MicroRNA Targeting Specificity in Mammals: Determinants beyond Seed Pairing
Open accessAbstract
Mammalian microRNAs (miRNAs) pair to 3'UTRs of mRNAs to direct their posttranscriptional repression. Important for target recognition are approximately 7 nt sites that match the seed region of the miRNA. However, these seed matches are not always sufficient for repression, indicating that other characteristics help specify targeting. By combining computational and experimental approaches, we uncovered five general features of site context that boost site efficacy: AU-rich nucleotide composition near the site, proximity to sites for coexpressed miRNAs (which leads to cooperative action), proximity to residues pairing to miRNA nucleotides 13-16, positioning within the 3'UTR at least 15 nt from the stop codon, and positioning away from the center of long UTRs. A model combining these context determinants quantitatively predicts site performance both for exogenously added miRNAs and for endogenous miRNA-message interactions. Because it predicts site efficacy without recourse to evolutionary conservation, the model also identifies effective nonconserved sites and siRNA off-targets.
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Gene regulation by conserved miRNAs has a significant impact on 3′ UTR evolution, and evolutionarily maintained target sites mediate actions of miRNAs more effectively than non-conserved target sites.
“Gene regulation by conserved miRNAs has a significant impact on 3′ UTR evolution, and evolutionarily maintained target sites mediate actions of miRNAs more effectively than non-conserved target sites28.”
From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [28]
MicroRNA sites have been validated in coding sequence (CDS) regions, albeit with typically weaker repressive activity.
“MicroRNA sites have also been validated in coding sequence (CDS) regions, albeit with typically weaker repressive activity (Baek et al., 2008;Grimson et al., 2007).”
From Scalable and deep profiling of mRNA targets for individual microRNAs with chimeric eCLIP (2022) · cites this paper as Grimson et al., 2007
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- Authors
- Grimson, A., Farh, K. K.-H., Johnston, W. K., Garrett-Engele, P., Lim, L. P., & Bartel, D. P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lim, Lee P.
- Bartel, David P.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2007-07
- Volume
- 27
- Issue
- 1
- Pages
- 91-105
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3800283
- OpenAlex
- W2059073003
- Cited by
- 3,766
- References
- 6
- Citations by year
- 2026: 54 · 2025: 54 · 2024: 93 · 2023: 121 · 2022: 148 · 2021: 156 · 2020: 153 · 2019: 160 · 2018: 182 · 2017: 172 · 2016: 226 · 2015: 294 · 2014: 323 · 2013: 343 · 2012: 317
- FWCI
- 79.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Merck
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM067031)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
- Keywords
- 3' untranslated region, post-transcriptional gene silencing
- MeSH terms
- Animals, Base Sequence, Binding Sites, HeLa Cells, Humans, Mammals, Models, Genetic, Molecular Sequence Data, Nucleotides, RNA, Messenger, Substrate Specificity, Down-Regulation, Conserved Sequence, Codon, Terminator, Base Pairing, 3' Untranslated Regions, MicroRNAs
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