3'-UTR SIRF: A database for identifying clusters of short interspersed repeats in 3' untranslated regions
- Benjamin B Andken†1,
- In Lim†1,
- Gary Benson1, 2, 3,
- John J Vincent2,
- Matthew T Ferenc2,
- Bianca Heinrich2,
- Larissa A Jarzylo2,
- Heng-Ye Man2 and
- James O Deshler1, 2Email author
© Andken et al; licensee BioMed Central Ltd. 2007
Received: 13 February 2007
Accepted: 30 July 2007
Published: 30 July 2007
Short (~5 nucleotides) interspersed repeats regulate several aspects of post-transcriptional gene expression. Previously we developed an algorithm (REPFIND) that assigns P-values to all repeated motifs in a given nucleic acid sequence and reliably identifies clusters of short CAC-containing motifs required for mRNA localization in Xenopus oocytes.
In order to facilitate the identification of genes possessing clusters of repeats that regulate post-transcriptional aspects of gene expression in mammalian genes, we used REPFIND to create a database of all repeated motifs in the 3' untranslated regions (UTR) of genes from the Mammalian Gene Collection (MGC). The MGC database includes seven vertebrate species: human, cow, rat, mouse and three non-mammalian vertebrate species. A web-based application was developed to search this database of repeated motifs to generate species-specific lists of genes containing specific classes of repeats in their 3'-UTRs. This computational tool is called 3'-UTR SIRF (S hort I nterspersed R epeat F inder), and it reveals that hundreds of human genes contain an abundance of short CAC-rich and CAG-rich repeats in their 3'-UTRs that are similar to those found in mRNAs localized to the neurites of neurons. We tested four candidate mRNAs for localization in rat hippocampal neurons by in situ hybridization. Our results show that two candidate CAC-rich (Syntaxin 1B and Tubulin β4) and two candidate CAG-rich (Sec61α and Syntaxin 1A) mRNAs are localized to distal neurites, whereas two control mRNAs lacking repeated motifs in their 3'-UTR remain primarily in the cell body.
Computational data generated with 3'-UTR SIRF indicate that hundreds of mammalian genes have an abundance of short CA-containing motifs that may direct mRNA localization in neurons. In situ hybridization shows that four candidate mRNAs are localized to distal neurites of cultured hippocampal neurons. These data suggest that short CA-containing motifs may be part of a widely utilized genetic code that regulates mRNA localization in vertebrate cells. The use of 3'-UTR SIRF to search for new classes of motifs that regulate other aspects of gene expression should yield important information in future studies addressing cis-regulatory information located in 3'-UTRs.
Clusters of short interspersed repeats 4–7 nucleotides (nt) in length have been identified as cis-elements that regulate several aspects of gene expression. For example, the hexanucleotide motif UGCAUG is repeated 7 times downstream of exon EIIIB in the fibronectin gene, and mutational studies have shown that this motif is required for cell-type specific alternative splicing [1, 2]. (A/U)GGG is another repeated motif found in introns that regulates alternative splicing . Translation control can also be regulated by short repeats. The oskar gene in Drosophila, for example, contains 13 UUUAY motifs interspersed throughout its 3' untranslated region (UTR) that are required for translation of the oskar mRNA once it becomes localized to the posterior pole of Drosophila oocytes .
The localization of specific mRNAs to distinct regions of a cell is another aspect of gene control that involves short repeated motifs. This mechanism of gene regulation is one way that proteins become distributed to subcellular sites where they are needed. Since oocytes and neurons are highly polarized cells, both are extensively used as model systems for studies directed towards understanding the mechanisms of mRNA localization in animals. Interestingly, several proteins, such as Staufen [5–7] and Kinesin 2 [8, 9], mediate mRNA localization in oocytes as well as in neurons. This suggests that the cis-elements that specify mRNA localization in both oocytes and neurons may also share some common characteristics.
The cis-elements that specify mRNA localization are generally found in 3'-UTRs [10–12], and the role of short motifs in mRNA localization [13, 14] was initially discovered by visual inspection of the Vg1 mRNA localization element (LE) in Xenopus. The motif most important for Vg1 mRNA localization, UUCAC, is repeated four times in the ~350 nt Vg1 LE. Subsequently, UUCAC motifs were discovered to be important for the localization of another Xenopus mRNA, VegT[16, 17]. This motif is bound specifically by the RNA localization factor Vera/Vg1-RBP (called ZBP1 in neurons and fibroblasts) in both the Vg1 and the VegT LE. Binding of this protein to UUCAC motifs is thought to facilitate the formation of ribonucleoprotein complexes competent for localization [13, 17, 19].
Vg1 and VegT mRNAs both localize during mid-oogenesis in Xenopus. In a search for candidate motifs that may specify localization during early oogenesis in Xenopus, we developed a novel computational algorithm (REPFIND) . REPFIND facilitates the identification of short repeated motifs by assigning a P-value to all repeated motifs in an input nucleotide sequence, thus identifying the most significant repeats of any size. Using this algorithm we discovered UGCAC is an essential motif for RNA localization during early oogenesis. In addition, we showed that clusters of short CAC-containing motifs are a general and evolutionarily conserved cis-element for localization of many mRNAs in oocytes throughout the chordate lineage . Moreover, we showed that REPFIND reliably predicts new localized mRNAs from a 3' UTR database compiled from Xenopus cDNA sequences obtained from NCBI [9, 20].
In an effort to facilitate the discovery and characterization of new localized mRNAs and RNA localization elements in humans and other mammals, we used the REPFIND algorithm to construct a database of all repeated motifs (3–255 nucleotides long) present in the 3'-UTRs of ~60,000 genes from seven vertebrate species. A web search engine was also constructed which enables one to identify genes that contain an abundance of any selected class of repeated motif. Using this tool we identified hundreds of genes with significant clusters of short CAC- and CAG-containing repeats similar to those of known localized mRNAs. Four of these candidate mRNAs were shown by in situ hybridization to be localized to the neurites of cultured neurons.
Construction and content
All DNA sequence data used to generate the 3'-UTR SIRF motif database were obtained using the NCBI MGC retrieval tool located at: http://www.ncbi.nlm.nih.gov/FLC/getmgc.cgi. The mammalian gene collection (MGC) contains thousands of high quality cDNA sequences from seven organisms. The zebrafish gene collection (ZGC) and Xenopus gene collections (XGC) are part of the MGC and were included in all database constructions. At the time we extracted the sequence data the following numbers of sequences were retrieved for each organism:
Bos taurus: 1523
Dario rerio: 7965
Homo sapiens: 20924
Mus musculus: 16594
Rattus norvegicus: 5100
Xenopus laevis: 8406
Xenopus tropicalis: 2921
The MGC was utilized because each included gene has all of the annotations that are needed to properly extract the 3'-UTR of the gene. Additionally, the genes included in the MGC are estimated to be full-length cDNAs which are most likely to contain entire 3'-UTRs.
A Perl XML parser was written to extract the useful information from each gene.
The data collected from each gene included:
These data were stripped out of the XML files and inserted into a new database that was constructed specifically for the purposes here.
Randomly Generated Genes
The database implemented in MySQL is divided into two sections. The first stores the gene sequences obtained from NCBI. The schema for storing the sequences is shown in Figure 1, and the entire gene sequence was stored with exactly one entry per gene in the INSDSeq Table. This table uses a binary tree index since the data are read only, and it is quite large.
The second part of the database contains the REPFIND results tables. This part is split into two identical tables, 'match' and 'match_random'. All motif clusters having P-value less than 10-4 were stored for retrieval and analysis. Clusters with P-values higher than 10-4 were not included in these tables. There are two indices for both the 'match' and the 'match_random' tables. One indexes on P-value and uses the binary tree implementation (favours P-value range lookup), and one indexes on motif and uses the hash table implementation (favours value lookup). Value searches are used in the single query cases and range queries are used for the trend searches. The 'match_random' table has exactly the same characteristics and options as the 'match' table, and both tables are indexed to allow fast joining to the 'insdseq' table.
Generation of motif data for 'match' and 'match_random' tables
REPFIND was used to identify the clustered motifs in each of the 3'-UTRS. REPFIND functions by calculating a P-value for every cluster of every repeated motif greater than 3 nucleotides long in a single 3'-UTR. It then outputs only the cluster with the lowest P-value while all other clusters of the motif are discarded. Consequently, REPFIND reveals the region of the 3' UTR that has the most significant number of a repeated motif its specific nucleotide composition . REPFIND is available from http://zlab.bu.edu/repfind/. Each 3'-UTR sequence was read from the database, and collected into a single file. This entire file was input into REPFIND, which operates on each gene independently. Since long repeats are easily identified with alignment tools we included all motifs from 3–255 in length, but repeats longer than 255 were not included. Using REPFIND on a large number of genes requires a lot of computing cycles. Therefore, each organism was analyzed individually on different computers in order to parallelize the process. The data were collected into files that were easy to import into the database.
Creation of the 3'-UTR SIRF website
A web application was developed to analyze the contents of the databases. There are two main features this website. The first is a Single-motif search that generates lists of genes containing an abundance of a given motif in its 3' UTR. The second is a Trends graphing which shows how frequently clusters of a given class of motifs occurs in the 'match' and 'match_random' tables.
This feature provides query windows that are used to set the search parameters to describe a specific class of repeated motifs. The user provides an organism, maximum and minimum motif length, a motif or sub-motif in the IUB/IUPAC format, and a P-value cut-off. The application returns all genes containing this class of motif as a list. At the top of the list is the total number of genes identified in the 'match' and 'match_random' tables. This number is useful for providing the user a sense of whether the number of genes would be expected by chance. For example, if a search is carried out for motifs that contain "CAC", are 5–7 nucleotides long, and are found in clusters with P < 10-6, 298 genes are identified in the human 'match' database, whereas only 1 gene meets these search criteria in the human 'match_random' database. This suggests that most, if not all clusters of CAC-containing motifs did not arise by chance, and may therefore have been selected through evolution for a specific biological function. The user can see which of the genes when randomized produced a cluster of CAC-containing motifs meeting the search criteria by clicking the 'randomized UTRs' button. This information may be useful for some purposes.
On this same search application is a checkbox to specify "Show only best match" (Match with lowest P-Value). The default is to leave this in the checked state such that searching for TGCAC in Xenopus laevis returns only the TTGCAC motif for BC076786 even though clusters of three other similar motifs (ATTGCAC, TGCACT, TGCAC) exist in this same 3'-UTR (P < 10-6); these two additional motifs are shown if the "Show only best match" is unchecked. In addition, unchecking the "Show only best match" box causes the number of total clusters (not genes) to be given for the 'match' and 'match_random', respectively. For example, unchecking the "Show only best match" box with the same search parameters used above for CAC-containing motifs (P < 10-6, 5–7 mers) in human 3' UTRs yields 645 clusters in the real and 1 cluster in the randomized data set. This indicates that the real 298 3'-UTRs identified in this search contain an average of two CAC clusters each, and the gene which appears on the randomized list has only 1 cluster of a CAC-containing repeat. When the results are returned from the database, this web application outputs the genes ranked by P-value, including a brief description of each gene, and a link to the GenBank sequence entry on NCBI. The number of motifs and size of the cluster in nucleotides is also provided with the indicated P-value. Since these motifs are small, they are often also found outside the indicated cluster. However, including motifs outside the indicated cluster was determined by REPFIND to increase the P-value and such clusters of that specific motif were consequently not included in the database.
