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• W2744996861 abstract "Long noncoding RNAs are investigated using a CRISPR–Cas9 activation screen and shown to confer BRAF inhibitor resistance on melanoma cells through various local mechanisms. Long non-coding RNA (lncRNA) loci are very abundant in the human genome, but identifying the functional roles of many of these regions in health and disease has been challenging. The authors developed a genome-scale CRISPR–Cas9 activation screening approach to identify lncRNA loci that influence resistance to BRAF inhibitors in melanoma cells. The screen identified several novel candidate loci with a local and distant role on gene expression. These lncRNA loci include EMICERI, which controls the activation of genes that drive resistance to vemurafenib, a clinically approved therapy for late-stage melanoma. Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs)1,2, some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms3,4,5,6,7,8. Although some lncRNA loci encode RNAs that act non-locally (in trans)5, there is emerging evidence that many lncRNA loci act locally (in cis) to regulate the expression of nearby genes—for example, through functions of the lncRNA promoter, transcription, or transcript itself3,6,7,8. Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms. Here, to address these challenges, we developed a genome-scale CRISPR–Cas9 activation screen that targets more than 10,000 lncRNA transcriptional start sites to identify noncoding loci that influence a phenotype of interest. We found 11 lncRNA loci that, upon recruitment of an activator, mediate resistance to BRAF inhibitors in human melanoma cells. Most candidate loci appear to regulate nearby genes. Detailed analysis of one candidate, termed EMICERI, revealed that its transcriptional activation resulted in dosage-dependent activation of four neighbouring protein-coding genes, one of which confers the resistance phenotype. Our screening and characterization approach provides a CRISPR toolkit with which to systematically discover the functions of noncoding loci and elucidate their diverse roles in gene regulation and cellular function." @default.
• W2744996861 created "2017-08-17" @default.
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• W2744996861 date "2017-08-11" @default.
• W2744996861 modified "2023-10-06" @default.
• W2744996861 title "Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood" @default.
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• W2744996861 doi "https://doi.org/10.1038/nature23451" @default.
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