Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-12-10

AUTHORS

Silvana Konermann, Mark D. Brigham, Alexandro E. Trevino, Julia Joung, Omar O. Abudayyeh, Clea Barcena, Patrick D. Hsu, Naomi Habib, Jonathan S. Gootenberg, Hiroshi Nishimasu, Osamu Nureki, Feng Zhang

ABSTRACT

Systematic interrogation of gene function requires the ability to perturb gene expression in a robust and generalizable manner. Here we describe structure-guided engineering of a CRISPR-Cas9 complex to mediate efficient transcriptional activation at endogenous genomic loci. We used these engineered Cas9 activation complexes to investigate single-guide RNA (sgRNA) targeting rules for effective transcriptional activation, to demonstrate multiplexed activation of ten genes simultaneously, and to upregulate long intergenic non-coding RNA (lincRNA) transcripts. We also synthesized a library consisting of 70,290 guides targeting all human RefSeq coding isoforms to screen for genes that, upon activation, confer resistance to a BRAF inhibitor. The top hits included genes previously shown to be able to confer resistance, and novel candidates were validated using individual sgRNA and complementary DNA overexpression. A gene expression signature based on the top screening hits correlated with markers of BRAF inhibitor resistance in cell lines and patient-derived samples. These results collectively demonstrate the potential of Cas9-based activators as a powerful genetic perturbation technology. More... »

PAGES

583-588

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  • Journal

    TITLE

    Nature

    ISSUE

    7536

    VOLUME

    517

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature14136

    DOI

    http://dx.doi.org/10.1038/nature14136

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1048954459

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/25494202


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