Deconvolution of seed and RNA-binding protein crosstalk in RNAi-based functional genomics
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Author(s)
Spengler, Ryan M.
Grigelioniene, Giedre
Kobayashi, Tatsuya
Suzuki, Hiroshi
Sharp, Phillip A.
Date Issued
April 2018
Journal
Nature Genetics
Publisher
Nature Publishing Group
Citation
Suzuki, Hiroshi I. et al. “Deconvolution of Seed and RNA-Binding Protein Crosstalk in RNAi-Based Functional Genomics.” Nature Genetics 50, 5 (April 2018): 657–661 © 2018 The Author(s)
Version
Author's final manuscript
Abstract
RNA interference (RNAi) is a major, powerful platform for gene perturbations, but is restricted by off-target mechanisms. Communication between RNAs, small RNAs, and RNA-binding proteins (RBPs) is a pervasive feature of cellular RNA networks. We present a crosstalk scenario, designated as crosstalk with endogenous RBPs' (ceRBP), in which small interfering RNAs or microRNAs with seed sequences that overlap RBP motifs have extended biological effects by perturbing endogenous RBP activity. Systematic analysis of small interfering RNA (siRNA) off-target data and genome-wide RNAi cancer lethality screens using 501 human cancer cell lines, a cancer dependency map, identified that seed-to-RBP crosstalk is widespread, contributes to off-target activity, and affects RNAi performance. Specifically, deconvolution of the interactions between gene knockdown and seed-mediated silencing effects in the cancer dependency map showed widespread contributions of seed-to-RBP crosstalk to growth-phenotype modulation. These findings suggest a novel aspect of microRNA biology and offer a basis for improvement of RNAi agents and RNAi-based functional genomics.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/s41588-018-0104-1
