CANTATA-prediction of missing links in Boolean networks using genetic programming.

MOTIVATION: Biological processes are complex systems with distinct behaviour. Despite the growing amount of available data, knowledge is sparse and often insufficient to investigate the complex regulatory behaviour of these systems. Moreover, different cellular phenotypes are possible under varying conditions. Mathematical models attempt to unravel these mechanisms by investigating the dynamics of regulatory networks. Therefore, a major challenge is to combine regulations and phenotypical information as well as the underlying mechanisms. To predict regulatory links in these models, we established an approach called CANTATA to support the integration of information into regulatory networks and retrieve potential underlying regulations. This is achieved by optimizing both static and dynamic properties of these networks. RESULTS: Initial results show that the algorithm predicts missing interactions by recapitulating the known phenotypes while preserving the original topology and optimizing the robustness of the model. The resulting models allow for hypothesizing about the biological impact of certain regulatory dependencies. AVAILABILITY AND IMPLEMENTATION: Source code of the application, example files and results are available at https://github.com/sysbio-bioinf/Cantata. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A model of the onset of the senescence associated secretory phenotype after DNA damage induced senescence.

Cells and tissues are exposed to stress from numerous sources. Senescence is a protective mechanism that prevents malignant tissue changes and constitutes a fundamental mechanism of aging. It can be accompanied by a senescence associated secretory phenotype (SASP) that causes chronic inflammation. We present a Boolean network model-based gene regulatory network of the SASP, incorporating published gene interaction data. The simulation results describe current biological knowledge. The model predicts different in-silico knockouts that prevent key SASP-mediators, IL-6 and IL-8, from getting activated upon DNA damage. The NF-κB Essential Modulator (NEMO) was the most promising in-silico knockout candidate and we were able to show its importance in the inhibition of IL-6 and IL-8 following DNA-damage in murine dermal fibroblasts in-vitro. We strengthen the speculated regulator function of the NF-κB signaling pathway in the onset and maintenance of the SASP using in-silico and in-vitro approaches. We were able to mechanistically show, that DNA damage mediated SASP triggering of IL-6 and IL-8 is mainly relayed through NF-κB, giving access to possible therapy targets for SASP-accompanied diseases.

ViSiBooL-visualization and simulation of Boolean networks with temporal constraints.

Summary: Mathematical models and their simulation are increasingly used to gain insights into cellular pathways and regulatory networks. Dynamics of regulatory factors can be modeled using Boolean networks (BNs), among others. Text-based representations of models are precise descriptions, but hard to understand and interpret. ViSiBooL aims at providing a graphical way of modeling and simulating networks. By providing visualizations of static and dynamic network properties simultaneously, it is possible to directly observe the effects of changes in the network structure on the behavior. In order to address the challenges of clear design and a user-friendly graphical user interface (GUI), ViSiBooL implements visual representations of BNs. Additionally temporal extensions of the BNs for the modeling of regulatory time delays are incorporated. The GUI of ViSiBooL allows to model, organize, simulate and visualize BNs as well as corresponding simulation results such as attractors. Attractor searches are performed in parallel to the modeling process. Hence, changes in the network behavior are visualized at the same time. Availability and Implementation: ViSiBooL (Java 8) is freely available at http://sysbio.uni-ulm.de/?Software:ViSiBooL . Contact: hans.kestler@uni-ulm.de.

GiANT: gene set uncertainty in enrichment analysis.

UNLABELLED: Over the past years growing knowledge about biological processes and pathways revealed complex interaction networks involving many genes. In order to understand these networks, analysis of differential expression has continuously moved from single genes towards the study of gene sets. Various approaches for the assessment of gene sets have been developed in the context of gene set analysis (GSA). These approaches are bridging the gap between raw measurements and semantically meaningful terms.We present a novel approach for assessing uncertainty in the definition of gene sets. This is an essential step when new gene sets are constructed from domain knowledge or given gene sets are suspected to be affected by uncertainty. Quantification of uncertainty is implemented in the R-package GiANT. We also included widely used GSA methods, embedded in a generic framework that can readily be extended by custom methods. The package provides an easy to use front end and allows for fast parallelization. AVAILABILITY AND IMPLEMENTATION: The package GiANT is available on CRAN. CONTACTS: hans.kestler@leibniz-fli.de or hans.kestler@uni-ulm.de.

Boolean modeling identifies Greatwall/MASTL as an important regulator in the AURKA network of neuroblastoma.

