Gene regulatory network inference: Data integration in dynamic models—A review

The increasing amount of data produced by current high-throughput technologies allows for a better understanding of disease-related phenotypic traits and yet the molecular mechanisms stabilizing them are predominantly unknown. The inference of gene regulatory networks (GRNs) has potential to significantly enhance the discovery of disease-related and context-specific interactomes [1]. However, GRN inference remains a major challenge due to the combinatorial explosion of solutions and the underdetermined nature of the problem, which can be overcome by adding more context-specific information, such as gene expression, chromatin conformation or covalent modifications. Even though integrating multiple layers of information has been attempted before, all methods are tailored to specific needs [2,3]. In this work an Integer Linear Programming approach is proposed for inferring context-specific Boolean GRNs. In order to guide the optimization to a more reliable GRN, both context-independent and context-specific information is encoded into constraints. In contrast to previous methods that explore the search space using heuristics, the proposed methodology guarantees global optimality, significantly reduced runtime, and scalability. The optimization-based approach was validated on various human cell lines and outperformed previous methods in all cases when comparing the amount of retained cell-line specific ChIP-Seq interactions. We believe that our modular framework will significantly enhance the discovery of disease motifs and drug target prediction by providing more reliable context-specific GRNs.

Despite extensive research efforts, reconstruction of gene regulatory networks (GRNs) from transcriptomics data remains a pressing challenge in systems biology. While non-linear approaches for reconstruction of GRNs show improved performance over simpler alternatives, we do not yet have understanding if joint modelling of multiple target genes may improve performance, even under linearity assumptions. To address this problem, we propose two novel approaches that cast the GRN reconstruction problem as a blend between regularized multivariate regression and graphical models that combine the L2,1-norm with classical regularization techniques. We used data and networks from the DREAM5 challenge to show that the proposed models provide consistently good performance in comparison to contenders whose performance varies with data sets from simulation and experiments from model unicellular organisms Escherichia coli and Saccharomyces cerevisiae. Since the models' formulation facilitates the prediction of master regulators, we also used the resulting findings to identify master regulators over all data sets as well as their plasticity across different environments. Our results demonstrate that the identified master regulators are in line with experimental evidence from the model bacterium E. coli. Together, our study demonstrates that simultaneous modelling of several target genes results in improved inference of GRNs and can be used as an alternative in different applications.

Reconstruction of gene regulatory networks (GRNs), which explicitly represent the causality of developmental or regulatory process, is of utmost interest and has become a challenging computational problem for understanding the complex regulatory mechanisms in cellular systems. However, all existing methods of inferring GRNs from gene expression profiles have their strengths and weaknesses. In particular, many properties of GRNs, such as topology sparseness and non-linear dependence, are generally in regulation mechanism but seldom are taken into account simultaneously in one computational method. In this work, we present a novel method for inferring GRNs from gene expression data considering the non-linear dependence and topological structure of GRNs by employing path consistency algorithm (PCA) based on conditional mutual information (CMI). In this algorithm, the conditional dependence between a pair of genes is represented by the CMI between them. With the general hypothesis of Gaussian distribution underlying gene expression data, CMI between a pair of genes is computed by a concise formula involving the covariance matrices of the related gene expression profiles. The method is validated on the benchmark GRNs from the DREAM challenge and the widely used SOS DNA repair network in Escherichia coli. The cross-validation results confirmed the effectiveness of our method (PCA-CMI), which outperforms significantly other previous methods. Besides its high accuracy, our method is able to distinguish direct (or causal) interactions from indirect associations. All the source data and code are available at: http://csb.shu.edu.cn/subweb/grn.htm. lnchen@sibs.ac.cn; zpliu@sibs.ac.cn Supplementary data are available at Bioinformatics online.

The inference of gene regulatory networks from expression data is an important area of research that provides insight to the inner workings of a biological system. In this paper we present a new reverse-engineering framework for gene regulatory network reconstruction. It exploits some interesting characteristics of genetic programming, like the ability of solving complex regression problems with little or no information about the underlying data and the ability of performing an automatic selection of features at learning time. Our framework not only reconstructs the topology of the network, but it is also able to simulate its dynamic behaviour, forecasting the gene expression values in the timepoints subsequent to the initial one. In this paper, we test the proposed framework on the well-known IRMA gene regulatory network, and we show that its performances are promising.

Genes encode proteins, some of which in turn regulate other genes. Such interactions make up a gene regulatory network. The understanding and unraveling of gene regulatory networks have been proven very useful in disease diagnosis and genomic drug design. Due to the complexity of gene regulatory networks, the completely understanding of their dynamics is difficult to achieve only through biological experiments without any computational aids. As a consequence, computational models for gene regulatory networks are indispensable. Recently a wide variety of different computational models have been proposed for inferring gene regulatory networks. This paper surveys some of computational models for inferring large gene regulatory networks, in particular, Boolean network model, differential/ difference equation models, and state-space models. Some advantages and disadvantages of these models are commented on. Some criteria for validating the inferred gene regulatory networks are also discussed from the bioinformatics perspective. Finally, several directions of the future work for modeling gene regulatory networks are proposed.

