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dc.date.accessioned2019-06-12T21:03:40Z
dc.date.available2019-06-12T21:03:40Z
dc.date.issued2017-10
dc.date.submitted2017-06
dc.identifier.issn1097-2765
dc.identifier.issn1097-4164
dc.identifier.urihttps://hdl.handle.net/1721.1/121267
dc.description.abstractThe 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. Chen et al. created PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a CRISPR-Cas screening technology, to discover modulators of complex disease phenotypes by global transcriptional network reprogramming. A randomized library of transcription factors identified individual and combinatorial genes protective against alpha-synuclein toxicity in yeast and neuronal models of Parkinson's disease. Keywords: CRISPR screening; Parkinson’s disease; alpha-synuclein; global transcriptional perturbations; synthetic transcription factors; randomized gRNA library; PRISM; Perturbing Regulatory Interactions by Synthetic Modulatorsen_US
dc.language.isoen
dc.publisherElsevier BVen_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/J.MOLCEL.2017.09.014en_US
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs Licenseen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.sourcePMCen_US
dc.titleRandomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicityen_US
dc.typeArticleen_US
dc.identifier.citationChen, Ying-Chou et al. "Randomized CRISPR-Cas Transcriptional Perturbation Screening Reveals Protective Genes against Alpha-Synuclein Toxicity." Molecular Cell 68, 1 (October 2017): 247-257en_US
dc.contributor.departmentMassachusetts Institute of Technology. Synthetic Biology Centeren_US
dc.contributor.departmentMassachusetts Institute of Technology. Research Laboratory of Electronicsen_US
dc.contributor.departmentMassachusetts Institute of Technology. Microbiology Graduate Programen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Electrical Engineering and Computer Scienceen_US
dc.relation.journalMolecular Cellen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2019-06-12T17:44:29Z
dspace.date.submission2019-06-12T17:44:30Z
mit.journal.volume68en_US
mit.journal.issue1en_US


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