Query by NCBI Accession
This feature provided on the 3'-UTR SIRF website displays all motifs that are associated with a specific gene. They are ordered by P-value. Because of the low P-values characteristic of long repeats, the list is often dominated by motifs greater than 50 nucleotides in length if such motifs exist in the sequence.
Another component of 3'-UTR SIRF is the "Multi-Motif Search" tool which can be used to identify genes containing two distinct repeated motifs of interest. For example, a search for human 3'-UTRs containing two specific 3 mers (CAC, CAG) with P < 10-4, reveals 717 genes that contain significant numbers of both motifs in their 3' UTRs. No genes fitting these criteria were identified in the shuffled dataset. This search engine is highly specific in that it requires a perfect match to the input motifs and does not yet have the ability to search for combinations of general motifs classes.
Utility and discussion
The utility of any new Bioinformatics tool such as 3'-UTR SIRF resides in its ability to make valid predictions that lead to progress in our understanding of a particular biological process. As mentioned above, the cis-elements that specify cytoplasmic mRNA localization in vertebrates often contain many short repeated RNA motifs that are required for their function [13, 14, 16, 17, 20–22]. To identify new RNA localization elements in human genes we used two computational strategies. The first strategy involved utilization of 3'-UTR SIRF to identify human genes that contain significant clusters of short CAC-containing motifs characteristic of many RNAs that become localized to the vegetal pole of Xenopus oocytes [13, 14, 16, 17, 20–22]. In the second approach, we used REPFIND to analyze the 3' UTRs of mRNAs that are known to localize to the dendrites of mammalian neurons. We discovered that CAG-containing motifs are abundant in many of these transcripts and used 3' UTR SIRF to identify additional transcripts with CAG-rich 3' UTRs. We then tested whether these mRNAs are also localized in mammalian neurons. Our results suggest that both approaches are viable for computationally predicting localized mRNAs from mRNA databases.
Identification of functional CAC-rich RNA localization elements in human genes
In our first approach to identify human RNA localization elements, we used 3'-UTR SIRF to search for mRNAs that contain clusters of CAC-containing motifs with low P-values in their 3'-UTR. This was done for two reasons. First, mRNAs localized in mammalian neurons, such as β-actin and RhoA, contain clusters of CAC-containing motifs similar to those required for RNA localization in Xenopus oocytes  (data not shown). Secondly, a computational search for 3'-UTRs containing significant clusters of CAC-containing motifs in Xenopus resulted in the reliable prediction of new localized mRNAs in oocytes [9, 20]. To identify new localized mRNAs in humans, we used 3'-UTR SIRF to search for mRNAs with repeated CAC-containing motifs 5–7 nucleotides long with P-values less than 10-6. Trends revealed a large separation between the cumulative frequencies of these CAC-rich motif clusters in the human 3'-UTRs and their shuffled counterparts (Figure 2), and this degree of separation is observed in all vertebrate species in the database (data not shown). In addition, this difference between real and shuffled is maintained when multiple independently shuffled databases are used as a control data set; the cumulative frequencies of repeats found in independently shuffled databases vary only by about two fold (data not shown). As mentioned above these search parameters (CAC 5–7 mers, P < 10-6) yield 298 human genes with only one in the random set.
Human Stx1B2 is the second CAC-rich 3'-UTR that we tested for localization in Xenopus oocytes. This gene encodes a tSNARE that is thought to be important for vesicle docking and the release of neurotransmitters that contribute to memory functions of the hippocampus . In addition, Stx1B2 protein localizes to axons and synaptic terminals of motor neurons . When the human STX1B2 3'-UTR is fluorescently labelled and injected into early stage Xenopus oocytes it also becomes localized to the vegetal pole. In fact, the extent of its localization, characterized by the amount of fluorescent signal in the vegetal region compared to the surrounding cytoplasm, is more robust than that of the Tubβ4 3'-UTR (Figure 3).
