transgenes
alfa-Sinucleína/antagonistas & inibidores
alfa-Sinucleína/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Guide); 0 (Transcription Factors); 0 (alpha-Synuclein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE



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BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde