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Exact p-value calculation for heterotypic clusters of regulatory motifs and its application in computational annotation of cis-regulatory modules.

ABSTRACT: BACKGROUND:cis-Regulatory modules (CRMs) of eukaryotic genes often contain multiple binding sites for transcription factors. The phenomenon that binding sites form clusters in CRMs is exploited in many algorithms to locate CRMs in a genome. This gives rise to the problem of calculating the statistical significance of the event that multiple sites, recognized by different factors, would be found simultaneously in a text of a fixed length. The main difficulty comes from overlapping occurrences of motifs. So far, no tools have been developed allowing the computation of p-values for simultaneous occurrences of different motifs which can overlap. RESULTS:We developed and implemented an algorithm computing the p-value that s different motifs occur respectively k1, ..., ks or more times, possibly overlapping, in a random text. Motifs can be represented with a majority of popular motif models, but in all cases, without indels. Zero or first order Markov chains can be adopted as a model for the random text. The computational tool was tested on the set of cis-regulatory modules involved in D. melanogaster early development, for which there exists an annotation of binding sites for transcription factors. Our test allowed us to correctly identify transcription factors cooperatively/competitively binding to DNA. METHOD:The algorithm that precisely computes the probability of simultaneous motif occurrences is inspired by the Aho-Corasick automaton and employs a prefix tree together with a transition function. The algorithm runs with the O(n|Sigma|m|H| + K|sigma|K) Piiki) time complexity, where n is the length of the text |Sigma| is the alphabet size, m is the maximal motif length, |H| is the total number of words in motifs, K is the order of Markov model, and ki is the number of occurrences of the ith motif. CONCLUSION:The primary objective of the program is to assess the likelihood that a given DNA segment is CRM regulated with a known set of regulatory factors. In addition, the program can also be used to select the appropriate threshold for PWM scanning. Another application is assessing similarity of different motifs. AVAILABILITY:Project web page, stand-alone version and documentation can be found at http://bioinform.genetika.ru/AhoPro/

SUBMITTER: Boeva V

PROVIDER: S-EPMC2174486 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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Exact p-value calculation for heterotypic clusters of regulatory motifs and its application in computational annotation of cis-regulatory modules.

Boeva Valentina V Clément Julien J Régnier Mireille M Roytberg Mikhail A MA Makeev Vsevolod J VJ

Algorithms for molecular biology : AMB 20071010

<h4>Background</h4>cis-Regulatory modules (CRMs) of eukaryotic genes often contain multiple binding sites for transcription factors. The phenomenon that binding sites form clusters in CRMs is exploited in many algorithms to locate CRMs in a genome. This gives rise to the problem of calculating the statistical significance of the event that multiple sites, recognized by different factors, would be found simultaneously in a text of a fixed length. The main difficulty comes from overlapping occurre ...[more]

PMID: 17927813

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Project description:BackgroundMany studies report about detection and functional characterization of cis-regulatory motifs in untranslated regions (UTRs) of mRNAs but little is known about the nature and functional role of their distribution. To address this issue we have developed a computational approach based on the use of data mining techniques. The idea is that of mining frequent combinations of translation regulatory motifs, since their significant co-occurrences could reveal functional relationships important for the post-transcriptional control of gene expression. The experimentation has been focused on targeted mitochondrial transcripts to elucidate the role of translational control in mitochondrial biogenesis and function.ResultsThe analysis is based on a two-stepped procedure using a sequential pattern mining algorithm. The first step searches for frequent patterns (FPs) of motifs without taking into account their spatial displacement. In the second step, frequent sequential patterns (FSPs) of spaced motifs are generated by taking into account the conservation of spacers between each ordered pair of co-occurring motifs. The algorithm makes no assumption on the relation among motifs and on the number of motifs involved in a pattern. Different FSPs can be found depending on different combinations of two parameters, i.e. the threshold of the minimum percentage of sequences supporting the pattern, and the granularity of spacer discretization. Results can be retrieved at the UTRminer web site: http://utrminer.ba.itb.cnr.it/. The discovered FPs of motifs amount to 216 in the overall dataset and to 140 in the human subset. For each FP, the system provides information on the discovered FSPs, if any. A variety of search options help users in browsing the web resource. The list of sequence IDs supporting each pattern can be used for the retrieval of information from the UTRminer database.ConclusionComputational prediction of structural properties of regulatory sequences is not trivial. The presented data mining approach is able to overcome some limits observed in other competitive tools. Preliminary results on UTR sequences from nuclear transcripts targeting mitochondria are promising and lead us to be confident on the effectiveness of the approach for future developments.

Project description:Researchers seeking to unlock the genetic basis of human physiology and diseases have been studying gene transcription regulation. The temporal and spatial patterns of gene expression are controlled by mainly non-coding elements known as cis-regulatory modules (CRMs) and epigenetic factors. CRMs modulating related genes share the regulatory signature which consists of transcription factor (TF) binding sites (TFBSs). Identifying such CRMs is a challenging problem due to the prohibitive number of sequence sets that need to be analyzed.We formulated the challenge as a supervised classification problem even though experimentally validated CRMs were not required. Our efforts resulted in a software system named CrmMiner. The system mines for CRMs in the vicinity of related genes. CrmMiner requires two sets of sequences: a mixed set and a control set. Sequences in the vicinity of the related genes comprise the mixed set, whereas the control set includes random genomic sequences. CrmMiner assumes that a large percentage of the mixed set is made of background sequences that do not include CRMs. The system identifies pairs of closely located motifs representing vertebrate TFBSs that are enriched in the training mixed set consisting of 50% of the gene loci. In addition, CrmMiner selects a group of the enriched pairs to represent the tissue-specific regulatory signature. The mixed and the control sets are searched for candidate sequences that include any of the selected pairs. Next, an optimal Bayesian classifier is used to distinguish candidates found in the mixed set from their control counterparts. Our study proposes 62 tissue-specific regulatory signatures and putative CRMs for different human tissues and cell types. These signatures consist of assortments of ubiquitously expressed TFs and tissue-specific TFs. Under controlled settings, CrmMiner identified known CRMs in noisy sets up to 1:25 signal-to-noise ratio. CrmMiner was 21-75% more precise than a related CRM predictor. The sensitivity of the system to locate known human heart enhancers reached up to 83%. CrmMiner precision reached 82% while mining for CRMs specific to the human CD4+ T cells. On several data sets, the system achieved 99% specificity.These results suggest that CrmMiner predictions are accurate and likely to be tissue-specific CRMs. We expect that the predicted tissue-specific CRMs and the regulatory signatures broaden our knowledge of gene transcription regulation.

Dataset Information

Exact p-value calculation for heterotypic clusters of regulatory motifs and its application in computational annotation of cis-regulatory modules.

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Exact p-value calculation for heterotypic clusters of regulatory motifs and its application in computational annotation of cis-regulatory modules.

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