Atlas of utr regulatory activity

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Atlas of utr regulatory activity

Patricia R. Burns, Luiz O. Translation regulation plays important roles in both normal physiological conditions and diseases states. Gene expression can be modulated at multiple levels from chromatin modification to mRNA translation. Despite the importance of transcriptional regulation, it is clear at this point that mRNA levels cannot be used as a sole parameter to justify the protein content of a cell.

In fact, in a recent study from our lab, we determined that a direct correlation between mRNA and protein exists for less than a third of analyzed genes in a human cell line.

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Translation regulation also plays a significant role during development and cell differentiation by altering the levels of expression of specific mRNA subsets during a particular time window while the majority of transcripts remain unchanged reviewed in [ 2 — 4 ]. In the context of hairpin structures, GC content can affect protein translation efficiency independent of hairpin thermal stability and hairpin position [ 7 ]. The initiation codon is generally located far downstream, requiring ribosomal movement to this site.

This movement appears to be nonlinear for some mRNAs i. Important examples are provided by the cauliflower mosaic virus [ 8 ] and adenovirus [ 9 ] mRNAs. BRCA1 is a tumor suppressor, frequently mutated in breast cancer with functions in cell cycle, apoptosis, and DNA damage repair.

A shorter transcript is expressed in cancerous as well as noncancerous breast tissue and efficiently translated, while a longer transcript is predominantly expressed in breast cancers. The presence of several uAUGs and a more complex structure dramatically affect the translation of this longer transcript. This causes an overall decrease in BRAC1 levels in tumor cells, leading to a relief in growth inhibition [ 14 ]. The presence of 11 uORFs in the longer transcript dramatically inhibits its translation while the shorter transcript is efficiently translated [ 1516 ].

A correlation with gene function has been suggested; secondary structures have been determined to be particularly prevalent among mRNAs encoding transcription factors, protooncogenes, growth factors, and their receptors and proteins poorly translated under normal conditions. These structures are very effective in inhibiting translation.

Stable secondary structure can resist the unwinding activity of the helicase elF4A. This effect can be overcome partially by the overexpression of elF4A in partnership with elF4B [ 19 ]. Not surprisingly, the overexpression of components of the translation initiation machinery including elf4E has been linked to tumorigenesis reviewed in [ 1820 ].

However, this structure by itself is not sufficient to block translation. The human genome is predicted to encode circa 1, RNA binding proteins RBPs with a large percentage of them implicated in translation. Regarding this later group, it has been observed that RBPs can use distinct mechanisms to increase or inhibit translation. Although several exceptions are known, it can be said that RBPs often recognize specific motifs in UTRs and interact with the translation machinery to control expression.

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Interference with translation normally takes place during the initiation step reviewed in [ 25 ]. These proteins recognize a highly conserved stem loop structure with circa 30 nucleotides, known as the iron response element IRE. This regulation is crucial in maintaining cellular iron homeostasis as a large number of mRNAs connected to iron storage and metabolism including ferritin, mitochondrial aconitase, succinate dehydrogenase-iron protein, erythroid 5-aminolevulinate synthetase eALASand an iron-exportin molecule named ferroportin FPN1 have their expression modulated by this system.

IREs tend to be positioned close to the cap, which causes a steric inhibition of the binding of 40S ribosomal subunits to the transcript.

Before It Gets Started: Regulating Translation at the 5′ UTR

When located distant to the cap, rather than affecting 40S recruitment, the IRE-IRP complex blocks ribosomal scanning reviewed in [ 26 ].You are using AURA v2. To start, select one of the search modes in the search console above. For a complete description of AURA search modes and features, please refer to the help topics and step-by-step tutorial which you can access through the help button in the menu bar.

We welcome the submission of your data about post-transcriptional events! Please contact us. Data and bugfix update Feb. New data and bugfix update for AURA, now at version 2. Normal operations will resume on March, Thank you for your understanding! GO term Chromosome. Browser display Post-transcriptional regulatory network Regulatory element enrichment. This page allows to display several predefined post-transcriptional networks extracted from the literature. Your browser does not support iframe.

