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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.
Pubmed ID: 28985507 RIS Download
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A promoter database of Saccharomyces cerevisiae. Users can explore the promoter regions of ~6000 genes and ORFs in yeast genome, annotate putative regulatory sites of all genes and ORFs, locate intergenic regions, and retrieve sequence of the promoter region. In regards to regulatory elements and transcription factors, users can provide information on transcriptionally related genes, browse matrix and consensus sequences, view the correlation between elements, observe binding affinity and expression, and look at genomewise distribution. SCPD also provides some simple but useful tools for promoter sequence analysis. Gene, consensus and matrix records may be submitted.
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