Expanding the MicroRNA Targeting Code: Functional Sites with Centered Pairing
Open accessAbstract
Most metazoan microRNA (miRNA) target sites have perfect pairing to the seed region, located near the miRNA 5' end. Although pairing to the 3' region sometimes supplements seed matches or compensates for mismatches, pairing to the central region has been known to function only at rare sites that impart Argonaute-catalyzed mRNA cleavage. Here, we present "centered sites," a class of miRNA target sites that lack both perfect seed pairing and 3'-compensatory pairing and instead have 11-12 contiguous Watson-Crick pairs to the center of the miRNA. Although centered sites can impart mRNA cleavage in vitro (in elevated Mg(2+)), in cells they repress protein output without consequential Argonaute-catalyzed cleavage. Our study also identified extensively paired sites that are cleavage substrates in cultured cells and human brain. This expanded repertoire of cleavage targets and the identification of the centered site type help explain why central regions of many miRNAs are evolutionarily conserved.
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Approximately 300 out of ~2,500 total human miRNAs were detected in human brain tissues.
“Because miRNAs have strong tissue-specific expression patterns, only approximately 300 miRNAs out of ~2,500 total human miRNAs were detected in human brain tissues, and about 100 miRNAs account for most miRNAs in the brain38,39.”
From Intra- and Inter-individual Variability of microRNA Levels in Human Cerebrospinal Fluid: Critical Implications for Biomarker Discovery (2017) · cites this paper as [38]
The Results section, “MicroRNA-directed Cleavage in HeLa Cells and Human brain” (page not available), says that miRNAs expressed in human brain tissue were identified by small-RNA sequencing. It does not give the claimed count of approximately 300 or a total of approximately 2,500 human miRNAs; searches for those numbers found no supporting passage. (LLM, conf=0.82)
Experimental — accuracy not yet measuredmiRNAs have strong tissue-specific expression patterns.
“Because miRNAs have strong tissue-specific expression patterns, only approximately 300 miRNAs out of ~2,500 total human miRNAs were detected in human brain tissues, and about 100 miRNAs account for most miRNAs in the brain38,39.”
From Intra- and Inter-individual Variability of microRNA Levels in Human Cerebrospinal Fluid: Critical Implications for Biomarker Discovery (2017) · cites this paper as [38]
The Discussion section (page unavailable) attributes the small overlap in cleavage targets between human brain and HeLa cells partly to differential expression of miRNAs or mRNAs. That supports expression differences between these samples, but it does not establish strong tissue-specific expression patterns for miRNAs generally. The passages also do not support the cited sentence’s counts of approximately 300 brain miRNAs or 100 accounting for most brain miRNAs. (LLM, conf=0.77)
Experimental — accuracy not yet measuredOnly a small population of miRNAs accounts for a majority of miRNA pool in the brain.
“Previous studies have shown that only a small population of miRNAs accounts for a majority of miRNA pool in the brain (Shin et al. 2010, Hu et al. 2011, Landgraf et al. 2007, Berezikov et al. 2006).”
From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as Shin et al. 2010
The Results section, “MicroRNA-directed Cleavage in HeLa Cells and Human brain” (page unavailable), says that brain miRNAs were identified by small-RNA sequencing, but does not report what fraction of the miRNA pool is made up by a small number of miRNAs. Searches for brain miRNA abundance and the proportion of total miRNA reads found no passage addressing that distribution. (LLM, conf=0.72)
Experimental — accuracy not yet measuredAbout 100 miRNAs account for most miRNAs in the brain.
“Because miRNAs have strong tissue-specific expression patterns, only approximately 300 miRNAs out of ~2,500 total human miRNAs were detected in human brain tissues, and about 100 miRNAs account for most miRNAs in the brain38,39.”
From Intra- and Inter-individual Variability of microRNA Levels in Human Cerebrospinal Fluid: Critical Implications for Biomarker Discovery (2017) · cites this paper as [38]
The Results section, “MicroRNA-directed Cleavage in HeLa Cells and Human brain” (page unavailable), says brain-expressed miRNAs were identified by small-RNA sequencing, but gives no count or distribution of their abundance. Searches for approximately 100 miRNAs and the most abundant brain miRNAs found no passage supporting the claim that about 100 account for most brain miRNAs. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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Cites
Most mammalian mRNAs are conserved targets of microRNAs
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“All eight cleavage sites were in 3’UTRs, and half were conserved in other mammals (Table 1 and Figure S5B).”
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BackgroundDirect transcriptional regulation by nuclear microRNAs
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- Authors
- Shin, C., Nam, J.-W., Farh, K. K.-H., Chiang, H. R., Shkumatava, A., & Bartel, D. P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bartel, David P.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2010-06
- Volume
- 38
- Issue
- 6
- Pages
- 789-802
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2942757
- OpenAlex
- W2155649150
- Cited by
- 611
- References
- 7
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 16 · 2023: 14 · 2022: 25 · 2021: 33 · 2020: 23 · 2019: 48 · 2018: 38 · 2017: 46 · 2016: 32 · 2015: 47 · 2014: 69 · 2013: 67 · 2012: 60
- FWCI
- 18.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- The Royal Society of Chemistry’s Journals, Books and Databases (The Royal Society of Chemistry) (submittedVersion)
- PMC
- Funders
- Howard Hughes Medical Institute
- Damon Runyon Cancer Research Foundation
- 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 Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- microRNA binding sites, mRNA silencing, miRNA evolution, human brain
- MeSH terms
- Animals, Base Sequence, Brain, Cations, Divalent, HeLa Cells, Humans, Magnesium, RNA, Double-Stranded, RNA, Messenger, Conserved Sequence, Base Pairing, 3' Untranslated Regions, Gene Expression Profiling, MicroRNAs, Mice
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