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News Data and bugfix update Feb. Maintenance downtime March 4,p. New data April 6,p. Homo sapiens hg19 Mus musculus mm Organism: Homo sapiens hg19 Mus musculus mm10 Search:. Filter binding assay. Fluorescence tagging. Protein pull-down. Organism: Homo sapiens hg19 Mus musculus mm10 Trans factors one per line :.

Organism: Homo sapiens hg19 Mus musculus mm10 Sequence:.Dassi, A.

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Malossini, A. Re, T. Mazza, T.

atlas of utr regulatory activity

Tebaldi, L. Caputi, A. Through its intuitive web interface, it provides full access to a wealth of information on UTRs that integrates phylogenetic conservation, RNA sequence and structure data, single nucleotide variation, gene expression and gene functional descriptions from literature and specialized databases.

Contact: aura science. Supplementary information: Supplementary data are available at Bioinformatics online. UTRs contain information for post-transcriptional regulation of mRNA, including transport, stability, localization and access to translation, and hence they largely determine the fate of mature mRNAs in the cell Keene, The experimentally determined sequence and structure binding constraints of UTRs vary widely between and within RBPs and non-coding RNAs, and the regulatory interactions are globally characterized by extreme complexity, since a regulator can bind to multiple UTRs in multiple sites and vice versa.

Moreover, the mRNA trans — cis interaction network undergoes remarkable plasticity, since the fate of an mRNA is determined by its temporally and spatially dependent association to several regulators Anderson et al.

atlas of utr regulatory activity

Unraveling the molecular code behind this sophisticated process is the key for: i understanding to what extent cell programs are regulated by the degree of mRNA abundance, localization and translation; ii deciphering how malfunction of trans -acting factors or mutation of target sites is at the root of some severely altered cellular phenotypes; iii identifying novel therapeutics aimed at modulating mRNA dynamics in the window between transport and translation.

With this aim, a growing number of studies, both mechanistic and systems-based, provide information on factors binding to UTRs. Nevertheless, integration of these data and annotation of UTRs in genome browsers are lacking or insufficient. The increasing centrality of post-transcriptional regulation among gene expression studies is witnessed by the recent release of several specialized databases.

RBPDB focuses on trans -acting proteins by collecting semi-manually curated literature data about RBPs and their demonstrated or predicted binding motifs Cook et al. In addition, more specialized resources allow the user to search and analyze a limited number of particularly well-known regulatory elements in greater detail e. AREsite, Gruber et al. Unlike these catalogs, AURA is designed to be a comprehensive and centralized warehouse of human UTR mapped annotations, both in terms of regulatory macromolecules and their site of binding.

Currently, it covers human UTRs, corresponding to 63 transcripts encoded by 19 protein coding genes. AURA is developed according to the convention that an RBP is a protein showing a reviewed RNA binding domain, and according to the rule that whenever positional data on mRNA regulatory binding sites are made available, the coordinates of each binding site are evaluated against the current genome annotation to verify the site lies within or overlaps the spliced UTR of a transcript.

A high-level schema of the database can be found in Supplementary Figure S1. The former query returns a list of genes whose HGNC gene symbol or synonyms contain the searched term; each gene in the list is annotated with its functional description, synonyms and UTRs. Furthermore, an exon—intron map of the UTRs is provided in order to allow proper discrimination between the different transcripts of a gene. On the other hand, the latter query results in a disambiguation list where all the trans- factors, whose names or synonyms contain the searching term, are shown.

To select the trans -factor of interest, the user might benefit from genes' short descriptions and functional summaries. Furthermore, the user can filter the results by selecting a combination of supporting experimental evidences. Results are reported in tables where a row corresponds to a condition, whereas the columns, in order, show the number of times the gene was observed to be up- or downregulated with respect to its mean expression value and the significance of the measure log 10 P -values.

In case of trans -factor search, a joint table containing gene expression experiments for both the gene coding for the trans -factor and the gene bearing the bound UTR is shown. Moreover, significant differences in common between regulator and target are highlighted to emphasize possible correlations or anti-correlations between them. Also shown are the overall conservation, which is the mean PhastCons single nucleotide conservation score for the UTR Fujita et al. Two further tracks are provided to show the trans- factors for which only partial information is available.