Aurora Kinase A (AURKA) is often overexpressed in neuroblastoma (NB) with poor outcome. The causes of AURKA overexpression in NB are unknown. Here, we describe a gene regulatory network consisting of core regulators of AURKA protein expression and activation during mitosis to identify potential causes. This network was transformed to a dynamic Boolean model. Simulated activation of the serine/threonine protein kinase Greatwall (GWL, encoded by MASTL) that attenuates the pivotal AURKA inhibitor PP2A, predicted stabilization of AURKA. Consistent with this notion, gene set enrichment analysis showed enrichment of mitotic spindle assembly genes and MYCN target genes in NB with high GWL/MASTL expression. In line with the prediction of GWL/MASTL enhancing AURKA, elevated expression of GWL/MASTL was associated with NB risk factors and poor survival of patients. These results establish Boolean network modeling of oncogenic pathways in NB as a useful means for guided discovery in this enigmatic cancer.

BiTrinA--multiscale binarization and trinarization with quality analysis.

MOTIVATION: When processing gene expression profiles or other biological data, it is often required to assign measurements to distinct categories (e.g. 'high' and 'low' and possibly 'intermediate'). Subsequent analyses strongly depend on the results of this quantization. Poor quantization will have potentially misleading effects on further investigations. We propose the BiTrinA package that integrates different multiscale algorithms for binarization and for trinarization of one-dimensional data with methods for quality assessment and visualization of the results. By identifying measurements that show large variations over different time points or conditions, this quality assessment can determine candidates that are related to the specific experimental setting. AVAILABILITY AND IMPLEMENTATION: BiTrinA is freely available on CRAN. CONTACT: hans.kestler@leibniz-fli.de or hans.kestler@uni-ulm.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cooperative development of logical modelling standards and tools with CoLoMoTo.

The identification of large regulatory and signalling networks involved in the control of crucial cellular processes calls for proper modelling approaches. Indeed, models can help elucidate properties of these networks, understand their behaviour and provide (testable) predictions by performing in silico experiments. In this context, qualitative, logical frameworks have emerged as relevant approaches, as demonstrated by a growing number of published models, along with new methodologies and software tools. This productive activity now requires a concerted effort to ensure model reusability and interoperability between tools. Following an outline of the logical modelling framework, we present the most important achievements of the Consortium for Logical Models and Tools, along with future objectives. Our aim is to advertise this open community, which welcomes contributions from all researchers interested in logical modelling or in related mathematical and computational developments.

Multiscale binarization of gene expression data for reconstructing Boolean networks.

Network inference algorithms can assist life scientists in unraveling gene-regulatory systems on a molecular level. In recent years, great attention has been drawn to the reconstruction of Boolean networks from time series. These need to be binarized, as such networks model genes as binary variables (either "expressed" or "not expressed"). Common binarization methods often cluster measurements or separate them according to statistical or information theoretic characteristics and may require many data points to determine a robust threshold. Yet, time series measurements frequently comprise only a small number of samples. To overcome this limitation, we propose a binarization that incorporates measurements at multiple resolutions. We introduce two such binarization approaches which determine thresholds based on limited numbers of samples and additionally provide a measure of threshold validity. Thus, network reconstruction and further analysis can be restricted to genes with meaningful thresholds. This reduces the complexity of network inference. The performance of our binarization algorithms was evaluated in network reconstruction experiments using artificial data as well as real-world yeast expression time series. The new approaches yield considerably improved correct network identification rates compared to other binarization techniques by effectively reducing the amount of candidate networks.

BoolNet--an R package for generation, reconstruction and analysis of Boolean networks.

MOTIVATION: As the study of information processing in living cells moves from individual pathways to complex regulatory networks, mathematical models and simulation become indispensable tools for analyzing the complex behavior of such networks and can provide deep insights into the functioning of cells. The dynamics of gene expression, for example, can be modeled with Boolean networks (BNs). These are mathematical models of low complexity, but have the advantage of being able to capture essential properties of gene-regulatory networks. However, current implementations of BNs only focus on different sub-aspects of this model and do not allow for a seamless integration into existing preprocessing pipelines. RESULTS: BoolNet efficiently integrates methods for synchronous, asynchronous and probabilistic BNs. This includes reconstructing networks from time series, generating random networks, robustness analysis via perturbation, Markov chain simulations, and identification and visualization of attractors. AVAILABILITY: The package BoolNet is freely available from the R project at http://cran.r-project.org/ or http://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/boolnet/ under Artistic License 2.0. CONTACT: hans.kestler@uni-ulm.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.