Deconvolution of seed and RNA-binding protein crosstalk in RNAi-based functional genomics
Open accessAbstract
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.
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ceRBP effects are widespread in RNAi and contribute to off-target effects and phenotype modulation.
“We observed that ceRBP effects are widespread in RNAi and contributes to off-target effects and phenotype modulation40.”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [40]
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A compendium of RNA-binding motifs for decoding gene regulation
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Gain-of-function mutation of microRNA-140 in human skeletal dysplasia
Grigelioniene, G., Suzuki, H. I., Taylan, F., Mirzamohammadi, F., Borochowitz, Z. U., Ayturk, U. M., Tzur, S., Horemuzova, E., Lindstrand, A., Weis, M. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0353-2 · Cited by 103 · see citing works
Self-citation
- Authors
- Suzuki, H. I., Spengler, R. M., Grigelioniene, G., Kobayashi, T., & Sharp, P. A.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- University of Michigan (US)
- Harvard University (US)
- Corresponding author
- Sharp, Phillip A.
- Venue
- Nature Genetics
- Published
- 2018-04-16
- Volume
- 50
- Issue
- 5
- Pages
- 657-661
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5934319
- OpenAlex
- W2797194783
- Cited by
- 23
- References
- 2
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 2
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- National Cancer Institute (R01CA133404, P30CA014051)
- National Institute of General Medical Sciences (R01GM034277)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056645)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- RNA-binding proteins, seed sequence, siRNA off-target effects, microRNA, RNA interference, cancer cell lines, DepMap, gene knockdown, RNA silencing
- MeSH terms
- Humans, Neoplasms, RNA-Binding Proteins, Genomics, RNA Interference, RNA, Small Interfering, MicroRNAs, Cell Line, Tumor
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