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Cited by 103RNA and protein synthesis mechanismsIron Metabolism and DisordersRNA Research and Splicing

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SIREs: searching for iron-responsive elements

Open access
Campillos, M., Cases, I., Hentze, M. W., Sanchez, M.·2010·Nucleic Acids Research
DOI 10.1093/nar/gkq371PMC PMC2896125
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Abstract

The iron regulatory protein/iron-responsive element regulatory system plays a crucial role in the post-transcriptional regulation of gene expression and its disruption results in human disease. IREs are cis-acting regulatory motifs present in mRNAs that encode proteins involved in iron metabolism. They function as binding sites for two related trans-acting factors, namely the IRP-1 and -2. Among cis-acting RNA regulatory elements, the IRE is one of the best characterized. It is defined by a combination of RNA sequence and structure. However, currently available programs to predict IREs do not show a satisfactory level of sensitivity and fail to detect some of the functional IREs. Here, we report an improved software for the prediction of IREs implemented as a user-friendly web server tool. The SIREs web server uses a simple data input interface and provides structure analysis, predicted RNA folds, folding energy data and an overall quality flag based on properties of well characterized IREs. Results are reported in a tabular format and as a schematic visual representation that highlights important features of the IRE. The SIREs (Search for iron-responsive elements) web server is freely available on the web at http://ccbg.imppc.org/sires/index.html.

