Engineering Of Gene Regulatory Networks Research Articles

The non-specific lethal complex regulates genes and pathways genetically linked to Parkinson's disease.

Genetic variants conferring risks for Parkinson's disease have been highlighted through genome-wide association studies, yet exploration of their specific disease mechanisms is lacking. Two Parkinson's disease candidate genes, KAT8 and KANSL1, identified through genome-wide studies and a PINK1-mitophagy screen, encode part of the histone acetylating non-specific lethal complex. This complex localizes to the nucleus, where it plays a role in transcriptional activation, and to mitochondria, where it has been suggested to have a role in mitochondrial transcription. In this study, we sought to identify whether the non-specific lethal complex has potential regulatory relationships with other genes associated with Parkinson's disease in human brain. Correlation in the expression of non-specific lethal genes and Parkinson's disease-associated genes was investigated in primary gene co-expression networks using publicly-available transcriptomic data from multiple brain regions (provided by the Genotype-Tissue Expression Consortium and UK Brain Expression Consortium), whilst secondary networks were used to examine cell type specificity. Reverse engineering of gene regulatory networks generated regulons of the complex, which were tested for heritability using stratified linkage disequilibrium score regression. Prioritized gene targets were then validated in vitro using a QuantiGene multiplex assay and publicly-available chromatin immunoprecipitation-sequencing data. Significant clustering of non-specific lethal genes was revealed alongside Parkinson's disease-associated genes in frontal cortex primary co-expression modules, amongst other brain regions. Both primary and secondary co-expression modules containing these genes were enriched for mainly neuronal cell types. Regulons of the complex contained Parkinson's disease-associated genes and were enriched for biological pathways genetically linked to disease. When examined in a neuroblastoma cell line, 41% of prioritized gene targets showed significant changes in mRNA expression following KANSL1 or KAT8 perturbation. KANSL1 and H4K8 chromatin immunoprecipitation-sequencing data demonstrated non-specific lethal complex activity at many of these genes. In conclusion, genes encoding the non-specific lethal complex are highly correlated with and regulate genes associated with Parkinson's disease. Overall, these findings reveal a potentially wider role for this protein complex in regulating genes and pathways implicated in Parkinson's disease.

Application of modular response analysis to medium- to large-size biological systems.

The development of high-throughput genomic technologies associated with recent genetic perturbation techniques such as short hairpin RNA (shRNA), gene trapping, or gene editing (CRISPR/Cas9) has made it possible to obtain large perturbation data sets. These data sets are invaluable sources of information regarding the function of genes, and they offer unique opportunities to reverse engineer gene regulatory networks in specific cell types. Modular response analysis (MRA) is a well-accepted mathematical modeling method that is precisely aimed at such network inference tasks, but its use has been limited to rather small biological systems so far. In this study, we show that MRA can be employed on large systems with almost 1,000 network components. In particular, we show that MRA performance surpasses general-purpose mutual information-based algorithms. Part of these competitive results was obtained by the application of a novel heuristic that pruned MRA-inferred interactions a posteriori. We also exploited a block structure in MRA linear algebra to parallelize large system resolutions.

Accurate inference of gene regulatory interactions from spatial gene expression with deep contrastive learning.

Reverse engineering of gene regulatory networks (GRNs) has long been an attractive research topic in system biology. Computational prediction of gene regulatory interactions has remained a challenging problem due to the complexity of gene expression and scarce information resources. The high-throughput spatial gene expression data, like in situ hybridization images that exhibit temporal and spatial expression patterns, has provided abundant and reliable information for the inference of GRNs. However, computational tools for analyzing the spatial gene expression data are highly underdeveloped. In this study, we develop a new method for identifying gene regulatory interactions from gene expression images, called ConGRI. The method is featured by a contrastive learning scheme and deep Siamese convolutional neural network architecture, which automatically learns high-level feature embeddings for the expression images and then feeds the embeddings to an artificial neural network to determine whether or not the interaction exists. We apply the method to a Drosophila embryogenesis dataset and identify GRNs of eye development and mesoderm development. Experimental results show that ConGRI outperforms previous traditional and deep learning methods by a large margin, which achieves accuracies of 76.7% and 68.7% for the GRNs of early eye development and mesoderm development, respectively. It also reveals some master regulators for Drosophila eye development. https://github.com/lugimzheng/ConGRI. Supplementary data are available at Bioinformatics online.

