BACKGROUND: The study of control mechanisms of biological systems allows for interesting applications in bioengineering and medicine, for instance in cell reprogramming or drug target identification. A control strategy often consists of a set of interventions that, by fixing the values of some components, ensure that the long term dynamics of the controlled system is in a desired state. A common approach to control in the Boolean framework consists in checking how the fixed values propagate through the network, to establish whether the effect of percolating the interventions is sufficient to induce the target state. Although methods based uniquely on value percolation allow for efficient computation, they can miss many control strategies. Exhaustive methods for control strategy identification, on the other hand, often entail high computational costs. In order to increase the number of control strategies identified while still benefiting from an efficient implementation, we introduce the use of trap spaces, subspaces of the state space that are closed with respect to the dynamics, and that can usually be easily computed in biological networks. RESULTS: This work presents a method based on value percolation that uses trap spaces to uncover new control strategies. It allows for node interventions, which fix the value of certain components, and edge interventions, which fix the effect that one component has on another. The method is implemented using Answer Set Programming, extending an existing efficient implementation of value percolation to allow for the use of trap spaces and edge control. The applicability of the approach is studied for different control targets in a biological case study, identifying in all cases new control strategies. CONCLUSION: The method presented here provides a new tool for control strategy identification in Boolean networks that allows for more diversity of interventions and for the possibility of efficiently finding new control strategies that would escape usual percolation-based methods, widening the possibility for potential applications.

The attractors of Boolean networks and their basins have been shown to be highly relevant for model validation and predictive modeling, e.g., in systems biology. Yet, there are currently very few tools available that are able to compute and visualize not only attractors but also their basins. In the realm of asynchronous, non-deterministic modeling not only is the repertoire of software even more limited, but also the formal notions for basins of attraction are often lacking. In this setting, the difficulty both for theory and computation arises from the fact that states may be elements of several distinct basins. In this paper, we address this topic by partitioning the state space into sets that are committed to the same attractors. These commitment sets can easily be generalized to sets that are equivalent w.r.t. the long-term behaviors of pre-selected nodes which leads us to the notions of markers and phenotypes which we illustrate in a case study on bladder tumorigenesis. For every concept, we propose equivalent CTL model checking queries and an extension of the state of the art model checking software NuSMV is made available that is capable of computing the respective sets. All notions are fully integrated as three new modules in our Python package PyBoolNet, including functions for visualizing the basins, commitment sets, and phenotypes as quotient graphs and pie charts.

BACKGROUND: Although several studies have provided insights into the role of long non-coding RNAs (lncRNAs), the majority of them have unknown function. Recent evidence has shown the importance of both lncRNAs and chromatin interactions in transcriptional regulation. Although network-based methods, mainly exploiting gene-lncRNA co-expression, have been applied to characterize lncRNA of unknown function by means of 'guilt-by-association', no strategy exists so far which identifies mRNA-lncRNA functional modules based on the 3D chromatin interaction graph. RESULTS: To better understand the function of chromatin interactions in the context of lncRNA-mediated gene regulation, we have developed a multi-step graph analysis approach to examine the RNA polymerase II ChIA-PET chromatin interaction network in the K562 human cell line. We have annotated the network with gene and lncRNA coordinates, and chromatin states from the ENCODE project. We used centrality measures, as well as an adaptation of our previously developed Markov State Models (MSM) clustering method, to gain a better understanding of lncRNAs in transcriptional regulation. The novelty of our approach resides in the detection of fuzzy regulatory modules based on network properties and their optimization based on co-expression analysis between genes and gene-lncRNA pairs. This results in our method returning more bona fide regulatory modules than other state-of-the art approaches for clustering on graphs. CONCLUSIONS: Interestingly, we find that lncRNA network hubs tend to be significantly enriched in evolutionary conserved lncRNAs and enhancer-like functions. We validated regulatory functions for well known lncRNAs, such as MALAT1 and the enhancer-like lncRNA FALEC. In addition, by investigating the modular structure of bigger components we mine putative regulatory functions for uncharacterized lncRNAs.

Motivation: The goal of this project is to provide a simple interface to working with Boolean networks. Emphasis is put on easy access to a large number of common tasks including the generation and manipulation of networks, attractor and basin computation, model checking and trap space computation, execution of established graph algorithms as well as graph drawing and layouts. Results: P y B ool N et is a Python package for working with Boolean networks that supports simple access to model checking via N u SMV, standard graph algorithms via N etwork X and visualization via dot . In addition, state of the art attractor computation exploiting P otassco ASP is implemented. The package is function-based and uses only native Python and N etwork X data types. Availability and Implementation: https://github.com/hklarner/PyBoolNet. Contact: [email protected].

This paper is concerned with the analysis of labeled Thomas networks using discrete time series. It focuses on refining the given edge labels and on assessing the data quality. The results are aimed at being exploitable for experimental design and include the prediction of new activatory or inhibitory effects of given interactions and yet unobserved oscillations of specific components in between specific sampling intervals. On the formal side, we generalize the concept of edge labels and introduce a discrete time series interpretation. This interpretation features two original concepts: 1) Incomplete measurements are admissible, and 2) it allows qualitative assumptions about the changes in gene expression by means of monotonicity. On the computational side, we provide a Python script, erda.py, that automates the suggested workflow by model checking and constraint satisfaction. We illustrate the workflow by investigating the yeast network IRMA.