A survey of the methodological process of modeling, inference, and evaluation of gene regulatory networks using scRNA-Seq data.

Joint reconstruction of multiple gene regulatory networks (GRNs) using gene expression data from multiple tissues/conditions is very important for understanding common and tissue/condition-specific regulation. However, there are currently no computational models and methods available for directly constructing such multiple GRNs that not only share some common hub genes but also possess tissue/condition-specific regulatory edges. In this paper, we proposed a new graphic Gaussian model for joint reconstruction of multiple gene regulatory networks (JRmGRN), which highlighted hub genes, using gene expression data from several tissues/conditions. Under the framework of Gaussian graphical model, JRmGRN method constructs the GRNs through maximizing a penalized log likelihood function. We formulated it as a convex optimization problem, and then solved it with an alternating direction method of multipliers (ADMM) algorithm. The performance of JRmGRN was first evaluated with synthetic data and the results showed that JRmGRN outperformed several other methods for reconstruction of GRNs. We also applied our method to real Arabidopsis thaliana RNA-seq data from two light regime conditions in comparison with other methods, and both common hub genes and some conditions-specific hub genes were identified with higher accuracy and precision. JRmGRN is available as a R program from: https://github.com/wenpingd. Supplementary data are available at Bioinformatics online.

Living cells can be observed as complex dynamical systems that are constantly remodelling themselves as response to changes in their environment (Zak et al., 2005). The cell metabolism includes number of reactions and products of reactions which interact forming a metabolic network. Due to the fact that large amount of date about processes in living cells are being collected every day, it become necessary to use computers for data processing and analysis. Introducing computer technologies into biology new discipline has been develop, systems biology or computational biology. The aim of system biology is describing and understanding how parts of organism interact in one complex system ; systems biology aims to develop mathematical model of biological systems by integrating experimental and theoretical techniques (Hecker et al., 2009, Albert, 2004). Systems biology studies biological systems by systematically perturbating them (biologically, genetically or chemically) monitoring the genes, proteins and informational pathway response (Strizh et al., 2007). Progress in molecular biology led to development of complete maps of genomes of many organisms ; it is also possible to identify and classify proteins. Although the number of completely sequenced genomes is mounting rapidly, our knowledge of transcription regulation is limited to a few model organisms (Janga and Collado-Vides, 2007). The interactive regulation of genes, working together to create gene networks has been considered the origin of many functions of organism (Mochizuki, 2008). According to Bruggeman and Westerholl, a complete systems biology approach requires (i) characterisation of organism molecular composition, (ii) components dynamics (spatial and temporal) and (iii) detail analysis of molecular response to internal and external stimuli. All these facts are included in development of gene regulatory network. In this chapter the theory of gene regulatory networks will be presented. The chapter will start with ideas how gene regulatory networks are constructed. There will be data on different types of gene regulatory networks and approaches for modeling those systems. This chapter will try to explain why is the modeling of complex regulatory networks important for genetic engineering and how can the mathematical analysis of gene regulatory networks be used for genetic engineering experiments planning and results interpretation.

Reconstruction of gene regulatory networks (GRNs) from expression data is a significant open problem. Common approaches train a machine learning (ML) model to predict a gene's expression using transcription factors' (TFs') expression as features and designate important features/TFs as regulators of the gene. Here, we present an entirely different paradigm, where GRN edges are directly predicted by the ML model. The new approach, named "SPREd," is a simulation-supervised neural network for GRN inference. Its inputs comprise expression relationships (e.g. correlation, mutual information) between the target gene and each TF and between pairs of TFs. The output includes binary labels indicating whether each TF regulates the target gene. We train the neural network model using synthetic expression data generated by a biophysics-inspired simulation model that incorporates linear as well as non-linear TF-gene relationships and diverse GRN configurations. We show SPREd to outperform state-of-the-art GRN reconstruction tools GENIE3, ENNET, PORTIA, and TIGRESS on synthetic datasets with high co-expression among TFs, similar to that seen in real data. A key advantage of the new approach is its robustness to relatively small numbers of conditions (columns) in the expression matrix, which is a common problem faced by existing methods. Finally, we evaluate SPREd on real data sets in yeast that represent gold-standard benchmarks of GRN reconstruction and show it to perform significantly better than or comparably to existing methods. In addition to its high accuracy and speed, SPREd marks a first step toward incorporating biophysics principles of gene regulation into ML-based approaches to GRN reconstruction. Data and code are available from https://github.com/iiiime/SPREd.