While CAC-containing motifs have been shown to be required for localization of several mRNAs in Xenopus oocytes, the motifs alone are not sufficient for RNA localization  suggesting that the sequence context of CAC motifs is critical for the functional integrity of these localization elements. Since Tubβ4 and Stx1B2 have an abundance of CAC motifs and localize in Xenopus oocytes (Figure 3), we conclude that both the human Tubβ4 and Stx1B2 genes contain a bona fide CAC-rich mRNA localization element in their 3'-UTRs. This functional analysis of two human CAC-rich 3' UTRs in Xenopus oocytes demonstrates for the first time that RNA localization signals in non-coding regions of mRNAs can be identified in human genes using computational methods. Moreover, since two CAC-rich 3' UTRs, of two tested, have localization activity, these results suggest that the reliability at which 3' UTR SIRF predicts functional RNA localization signals may be quite high. However, more genes need to be tested to determine the success rate of predicting CAC-rich RNA localization elements in the 3'-UTR SIRF database.
Identification of abundant CAG-containing motifs as another feature of mRNAs localized to the neurites of mammalian neurons
To identify other genes that contain an unusually high number of CAG motifs in their 3'-UTRs, we performed a Single-motif search with parameters identical to those used to identify CAC-rich genes. The result was 749 human genes containing clusters of CAG-containing motifs 5–7 nucleotides long (P < 10-6), with only two genes being present in the shuffled data set. Moreover, Trends showed a large number of CAG-containing clusters in the real, but not the shuffled 3'-UTR dataset (data not shown).
DNA Oligonucleotides used for PCR amplification and cloning of 3' UTRs with restriction sites in bold text.
PCR Product Size
Percentage of CAC-rich 3'-UTRs in vertebrate genes.
CAC 5–7 mer
P < 10 -7
P < 10 -6
P < 10 -5
P < 10 -4
Percentage of CAG-rich 3'-UTRs in vertebrate genes.
CAG 5–7 mer
P < 10 -7
P < 10 -6
P < 10 -5
P < 10 -4
In this work we used the REPFIND algorithm  to identify all repeated motifs in thousands of 3'-UTRs from seven vertebrate sequences available in the Mammalian Gene Collection at NCBI. These motifs were stored in the 3'-UTR SIRF database, and a search tool was developed to extract individual sequences that contain an abundance of any user-defined repeat. Since previous work has shown that mRNA localization signals in Xenopus are often enriched in short CAC-containing motifs we searched for human and other mammalian genes that contain clusters of CAC motifs in their 3'-UTRs. This computational analysis suggests that up to 10 percent of human genes may contain CAC-rich RNA localization signals, and two of these genes, Tubβ4 and Stx1B2, were experimentally validated to contain functional RNA localization sequences. In addition, we discovered that several RNAs shown previously to localize to the dendrites of mammalian neurons are enriched in short CAG-containing motifs. In situ hybridization was used to validated that two new candidate CAG-rich mRNAs identified with 3'-UTR SIRF are also localized to neurites of cultured neurons, whereas control RNAs lacking repeated motifs remain in the cell body. Together these studies suggest that short reiterated RNA sequence motifs may comprise part of a widespread genetic signal present in thousands of genes for generating polarized patterns of gene expression in mammalian cells. Further work will be required to test this idea directly and to determine whether CAC motifs, CAG motifs, and/or higher order RNA structure may specify whether distinct mRNAs become targeted preferentially to axons or dendrites in mammalian neurons.
Availability and requirements
3'-UTR SIRF is freely available to those in academic settings . However, those wishing to use it for commercial purposes must contact JOD or Boston University prior to doing so.
This work was supported by a Special Program for Research Initiation Grant (SPRInG Award) from Boston University (JOD) as well as a Grant from the Whitehall Foundation (JOD). JJV was supported by funds from the Undergraduate Research Opportunities Program (UROP) at Boston University. GB was partially supported by grant IIS-0612153 from the National Science Foundation.
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- 3'-UTR SIRF[http://deshlerlab2.bu.edu/GeneFinder/index.aspx]
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