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PEPN-GRN: A Petri net-based approach for the inference of gene regulatory networks from noisy gene expression data.

ABSTRACT: The inference of gene regulatory networks (GRNs) from expression data is a challenging problem in systems biology. The stochasticity or fluctuations in the biochemical processes that regulate the transcription process poses as one of the major challenges. In this paper, we propose a novel GRN inference approach, named the Probabilistic Extended Petri Net for Gene Regulatory Network (PEPN-GRN), for the inference of gene regulatory networks from noisy expression data. The proposed inference approach makes use of transition of discrete gene expression levels across adjacent time points as different evidence types that relate to the production or decay of genes. The paper examines three variants of the PEPN-GRN method, which mainly differ by the way the scores of network edges are computed using evidence types. The proposed method is evaluated on the benchmark DREAM4 in silico data sets and a real time series data set of E. coli from the DREAM5 challenge. The PEPN-GRN_v3 variant (the third variant of the PEPN-GRN approach) sought to learn the weights of evidence types in accordance with their contribution to the activation and inhibition gene regulation process. The learned weights help understand the time-shifted and inverted time-shifted relationship between regulator and target gene. Thus, PEPN-GRN_v3, along with the inference of network edges, also provides a functional understanding of the gene regulation process.

SUBMITTER: Vatsa D

PROVIDER: S-EPMC8121333 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundStructural analysis of biochemical networks is a growing field in bioinformatics and systems biology. The availability of an increasing amount of biological data from molecular biological networks promises a deeper understanding but confronts researchers with the problem of combinatorial explosion. The amount of qualitative network data is growing much faster than the amount of quantitative data, such as enzyme kinetics. In many cases it is even impossible to measure quantitative data because of limitations of experimental methods, or for ethical reasons. Thus, a huge amount of qualitative data, such as interaction data, is available, but it was not sufficiently used for modeling purposes, until now. New approaches have been developed, but the complexity of data often limits the application of many of the methods. Biochemical Petri nets make it possible to explore static and dynamic qualitative system properties. One Petri net approach is model validation based on the computation of the system's invariant properties, focusing on t-invariants. T-invariants correspond to subnetworks, which describe the basic system behavior.With increasing system complexity, the basic behavior can only be expressed by a huge number of t-invariants. According to our validation criteria for biochemical Petri nets, the necessary verification of the biological meaning, by interpreting each subnetwork (t-invariant) manually, is not possible anymore. Thus, an automated, biologically meaningful classification would be helpful in analyzing t-invariants, and supporting the understanding of the basic behavior of the considered biological system.MethodsHere, we introduce a new approach to automatically classify t-invariants to cope with network complexity. We apply clustering techniques such as UPGMA, Complete Linkage, Single Linkage, and Neighbor Joining in combination with different distance measures to get biologically meaningful clusters (t-clusters), which can be interpreted as modules. To find the optimal number of t-clusters to consider for interpretation, the cluster validity measure, Silhouette Width, is applied.ResultsWe considered two different case studies as examples: a small signal transduction pathway (pheromone response pathway in Saccharomyces cerevisiae) and a medium-sized gene regulatory network (gene regulation of Duchenne muscular dystrophy). We automatically classified the t-invariants into functionally distinct t-clusters, which could be interpreted biologically as functional modules in the network. We found differences in the suitability of the various distance measures as well as the clustering methods. In terms of a biologically meaningful classification of t-invariants, the best results are obtained using the Tanimoto distance measure. Considering clustering methods, the obtained results suggest that UPGMA and Complete Linkage are suitable for clustering t-invariants with respect to the biological interpretability.ConclusionWe propose a new approach for the biological classification of Petri net t-invariants based on cluster analysis. Due to the biologically meaningful data reduction and structuring of network processes, large sets of t-invariants can be evaluated, allowing for model validation of qualitative biochemical Petri nets. This approach can also be applied to elementary mode analysis.

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PEPN-GRN: A Petri net-based approach for the inference of gene regulatory networks from noisy gene expression data.

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