All the annotations in the tracks are clickable: whenever the user clicks on an annotation, a description page containing binding sites and cross-references is shown. In this view, the minimal energy predicted secondary structure Fujita et al. AURA gathers data by aggregation, integration and summarization of knowledge from scientific literature and specialized databases.

Future developments include i the integration of the UTR mapping catalog according to RNA-Seq data; ii the enrichment of the trans -factor catalog with long non-coding RNAs; iii the expansion of the UTR regulatory annotations to include internal ribosomal entry sites and upstream open reading frame ORFs ; iv the inclusion of annotations coming from genome-wide RNAi-based gene silencing phenotypic screens; and v the improvement of the search engine as well as of the visualization and retrieval systems.

Google Scholar.Basic annotations, variations, half-life, uncoupling, trans-factors and cis-elements data are contained, along with the table structure, in the MySQL database dump which you can download below.

UTR sequences are obtained via a file that is external to the database and stored in the compressed 2bit format. Whole database download Basic annotations, variations, half-life, uncoupling, trans-factors and cis-elements data are contained, along with the table structure, in the MySQL database dump which you can download below.

Here you can download these two. In order to extract conservation scores from or to compress a file to Wiggle format you will need Jim Kent's tools and in particular the wigEncode and hgWiggle programs. A reduced form of the database, called AURAlight and including only regulatory sites for trans-factors and cis-elements on UTRs, with position, factor and UTR identity can be downloaded below.

Per-nucleotide UTR phylogenetic conservation scores are obtained via a pair of files that are external to the database and stored in the compressed Wiggle format.To browse Academia. Skip to main content. Log In Sign Up. Download Free PDF. Tommaso Mazza. Alessandro Quattrone.

Atlas of UTR Regulatory Activity

Mazza, T. Tebaldi, L. Caputi and A. Nevertheless, integration of these data and annotation of UTRs in genome browsers are lacking or insufficient. RBPDB focuses on trans-acting Received on May 11, ; revised on October 27, ; accepted proteins by collecting semi-manually curated literature data about on October 28, RBPs and their demonstrated or predicted binding motifs Cook et al.

UTRs contain generation high-throughput technologies Khorshid et al. AREsite, Gruber et al. Such events are mediated by hundreds of trans-acting factors: and UTRsite, Grillo et al. Moreover, the mRNA publications and consolidated information from several trans—cis interaction network undergoes remarkable plasticity, since specialized databases, including miRTarBase Hsu et al.

Currently, it covers human UTRs, Unraveling the molecular code behind this sophisticated process corresponding to 63 transcripts encoded by 19 protein is the key for: i understanding to what extent cell programs coding genes.

With this aim, a growing number of evaluated against the current genome annotation to verify the site lies within or overlaps the spliced UTR of a transcript. Published by Oxford University Press. All rights reserved.

For Permissions, please email: journals. All the annotations in the between UTRs and trans-acting factors include synteny information tracks are clickable: whenever the user clicks on an annotation, and joint visualization of gene expression profiles for the interacting a description page containing binding sites and cross-references partners.

Furthermore, the assessment of an interaction between an is shown.

How UTR Works - What is UTR?

A high-level schema nucleotide phylogenetic conservation, SNP locations and trans- of the database can be found in Supplementary Figure S1. The corresponds to a condition, whereas the columns, in order, show the former query returns a list of genes whose HGNC gene symbol number of times the gene was observed to be up- or downregulated or synonyms contain the searched term; each gene in the list is with respect to its mean expression value and the significance of the annotated with its functional description, synonyms and UTRs.

In case of trans-factor search, a joint table Furthermore, an exon—intron map of the UTRs is provided in order containing gene expression experiments for both the gene coding for to allow proper discrimination between the different transcripts of a the trans-factor and the gene bearing the bound UTR is shown. On the other hand, the latter query results in a disambiguation Moreover, significant differences in common between regulator list where all the trans-factors, whose names or synonyms contain and target are highlighted to emphasize possible correlations or the searching term, are shown.

To select the trans-factor of interest, anti-correlations between them. Furthermore, the user can filter the results by selecting a and provides all query functionalities offered by the well-known combination of supporting experimental evidences. Also shown are the overall conservation, the UTR regulatory annotations to include internal ribosomal entry which is the mean PhastCons single nucleotide conservation sites and upstream open reading frame ORFs ; iv the inclusion of score for the UTR Fujita et al.

