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Nature. 2017 Aug 17;548(7667):343-346. doi: 10.1038/nature23451. Epub 2017 Aug 11.

Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood.

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Department of Biological Engineering, MIT, Cambridge, Massachusetts 02139, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
McGovern Institute for Brain Research at MIT, Cambridge, Massachusetts 02139, USA.
Department of Brain and Cognitive Science, MIT, Cambridge, Massachusetts 02139, USA.
Division of Health Sciences and Technology, MIT, Cambridge, Massachusetts 02139, USA.
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.


Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs), some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms. Although some lncRNA loci encode RNAs that act non-locally (in trans), 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 itself. 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.

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