Cited by 283Chromosomal and Genetic VariationsMicroRNA in disease regulationPlant Molecular Biology Research

The DOI matches its Crossref record; 67 of the 68 references it cites were found in a registry or an index; 3 of the 39 sources its claims cite were checked for support.

A Family of Human MicroRNA Genes from Miniature Inverted-Repeat Transposable Elements

Open access

Abstract

While hundreds of novel microRNA (miRNA) genes have been discovered in the last few years alone, the origin and evolution of these non-coding regulatory sequences remain largely obscure. In this report, we demonstrate that members of a recently discovered family of human miRNA genes, hsa-mir-548, are derived from Made1 transposable elements. Made1 elements are short miniature inverted-repeat transposable elements (MITEs), which consist of two 37 base pair (bp) terminal inverted repeats that flank 6 bp of internal sequence. Thus, Made1 elements are nearly perfect palindromes, and when expressed as RNA they form highly stable hairpin loops. Apparently, these Made1-related structures are recognized by the RNA interference enzymatic machinery and processed to form 22 bp mature miRNA sequences. Consistent with their origin from MITEs, hsa-mir-548 genes are primate-specific and have many potential paralogs in the human genome. There are more than 3,500 putative hsa-mir-548 target genes; analysis of their expression profiles and functional affinities suggests cancer-related regulatory roles for hsa-mir-548. Taken together, the characteristics of Made1 elements, and MITEs in general, point to a specific mechanism for the generation of numerous small regulatory RNAs and target sites throughout the genome. The evolutionary lineage-specific nature of MITEs could also provide for the generation of novel regulatory phenotypes related to species diversification. Finally, we propose that MITEs may represent an evolutionary link between siRNAs and miRNAs.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

The paper reports that seven human hsa-mir-548 miRNA genes are derived from Made1 miniature inverted-repeat transposable elements, whose palindromic terminal inverted repeats can form hairpins processed into 22-nt mature miRNAs. It further predicts thousands of hsa-mir-548 target genes and links the family to cancer-related regulatory roles.

Key findings

  • Seven closely related hsa-mir-548 miRNA genes were co-located with Made1 elements; Made1 elements are 80 bp long, with two 37 bp terminal inverted repeats flanking 6 bp of internal sequence, and the mature hsa-mir-548 miRNAs are 22 nt.
  • Made1 sequences are expressed: 141 human ESTs matched the Made1 query with >80% similarity over >80% of the element, and hsa-mir-548 genes are primate-specific, with orthologous sequences confined to human, chimpanzee, and rhesus macaque.
  • Target prediction found 3,527 potential hsa-mir-548 target genes by miRBase/miRanda and 179 Made1-related targets; only 29 genes were shared, close to the random expectation of 27 (P = 0.07), and Made1-related targets were significantly less conserved than miRanda targets (0.082 ± 0.017 vs. 0.319 ± 0.007; t = 11.27, P = 5.7e-29).
  • Among 2,045 target genes with Symatlas expression data across 79 tissues, three co-expression clusters (12, 15, and 20) were down-regulated in colorectal adenocarcinoma; the colorectal sample had the lowest average relative expression for target genes (P < 0.001, Tukey test), and 22 putative targets had been previously linked to colorectal cancer by down-regulation.

Methods

  • The authors compared hg18 human genome coordinates of experimentally characterized miRNAs from miRBase 8.2 with RepeatMasker-annotated TEs using the UCSC Genome and Table Browsers, then used BLAT, ClustalW, BLASTN against dbEST, Mfold, and UCSC conservation tracks to analyze Made1-derived miRNA sequences.
  • Regulatory analysis used miRBase Targets/miRanda predictions plus a search of 3′ UTRs for Made1-derived target sites; random expectation was calculated from joint probabilities and the binomial distribution.
  • Expression analysis used Novartis Symatlas profiles across 79 tissues, with Genesis for k-means and hierarchical clustering and GOTree Machine for over-represented Gene Ontology biological process terms.

Limitations

  • The paper states that target site predictions are prone to false positives and notes that some up-regulated genes with predicted hsa-mir-548 target sites may be false positives or may reflect translational repression rather than mRNA degradation.
  • The paper also notes that the small overlap between miRBase and Made1 target sets may stem from the miRanda conservation criterion and the young evolutionary age of Made1.
  • Evident from the text: the MITE-to-miRNA processing model and most regulatory roles are inferred computationally from sequence, expression correlation, and target prediction, without direct experimental validation of processing or repression in this study.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0000203

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

3 of 39 cited sources checked · 3 supported · 0 flagged

Show all 61 claims

  • Probably not a substantial claim. 21
  • The quote only partly states this claim. 1
  • It may state two separate claims as one. 15
34 of 34
  • The paper relies on this without support.

    Made1 is an evolutionarily young TE family.

    “the fact that Made1 is an evolutionarily young TE family.”
  • The paper relies on this without support.

    The putative hsa-mir-548 target genes identified by miRBase predictions are actual regulatory targets of hsa-mir-548.

    “There are more than 3,500 putative hsa-mir-548 target genes; analysis of their expression profiles and functional affinities suggests cancer-related regulatory roles for hsa-mir-548.”
  • The paper relies on this without support.

    Made1 insertions generally occur in transcriptionally active genomic regions.

    “Made1 insertions into transcriptionally active genomic regions would yield viable pri-miRNA structures that would be processed into mature miRNA sequences by the RNA interference enzymatic machinery.”
  • The paper relies on this without support.

    Target site predictions are prone to false positives.

    “Consideration of target gene relative expression levels can also be used to help validate target site predictions, which are prone to false positives.”
  • The paper relies on this without support.

    The tissue samples used for expression analysis are similar to the colorectal samples from which hsa-mir-548 genes were cloned.

    “We sought to further evaluate the potential mRNA degradation-based regulatory effects of the hsa-mir-548 miRNAs by searching for down regulation of putative target genes in tissue samples similar to the colorectal samples from which they were cloned [10].”
5 of 5

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Metadata

Authors
Piriyapongsa, J., & Jordan, I. K.
Affiliations
Georgia Institute of Technology (US)
Corresponding author
Jordan, I. King
Venue
PLoS ONE
Published
2007-02-14
Volume
2
Issue
2
Pages
e203
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2074216902
Cited by
283
References
68
Citations by year
2026: 2 · 2025: 4 · 2023: 5 · 2022: 13 · 2021: 13 · 2020: 12 · 2019: 12 · 2018: 13 · 2017: 11 · 2016: 15 · 2015: 23 · 2014: 14 · 2013: 25 · 2012: 28
FWCI
10.20
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • SMARTech Repository (Georgia Institute of Technology) (submittedVersion, cc-by)
Funders
  • Georgia Institute of Technology
  • Ministry of Science and Technology of Thailand
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
Keywords
microRNA, miniature inverted-repeat transposable elements, RNA interference, small regulatory RNAs, paralogs, target genes, genome evolution
MeSH terms
Animals, Base Sequence, DNA Transposable Elements, Multigene Family, Humans, Mammals, Molecular Sequence Data, Sequence Homology, Nucleic Acid, Sequence Alignment, Expressed Sequence Tags, RNA Interference, RNA, Small Interfering, MicroRNAs, Comparative Genomic Hybridization, Inverted Repeat Sequences

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