An alternative mode of microRNA target recognition
Open accessAbstract
MicroRNAs (miRNAs) regulate mRNA targets through perfect pairing with their seed region (positions 2-7). Recently, a precise genome-wide map of miRNA interaction sites in mouse brain was generated by high-throughput sequencing and analysis of clusters of ~50-nucleotide mRNA tags cross-linked to Argonaute (Ago HITS-CLIP). By analyzing Ago HITS-CLIP 'orphan clusters'-Ago binding regions from HITS-CLIP that cannot be explained by canonical seed matches-we have now identified an alternative binding mode used by miRNAs. Specifically, G-bulge sites (positions 5-6) are often bound and regulated by miR-124 in brain. More generally, bulged sites comprise ≥15% of all Ago-miRNA interactions in mouse brain and are evolutionarily conserved. We call position 6 the 'pivot' nucleotide and suggest a model in which a transitional 'nucleation bulge' leads to functional bulge mRNA-miRNA interactions, expanding the number of potential miRNA regulatory sites.
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Current target prediction algorithms often identify many false positive target genes and there is no strong overlap in predicted target gene list among prediction algorithms.
“current target prediction algorithms often identify many false positive target genes and there is no strong overlap in the predicted target gene list among prediction algorithms [138-141].”
From MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer's disease (2016) · cites this paper as [140]
The Abstract reports that seed-based target-identification strategies have false-positive prediction rates of about 40–66%, supporting the first part of the claim. It does not compare predicted gene lists across algorithms or say that their overlap is weak. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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- Authors
- Chi, S. W., Hannon, G. J., & Darnell, R. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Chi, Sung Wook
- Darnell, Robert B
- Venue
- Nature Structural & Molecular Biology
- Published
- 2012-02-12
- Volume
- 19
- Issue
- 3
- Pages
- 321-327
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC3541676
- OpenAlex
- W2167754184
- Cited by
- 328
- References
- 46
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 7 · 2023: 5 · 2022: 13 · 2021: 21 · 2020: 14 · 2019: 21 · 2018: 25 · 2017: 27 · 2016: 34 · 2015: 41 · 2014: 45 · 2013: 38 · 2012: 31
- FWCI
- 16.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5p30ca045508-35)
- National Cancer Institute (P30-CA045508, P01CA013106)
- National Institute of General Medical Sciences (R01GM062534)
- National Institute of Neurological Disorders and Stroke (R01NS034389)
- 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
- miR-124, Argonaute proteins, HITS-CLIP, miRNA-mRNA interactions, mouse brain
- MeSH terms
- Binding Sites, HeLa Cells, Humans, Models, Genetic, Base Pairing, MicroRNAs
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