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Figure 1. (A) Schematic representation of an IRE. The SIREs prediction program allows the detection of IREs with 18 different apical motifs, one bulge at the 3′ (n20b, n21b, n22b and n23b) or one mismatch in the upper stem. (B) Main workflow of the SIREs prediction algorithm. Prediction is limited to the core IRE sequence containing the hexa-apical loop (n14–n19), the C8 bulge, the upper stem and the base pair n07–n25. After finding a matching sequence, additional nucleotides from the lower stem are also obtained and reported (n01–n06 and n26–n31).
Figure 1. (A) Schematic representation of an IRE. The SIREs prediction program allows the detection of IREs with 18 different apical motifs, one bulge at the 3′ (n20b, n21b, n22b and n23b) or one mismatch in the upper stem. (B) Main workflow of the SIREs prediction algorithm. Prediction is limited to the core IRE sequence containing the hexa-apical loop (n14–n19), the C8 bulge, the upper stem and the base pair n07–n25. After finding a matching sequence, additional nucleotides from the lower stem are also obtained and reported (n01–n06 and n26–n31).CC BY-NC · PubMed Central
Figure 2. Input page of the SIREs web server. The input page of the SIREs web server provides a simplified form where only the sequence in FASTA format is required. A partial sequence of the 5′UTR of the mouse ferritin-H cDNA (GenBank Accession number: NM_010239, nucleotides 1–240) that contains an IRE is given as an example of the FASTA format that can also be used as a rapid testing example. A navigation area is also presented, containing links to the documentation, FAQs, references and contact sections.
Figure 2. Input page of the SIREs web server. The input page of the SIREs web server provides a simplified form where only the sequence in FASTA format is required. A partial sequence of the 5′UTR of the mouse ferritin-H cDNA (GenBank Accession number: NM_010239, nucleotides 1–240) that contains an IRE is given as an example of the FASTA format that can also be used as a rapid testing example. A navigation area is also presented, containing links to the documentation, FAQs, references and contact sections.CC BY-NC · PubMed Central
Figure 3. The SIREs web server output. (A) The top part shows navigation links to all different sections of the web site. Below, a summary of the results is shown, including the total number of submitted sequences and predicted IREs, and a detailed table with features of each predicted IRE. This table can be sorted by several criteria and its content can be downloaded in GFF standard format. Each row is linked to a more detailed report. (B) For each predicted IRE, a detailed report is presented including the overall quality of the prediction, a graphical representation of the predicted structure and detailed description of the predicted IRE features. The scheme includes a legend and highlights important IRE features, including the apical loop (in red), the C-8 bulge (in green), GU/UG base pairs (in orange) and other bulges or mismatches (in yellow). This image can be downloaded in JPEG format. To the right, a summary of the predicted IRE features is provided. By clicking in each feature, the user accesses a short description of it. (C) The user can switch from the scheme described before to a graphical representation of the RNA folded by the RNAfold program from the Vienna Package, where also the apical loop (in red) and the C8 bulge (in green) are highlighted. (D) For each predicted IRE, the sequence ID and sequence context is also provided, with the predicted IRE sequence shown in red. The IRE sequence can be downloaded in FASTA format by clicking on the provided link. (E) The SIREs web server also provides the conventional representation of the RNA folding in Vienna format.
Figure 3. The SIREs web server output. (A) The top part shows navigation links to all different sections of the web site. Below, a summary of the results is shown, including the total number of submitted sequences and predicted IREs, and a detailed table with features of each predicted IRE. This table can be sorted by several criteria and its content can be downloaded in GFF standard format. Each row is linked to a more detailed report. (B) For each predicted IRE, a detailed report is presented including the overall quality of the prediction, a graphical representation of the predicted structure and detailed description of the predicted IRE features. The scheme includes a legend and highlights important IRE features, including the apical loop (in red), the C-8 bulge (in green), GU/UG base pairs (in orange) and other bulges or mismatches (in yellow). This image can be downloaded in JPEG format. To the right, a summary of the predicted IRE features is provided. By clicking in each feature, the user accesses a short description of it. (C) The user can switch from the scheme described before to a graphical representation of the RNA folded by the RNAfold program from the Vienna Package, where also the apical loop (in red) and the C8 bulge (in green) are highlighted. (D) For each predicted IRE, the sequence ID and sequence context is also provided, with the predicted IRE sequence shown in red. The IRE sequence can be downloaded in FASTA format by clicking on the provided link. (E) The SIREs web server also provides the conventional representation of the RNA folding in Vienna format.CC BY-NC · PubMed Central
Figure 4. Motif distribution of the 35 IRP target genes used in SIREs evaluation. Twenty-nine IREs were predicted by SIREs in 24 out of 35 novel IRP target genes. Canonical motif 1 and 2 and SELEX motif 8 were detected more abundantly. Stem types inside each motif are classified by color as no mismatch/3′ bulge (blue), mismatch (red) or 3′ bulge (green).
Figure 4. Motif distribution of the 35 IRP target genes used in SIREs evaluation. Twenty-nine IREs were predicted by SIREs in 24 out of 35 novel IRP target genes. Canonical motif 1 and 2 and SELEX motif 8 were detected more abundantly. Stem types inside each motif are classified by color as no mismatch/3′ bulge (blue), mismatch (red) or 3′ bulge (green).CC BY-NC · PubMed Central

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Metadata

Authors
Campillos, M., Cases, I., Hentze, M. W., & Sanchez, M.
Affiliations
  • European Molecular Biology Laboratory (DE)
  • European Molecular Biology Laboratory (ES)
ORCID
Venue
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Published
2010-05-11
Volume
38
Issue
Web Server
Pages
W360-W367
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
DOI
10.1093/nar/gkq371
PMC
PMC2896125
OpenAlex
W1967604392
Cited by
102
References
31
Citations by year
2026: 3 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 1 · 2021: 19 · 2020: 9 · 2019: 3 · 2018: 6 · 2017: 5 · 2016: 2 · 2015: 7 · 2014: 6 · 2013: 3 · 2012: 6
FWCI
2.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Hispana (publishedVersion, cc-by-nc)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Ministerio de Ciencia e Innovación (RYC-2008-02352)
  • Instituto de Salud Carlos III
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
iron-responsive element, iron regulatory proteins, post-transcriptional regulation, RNA secondary structure prediction, web server, iron metabolism
MeSH terms
Algorithms, Binding Sites, Humans, Iron, Nucleic Acid Conformation, RNA, Software, Internet, Untranslated Regions, Iron-Regulatory Proteins, Regulatory Sequences, Ribonucleic Acid

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