ModuleDigger: an itemset mining framework for the detection of cis-regulatory modules

Background: The detection of cis-regulatory modules (CRMs) that mediate transcriptional responses in eukaryotes remains a key challenge in the postgenomic era. A CRM is characterized by a set of co-occurring transcription factor binding sites (TFBS). In silico methods have been developed to search for CRMs by determining the combination of TFBS that are statistically overrepresented in a certain geneset. Most of these methods solve this combinatorial problem by relying on computational intensive optimization methods. As a result their usage is limited to finding CRMs in small datasets (containing a few genes only) and using binding sites for a restricted number of transcription factors (TFs) out of which the optimal module will be selected. Results: We present an itemset mining based strategy for computationally detecting cis-regulatory modules (CRMs) in a set of genes. We tested our method by applying it on a large benchmark data set, derived from a ChIP-Chip analysis and compared its performance with other well known cis-regulatory module detection tools. Conclusion: We show that by exploiting the computational efficiency of an itemset mining approach and combining it with a well-designed statistical scoring scheme, we were able to prioritize the biologically valid CRMs in a large set of coregulated genes using binding sites for a large number of potential TFs as input

Computational identification of transcriptional regulatory elements in DNA sequence

Identification and annotation of all the functional elements in the genome, including genes and the regulatory sequences, is a fundamental challenge in genomics and computational biology. Since regulatory elements are frequently short and variable, their identification and discovery using computational algorithms is difficult. However, significant advances have been made in the computational methods for modeling and detection of DNA regulatory elements. The availability of complete genome sequence from multiple organisms, as well as mRNA profiling and high-throughput experimental methods for mapping protein-binding sites in DNA, have contributed to the development of methods that utilize these auxiliary data to inform the detection of transcriptional regulatory elements. Progress is also being made in the identification of cis-regulatory modules and higher order structures of the regulatory sequences, which is essential to the understanding of transcription regulation in the metazoan genomes. This article reviews the computational approaches for modeling and identification of genomic regulatory elements, with an emphasis on the recent developments, and current challenges

Cis-regulatory module detection using constraint programming

We propose a method for finding CRMs in a set of co-regulated genes. Each CRM consists of a set of binding sites of transcription factors. We wish to find CRMs involving the same transcription factors in multiple sequences. Finding such a combination of transcription factors is inherently a combinatorial problem. We solve this problem by combining the principles of itemset mining and constraint programming. The constraints involve the putative binding sites of transcription factors, the number of sequences in which they co-occur and the proximity of the binding sites. Genomic background sequences are used to assess the significance of the modules. We experimentally validate our approach and compare it with state-of-the-art techniques

Unveiling combinatorial regulation through the combination of ChIP information and in silico cis-regulatory module detection

Computationally retrieving biologically relevant cis-regulatory modules (CRMs) is not straightforward. Because of the large number of candidates and the imperfection of the screening methods, many spurious CRMs are detected that are as high scoring as the biologically true ones. Using ChIP-information allows not only to reduce the regions in which the binding sites of the assayed transcription factor (TF) should be located, but also allows restricting the valid CRMs to those that contain the assayed TF (here referred to as applying CRM detection in a query-based mode). In this study, we show that exploiting ChIP-information in a query-based way makes in silico CRM detection a much more feasible endeavor. To be able to handle the large datasets, the query-based setting and other specificities proper to CRM detection on ChIP-Seq based data, we developed a novel powerful CRM detection method 'CPModule'. By applying it on a well-studied ChIP-Seq data set involved in self-renewal of mouse embryonic stem cells, we demonstrate how our tool can recover combinatorial regulation of five known TFs that are key in the self-renewal of mouse embryonic stem cells. Additionally, we make a number of new predictions on combinatorial regulation of these five key TFs with other TFs documented in TRANSFAC

Systematic identification of functional plant modules through the integration of complementary data sources

