The YEASTRACT (http://www.yeastract.com) information system is a tool for the analysis and prediction of transcription regulatory associations in Saccharomyces cerevisiae. Last updated in June 2013, this database contains over 200 000 regulatory associations between transcription factors (TFs) and target genes, including 326 DNA binding sites for 113 TFs. All regulatory associations stored in YEASTRACT were revisited and new information was added on the experimental conditions in which those associations take place and on whether the TF is acting on its target genes as activator or repressor. Based on this information, new queries were developed allowing the selection of specific environmental conditions, experimental evidence or positive/negative regulatory effect. This release further offers tools to rank the TFs controlling a gene or genome-wide response by their relative importance, based on (i) the percentage of target genes in the data set; (ii) the enrichment of the TF regulon in the data set when compared with the genome; or (iii) the score computed using the TFRank system, which selects and prioritizes the relevant TFs by walking through the yeast regulatory network. We expect that with the new data and services made available, the system will continue to be instrumental for yeast biologists and systems biology researchers.@en

Identifying patterns in temporal data is key to uncover meaningful relationships in diverse domains, from stock trading to social interactions. Also of great interest are clinical and biological applications, namely monitoring patient response to treatment or characterizing activity at the molecular level. In biology, researchers seek to gain insight into gene functions and dynamics of biological processes, as well as potential perturbations of these leading to disease, through the study of patterns emerging from gene expression time series. Clustering can group genes exhibiting similar expression profiles, but focuses on global patterns denoting rather broad, unspecific responses. Biclustering reveals local patterns, which more naturally capture the intricate collaboration between biological players, particularly under a temporal setting. Despite the general biclustering formulation being NP-hard, considering specific properties of time series has led to efficient solutions for the discovery of temporally aligned patterns. Notably, the identification of biclusters with time-lagged patterns, suggestive of transcriptional cascades, remains a challenge due to the combinatorial explosion of delayed occurrences. Herein, we propose LateBiclustering, a sensible heuristic algorithm enabling a polynomial rather than exponential time solution for the problem. We show that it identifies meaningful time-lagged biclusters relevant to the response of Saccharomyces cerevisiae to heat stress.@en

Identifying patterns in temporal data supports complex analyses in several domains, including stock markets (finance) and social interactions (social science). Clinical and biological applications, such as monitoring patient response to treatment or characterizing activity at the molecular level, are also of interest. In particular, researchers seek to gain insight into the dynamics of biological processes, and potential perturbations of these leading to disease, through the discovery of patterns in time series gene expression data. For many years, clustering has remained the standard technique to group genes exhibiting similar response profiles. However, clustering defines similarity across all time points, focusing on global patterns which tend to characterize rather broad and unspecific responses. It is widely believed that local patterns offer additional insight into the underlying intricate events leading to the overall observed behavior. Efficient biclustering algorithms have been devised for the discovery of temporally aligned local patterns in gene expression time series, but the extraction of time-lagged patterns remains a challenge due to the combinatorial explosion of pattern occurrence combinations when delays are considered. We present heuristic approaches enabling polynomial rather than exponential time solutions for the problem.

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Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched processes related to these biological events were identified. Ranking scores further suggested ability to discern the primary role of a gene (target or regulator). Prototype is available at: http://kdbio.inesc-id.pt/software/regulatorysnapshots.@en

Disease gene prioritization aims to suggest potential implications of genes in disease susceptibility. Often accomplished in a guilt-by-association scheme, promising candidates are sorted according to their relatedness to known disease genes. Network-based methods have been successfully exploiting this concept by capturing the interaction of genes or proteins into a score. Nonetheless, most current approaches yield at least some of the following limitations: (1) networks comprise only curated physical interactions leading to poor genome coverage and density, and bias toward a particular source; (2) scores focus on adjacencies (direct links) or the most direct paths (shortest paths) within a constrained neighborhood around the disease genes, ignoring potentially informative indirect paths; (3) global clustering is widely applied to partition the network in an unsupervised manner, attributing little importance to prior knowledge; (4) confidence weights and their contribution to edge differentiation and ranking reliability are often disregarded. We hypothesize that network-based prioritization related to local clustering on graphs and considering full topology of weighted gene association networks integrating heterogeneous sources should overcome the above challenges. We term such a strategy Interactogeneous. We conducted cross-validation tests to assess the impact of network sources, alternative path inclusion and confidence weights on the prioritization of putative genes for 29 diseases. Heat diffusion ranking proved the best prioritization method overall, increasing the gap to neighborhood and shortest paths scores mostly on single source networks. Heterogeneous associations consistently delivered superior performance over single source data across the majority of methods. Results on the contribution of confidence weights were inconclusive. Finally, the best Interactogeneous strategy, heat diffusion ranking and associations from the STRING database, was used to prioritize genes for Parkinson’s disease. This method effectively recovered known genes and uncovered interesting candidates which could be linked to pathogenic mechanisms of the disease.@en