Cell Biol. Cell Proteomics, 10, — Two Darty,K. Bioinformatics, 25, — Nucleic Acids Res. Nucleic transcript without any further mapping information.

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Instead, Acids Res. Dassi et al. Nucleic experimentally determined binding sites of RNA-binding proteins. Nucleic Acids Acids Res.

atlas of utr regulatory activity

Nucleic Acids AU-rich elements.Gene expression in vertebrate cells may be controlled post-transcriptionally through regulatory elements in mRNAs. In addition to searching pre-computed alignments, the tool provides users the flexibility to search their own sequences or alignments.

The regulatory elements may be filtered by expected value cutoffs and are cross-referenced back to their respective sources and literature. The output is an interactive graphical representation, highlighting potential regulatory elements and overlaps between them.

The output also provides simple statistics and links to related resources for complementary analyses. The overall process is intuitive and fast. As SFM is a free web-application, the user does not need to install any software or databases. This post-transcriptional regulatory information can affect the site at which a mRNA is polyadenylated, and then how, when and where it is translated [ 34 ].

A number of tools and methods have been developed to identify cis -regulatory elements CREsmany focusing on individual types of CREs in single sequences [ 56 ]. These may ignore the detection of other types of CREs in the neighboring regions [ 78 ].

For example, although there are a large number of algorithms to predict microRNA miRNA binding sites, reviewed in [ 910 ], only one has included specific consideration of a nearby RNA binding protein RBP site [ 11 ]. However, some miRNA targets are known to be affected by the presence of other elements or sequences nearby [ 111 - 13 ]. Visualisation of potential sites could improve the utility of predictions.

Recent publications have shown evidence that specific types of miRNAs and RBPs work in concert to influence transcript decay [ 111617 ] or translation [ 13 ] and this synergy has been included in some computational analyses for proteins [ 18 ] and miRNAs [ 19 ]. In many studies one specific gene of interest from a single species is being analysed. Recently developed systems: RegRNA 2. However, the analysis of sequence alignments, a representation of overlapping identified elements, E-value cutoff, and the ability to include custom sequence motifs in the analysis, are not currently available in a single tool.

The analysis has three phases: 1. The processes to identify and visualise the regulatory elements for any selected gene or given sequence s is done in parallel for speed. Input can be the name of a human gene e. However, the user can also input any sequence or alignment.

atlas of utr regulatory activity

Outline of the main modules and steps involved in a Scan for Motifs analysis. The user input sections are in dashed boxes. User selected analyses are executed on demand. These PFM can be used to distinguish between good and poor matches for short motifs. Other user specified sequences, regular expressions, or matrices can also be used in PatSearch format [ 22 ]. The 6mer seed is the middle 6-bases, and both the two overlapping 7mers are used 7mer-A1, denoted A1 in the output, and 7mer-M8 [ 8 ].

A bed format MySQL database table was created to hold the positional information for each of these miR-binding sites. A custom Perl script was written and used for checking and updating the positional information as above.

For 27 genes the sequences were found to be different in length, the TargetScan prediction data for these were discarded, as they could not be unambiguously assigned to the sequence. The user input is of two types, i query sequence s and ii query element s.

It supports input of a standard human gene symbol i. LIN28A given as source of the query sequence. In such cases relative sequence alignments of 23 vertebrates including human will be retrieved from previously processed sequences using the inputted gene symbol and used as query sequence.

SFM supports assigning reference sequence when the query sequence has more than one sequence. If a human gene symbol was used to get the input sequence, the reference sequence is assigned to be human. In all other cases, the first sequence is considered to be the reference sequence.

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Through its intuitive web interface, it provides full access to a wealth of information on UTRs that integrates phylogenetic conservation, RNA sequence and structure data, single nucleotide variation, gene expression and gene functional descriptions from literature and specialized databases. Bioinformatics — Oxford University Press. Enjoy affordable access to over 18 million articles from more than 15, peer-reviewed journals. Get unlimited, online access to over 18 million full-text articles from more than 15, scientific journals.

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AURA: Atlas of UTR Regulatory Activity

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