BackgroundInferring regulatory interactions between genes from transcriptomics time-resolved data, yielding reverse engineered gene regulatory networks, is of paramount importance to systems biology and bioinformatics studies. Accurate methods to address this problem can ultimately provide a deeper insight into the complexity, behavior, and functions of the underlying biological systems. However, the large number of interacting genes coupled with short and often noisy time-resolved read-outs of the system renders the reverse engineering a challenging task. Therefore, the development and assessment of methods which are computationally efficient, robust against noise, applicable to short time series data, and preferably capable of reconstructing the directionality of the regulatory interactions remains a pressing research problem with valuable applications.ResultsHere we perform the largest systematic analysis of a set of similarity measures and scoring schemes within the scope of the relevance network approach which are commonly used for gene regulatory network reconstruction from time series data. In addition, we define and analyze several novel measures and schemes which are particularly suitable for short transcriptomics time series. We also compare the considered 21 measures and 6 scoring schemes according to their ability to correctly reconstruct such networks from short time series data by calculating summary statistics based on the corresponding specificity and sensitivity. Our results demonstrate that rank and symbol based measures have the highest performance in inferring regulatory interactions. In addition, the proposed scoring scheme by asymmetric weighting has shown to be valuable in reducing the number of false positive interactions. On the other hand, Granger causality as well as information-theoretic measures, frequently used in inference of regulatory networks, show low performance on the short time series analyzed in this study.ConclusionsOur study is intended to serve as a guide for choosing a particular combination of similarity measures and scoring schemes suitable for reconstruction of gene regulatory networks from short time series data. We show that further improvement of algorithms for reverse engineering can be obtained if one considers measures that are rooted in the study of symbolic dynamics or ranks, in contrast to the application of common similarity measures which do not consider the temporal character of the employed data. Moreover, we establish that the asymmetric weighting scoring scheme together with symbol based measures (for low noise level) and rank based measures (for high noise level) are the most suitable choices.

Network motifs, as fundamental functional substructures in gene regulatory networks (GRNs), play a critical role in regulating gene expression. Despite the successful application of graph representation learning in GRN modeling, most existing approaches mainly capture pairwise relationships and overlook higher order regulatory patterns encoded by functional motifs, which limits the accuracy of regulatory inference. To address this limitation, we propose Motif-GRN, a motif-based hypergraph representation learning framework that captures the underlying biological logic in higher order semantic structures. We first identify statistically significant regulatory motifs and construct a multichannel motif-induced hypergraph. We then design a motif-aware hypergraph convolutional network to extract motif-centric semantic features, while a conventional graph convolution module preserves first-order relational information. In addition, we introduce cross-view contrastive learning to align heterogeneous representations and enhance gene embeddings. Building on Motif-GRN, we develop an inductive extension that enables cross-dataset generalization and effective GRN inference with limited labels. Extensive experiments on three ground-truth networks across seven cell types demonstrate that Motif-GRN outperforms state-of-the-art baselines in both transductive and inductive GRN inference tasks, highlighting its potential for higher order regulatory network modeling.

The inference of Gene Regulatory Networks (GRNs) from gene expression data is a hard and widely addressed scientific challenge with potential industrial and health-care use. Discrete and continuous models of GRNs are often used (i) to understand the process, and (ii) to predict the values of the relevant variables. Here, we propose a procedure to infer models of GRNs from data where (i) the data is binarized, (ii) a Boolean model is created using a Cartesian Genetic Programming technique, (iii) the obtained Boolean model is converted to a system of ordinary differential equations, and (iv) an Evolution Strategy defines the parameters of the continuous model. As a result, we expect to reduce the effect of noise and to improve biological interpretability. The proposed method is applied to two ODE systems that describe the circadian rhythm network dynamic, with 5 and 10 state variables. The models created by the proposed procedure are able to reproduce the behavior observed in the original data.

Understanding gene interactions in complex living systems can be seen as the ultimate goal of the systems biology revolution. Hence, to fully understand disease ontology and to reduce the cost of drug development, gene regulatory networks (GRN) have to be constructed. During the last decade, many GRN inference algorithms like ‘Bayesian network’ that are based on genome-wide data have been developed to unravel the complexity of gene regulation. Recently, many of structure learning algorithms were used to learn Bayesian network that have shown promise in gene regulatory network reconstruction. In this paper we apply different structure learning algorithms on actual microarray data to obtain a better understanding of their relative strengths and weaknesses on the system biology community and we evaluate their outputs from different perspectives.

Gene Regulatory Networks (GRNs) inference from gene expression data is a hard task and a widely addressed challenge. GRNs can be represented as Boolean models similarly to digital circuits. Cartesian Genetic Programming (CGP), often used for designing circuits, can thus be adopted in the inference of GRNs. The main CGP operator for generating candidate designs is mutation, making its choice important for obtaining good results. Although there are many mutation operators for CGP, to the best of our knowledge, there is no analysis of them in the GRN inference problem. An evaluation of the Single ActiveMutation (SAM) and the Semantically-Oriented Mutation Operator (SOMO)is performed here for GRNs inference. Also, a combination of both operators is proposed. We use a benchmark single-cell RNA-Sequencingtime series data and its evaluation pipeline to measure the performance of the approaches. The experiments indicate that (i) combining SOMOand SAM provides the best results, and (ii) the results obtained by the proposal are competitive with those from state-of-the-art methods.

To address one of the most challenging ecosystems issues at the cellular level, this paper surveys the fuzzy methods used in gene regulatory networks (GRNs) inference. GRNs represent causal relationships between genes that have a direct influence on the life and the development of living organisms, and provide a useful contribution to the understanding of the cellular functions as well as the mechanisms of diseases. The ecosystems impacted by GRN inference span various levels from cell to society -- globally.