A major challenge is to unravel how genes interact and are regulated to exert specific biological functions. The integration of genome-wide functional genomics data, followed by the construction of gene networks, provides a powerful approach to identify functional gene modules. Large-scale expression data, functional gene annotations, experimental protein-protein interactions, and transcription factor-target interactions were integrated to delineate modules in Arabidopsis (Arabidopsis thaliana). The different experimental input data sets showed little overlap, demonstrating the advantage of combining multiple data types to study gene function and regulation. In the set of 1,563 modules covering 13,142 genes, most modules displayed strong coexpression, but functional and cis-regulatory coherence was less prevalent. Highly connected hub genes showed a significant enrichment toward embryo lethality and evidence for cross talk between different biological processes. Comparative analysis revealed that 58% of the modules showed conserved coexpression across multiple plants. Using module-based functional predictions, 5,562 genes were annotated, and an evaluation experiment disclosed that, based on 197 recently experimentally characterized genes, 38.1% of these functions could be inferred through the module context. Examples of confirmed genes of unknown function related to cell wall biogenesis, xylem and phloem pattern formation, cell cycle, hormone stimulus, and circadian rhythm highlight the potential to identify new gene functions. The module-based predictions offer new biological hypotheses for functionally unknown genes in Arabidopsis (1,701 genes) and six other plant species (43,621 genes). Furthermore, the inferred modules provide new insights into the conservation of coexpression and coregulation as well as a starting point for comparative functional annotation

Signal Processing during Developmental Multicellular Patterning

Developing design strategies for tissue engineering and regenerative medicine is limited by our nascent understanding of how cell populations self-organize into multicellular structures on synthetic scaffolds. Mechanistic insights can be gleaned from the quantitative analysis of biomolecular signals that drive multicellular patterning during the natural processes of embryonic and adult development. This review describes three critical layers of signal processing that govern multicellular patterning: spatiotemporal presentation of extracellular cues, intracellular signaling networks that mediate crosstalk among extracellular cues, and finally, intranuclear signal integration at the level of transcriptional regulation. At every level in this hierarchy, the quantitative attributes of signals have a profound impact on patterning. We discuss how experiments and mathematical models are being used to uncover these quantitative features and their impact on multicellular phenotype

Detection of regulator genes and eQTLs in gene networks

Genetic differences between individuals associated to quantitative phenotypic traits, including disease states, are usually found in non-coding genomic regions. These genetic variants are often also associated to differences in expression levels of nearby genes (they are "expression quantitative trait loci" or eQTLs for short) and presumably play a gene regulatory role, affecting the status of molecular networks of interacting genes, proteins and metabolites. Computational systems biology approaches to reconstruct causal gene networks from large-scale omics data have therefore become essential to understand the structure of networks controlled by eQTLs together with other regulatory genes, and to generate detailed hypotheses about the molecular mechanisms that lead from genotype to phenotype. Here we review the main analytical methods and softwares to identify eQTLs and their associated genes, to reconstruct co-expression networks and modules, to reconstruct causal Bayesian gene and module networks, and to validate predicted networks in silico.Comment: minor revision with typos corrected; review article; 24 pages, 2 figure

A multiple-instance scoring method to predict tissue-specific cis-regulatory motifs and regions

Transcription is the central process of gene regulation. In higher eukaryotes, the transcription of a gene is usually regulated by multiple cis-regulatory regions (CRRs). In different tissues, different transcription factors bind to their cis-regulatory motifs in these CRRs to drive tissue-specific expression patterns of their target genes. By combining the genome-wide gene expression data with the genomic sequence data, we proposed multiple-instance scoring (MIS) method to predict the tissue-specific motifs and the corresponding CRRs. The method is mainly based on the assumption that only a subset of CRRs of the expressed gene should function in the studied tissue. By testing on the simulated datasets and the fly muscle dataset, MIS can identify true motifs when noise is high and shows higher specificity for predicting the tissue-specific functions of CRRs

Cross-species comparison significantly improves genome-wide prediction of cis-regulatory modules in Drosophila

BACKGROUND: The discovery of cis-regulatory modules in metazoan genomes is crucial for understanding the connection between genes and organism diversity. It is important to quantify how comparative genomics can improve computational detection of such modules. RESULTS: We run the Stubb software on the entire D. melanogaster genome, to obtain predictions of modules involved in segmentation of the embryo. Stubb uses a probabilistic model to score sequences for clustering of transcription factor binding sites, and can exploit multiple species data within the same probabilistic framework. The predictions are evaluated using publicly available gene expression data for thousands of genes, after careful manual annotation. We demonstrate that the use of a second genome (D. pseudoobscura) for cross-species comparison significantly improves the prediction accuracy of Stubb, and is a more sensitive approach than intersecting the results of separate runs over the two genomes. The entire list of predictions is made available online. CONCLUSION: Evolutionary conservation of modules serves as a filter to improve their detection in silico. The future availability of additional fruitfly genomes therefore carries the prospect of highly specific genome-wide predictions using Stubb