Transcription Factors (TFs) control transcription by binding to specific sites in the promoter regions of the target genes, which can be modelled by structured motifs. In this paper we propose AliBiMotif, a method combining sequence alignment and a biclustering approach based on efficient string matching techniques using suffix trees to unravel approximately conserved sets of blocks (structured motifs) while straightforwardly disregarding non-conserved stretches in-between. The ability to ignore the width of non-conserved regions is a major advantage of the proposed method over other motif finders, as the lengths of the binding sites are usually easier to estimate than the separating distances.@en

PINTA (available at http://www.esat.kuleuven.be/pinta/ ; this web site is free and open to all users and there is no login requirement) is a web resource for the prioritization of candidate genes based on the differential expression of their neighborhood in a genome-wide protein–protein interaction network. Our strategy is meant for biological and medical researchers aiming at identifying novel disease genes using disease specific expression data. PINTA supports both candidate gene prioritization (starting from a user defined set of candidate genes) as well as genome-wide gene prioritization and is available for five species (human, mouse, rat, worm and yeast). As input data, PINTA only requires disease specific expression data, whereas various platforms (e.g. Affymetrix) are supported. As a result, PINTA computes a gene ranking and presents the results as a table that can easily be browsed and downloaded by the user. @en

Motivation: Uncovering mechanisms underlying gene expression control is crucial to understand complex cellular responses. Studies in gene regulation often aim to identify regulatory players involved in a biological process of interest, either transcription factors coregulating a set of target genes or genes eventually controlled by a set of regulators. These are frequently prioritized with respect to a context-specific relevance score. Current approaches rely on relevance measures accounting exclusively for direct transcription factor–target interactions, namely overrepresentation of binding sites or target ratios. Gene regulation has, however, intricate behavior with overlapping, indirect effect that should not be neglected. In addition, the rapid accumulation of regulatory data already enables the prediction of large-scale networks suitable for higher level exploration by methods based on graph theory. A paradigm shift is thus emerging, where isolated and constrained analyses will likely be replaced by whole-network, systemic-aware strategies.
Results: We present TFRank, a graph-based framework to prioritize regulatory players involved in transcriptional responses within the regulatory network of an organism, whereby every regulatory path containing genes of interest is explored and incorporated into the analysis. TFRank selected important regulators of yeast adaptation to stress induced by quinine and acetic acid, which were missed by a direct effect approach. Notably, they reportedly confer resistance toward the chemicals. In a preliminary study in human, TFRank unveiled regulators involved in breast tumor growth and metastasis when applied to genes whose expression signatures correlated with short interval to metastasis.
Availability: Prototype at http://kdbio.inesc-id.pt/software/tfrank/.
Contact:[email protected]; [email protected];
Supplementary Information:Supplementary data are available at Bioinformatics online.
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Disease candidate gene prioritization addresses the association of novel genes with disease susceptibility or progression. Networkbased approaches explore the connectivity properties of biological networks to compute an association score between candidate and diseaserelated genes. Although several methods have been proposed to date, a number of concerns arise: (i) most networks used rely exclusively on curated physical interactions, resulting in poor coverage of the Human genome and leading to sparsity issues; (ii) most methods fail to incorporate interaction confidence weights; (iii) in some cases, relevance scores are computed as local measures based on the direct interactions with the disease-related genes, ignoring potentially relevant indirect interactions. In this study, we seek a robust network-based strategy by evaluating the performance of selected prioritization strategies using genes known to be involved in 29 different diseases.

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Background. The ability to monitor changes in expression patterns over time, and to observe the emergence of coherent temporal responses using expression time series, is critical to advance our understanding of complex biological processes. Biclustering has been recognized as an effective method for discovering local temporal expression patterns and unraveling potential regulatory mechanisms. The general biclustering problem is NP-hard. In the case of time series this problem is tractable, and efficient algorithms can be used. However, there is still a need for specialized applications able to take advantage of the temporal properties inherent to expression time series, both from a computational and a biological perspective. Findings. BiGGEsTS makes available state-of-the-art biclustering algorithms for analyzing expression time series. Gene Ontology (GO) annotations are used to assess the biological relevance of the biclusters. Methods for preprocessing expression time series and post-processing results are also included. The analysis is additionally supported by a visualization module capable of displaying informative representations of the data, including heatmaps, dendrograms, expression charts and graphs of enriched GO terms. Conclusion. BiGGEsTS is a free open source graphical software tool for revealing local coexpression of genes in specific intervals of time, while integrating meaningful information on gene annotations. It is freely available at: http://kdbio.inesc-id.pt/software/biggests. We present a case study on the discovery of transcriptional regulatory modules in the response of Saccharomyces cerevisiae to heat stress.

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