Reverse engineering gene regulatory network based on complex-valued ordinary differential equation model

BackgroundThe growing researches of molecular biology reveal that complex life phenomena have the ability to demonstrating various types of interactions in the level of genomics. To establish the interactions between genes or proteins and understand the intrinsic mechanisms of biological systems have become an urgent need and study hotspot.ResultsIn order to forecast gene expression data and identify more accurate gene regulatory network, complex-valued version of ordinary differential equation (CVODE) is proposed in this paper. In order to optimize CVODE model, a complex-valued hybrid evolutionary method based on Grammar-guided genetic programming and complex-valued firefly algorithm is presented.ConclusionsWhen tested on three real gene expression datasets from E.coli and Human Cell, the experiment results suggest that CVODE model could improve 20–50% prediction accuracy of gene expression data, which could also infer more true-positive regulatory relationships and less false-positive regulations than ordinary differential equation.

Gene Regulatory Network Analysis and Engineering Directs Development and Vascularization of Multilineage Human Liver Organoids.

SUMMARYPluripotent stem cell (PSC)-derived organoids have emerged as novel multicellular models of human tissue development but display immature phenotypes, aberrant tissue fates, and a limited subset of cells. Here, we demonstrate that integrated analysis and engineering of gene regulatory networks (GRNs) in PSC-derived multilineage human liver organoids direct maturation and vascular morphogenesis in vitro. Overexpression of PROX1 and ATF5, combined with targeted CRISPR-based transcriptional activation of endogenous CYP3A4, reprograms tissue GRNs and improves native liver functions, such as FXR signaling, CYP3A4 enzymatic activity, and stromal cell reactivity. The engineered tissues possess superior liver identity when compared with other PSC-derived liver organoids and show the presence of hepatocyte, biliary, endothelial, and stellate-like cell populations in single-cell RNA-seq analysis. Finally, they show hepatic functions when studied in vivo. Collectively, our approach provides an experimental framework to direct organogenesis in vitro by systematically probing molecular pathways and transcriptional networks that promote tissue development.

Globally learning gene regulatory networks based on hidden atomic regulators from transcriptomic big data

BackgroundGenes are regulated by various types of regulators and most of them are still unknown or unobserved. Current gene regulatory networks (GRNs) reverse engineering methods often neglect the unknown regulators and infer regulatory relationships in a local and sub-optimal manner.ResultsThis paper proposes a global GRNs inference framework based on dictionary learning, named dlGRN. The method intends to learn atomic regulators (ARs) from gene expression data using a modified dictionary learning (DL) algorithm, which reflects the whole gene regulatory system, and predicts the regulation between a known regulator and a target gene in a global regression way. The modified DL algorithm fits the scale-free property of biological network, rendering dlGRN intrinsically discern direct and indirect regulations.ConclusionsExtensive experimental results on simulation and real-world data demonstrate the effectiveness and efficiency of dlGRN in reverse engineering GRNs. A novel predicted transcription regulation between a TF TFAP2C and an oncogene EGFR was experimentally verified in lung cancer cells. Furthermore, the real application reveals the prevalence of DNA methylation regulation in gene regulatory system. dlGRN can be a standalone tool for GRN inference for its globalization and robustness.

Overview of Gene Regulatory Network Inference Based on Differential Equation Models.

Reconstruction of gene regulatory networks (GRN) plays an important role in understanding the complexity, functionality and pathways of biological systems, which could support the design of new drugs for diseases. Because differential equation models are flexible androbust, these models have been utilized to identify biochemical reactions and gene regulatory networks. This paper investigates the differential equation models for reverse engineering gene regulatory networks. We introduce three kinds of differential equation models, including ordinary differential equation (ODE), time-delayed differential equation (TDDE) and stochastic differential equation (SDE). ODE models include linear ODE, nonlinear ODE and S-system model. We also discuss the evolutionary algorithms, which are utilized to search the optimal structures and parameters of differential equation models. This investigation could provide a comprehensive understanding of differential equation models, and lead to the discovery of novel differential equation models.

Reverse engineering directed gene regulatory networks from transcriptomics and proteomics data of biomining bacterial communities with approximate Bayesian computation and steady-state signalling simulations

BackgroundNetwork inference is an important aim of systems biology. It enables the transformation of OMICs datasets into biological knowledge. It consists of reverse engineering gene regulatory networks from OMICs data, such as RNAseq or mass spectrometry-based proteomics data, through computational methods. This approach allows to identify signalling pathways involved in specific biological functions. The ability to infer causality in gene regulatory networks, in addition to correlation, is crucial for several modelling approaches and allows targeted control in biotechnology applications.MethodsWe performed simulations according to the approximate Bayesian computation method, where the core model consisted of a steady-state simulation algorithm used to study gene regulatory networks in systems for which a limited level of details is available. The simulations outcome was compared to experimentally measured transcriptomics and proteomics data through approximate Bayesian computation.ResultsThe structure of small gene regulatory networks responsible for the regulation of biological functions involved in biomining were inferred from multi OMICs data of mixed bacterial cultures. Several causal inter- and intraspecies interactions were inferred between genes coding for proteins involved in the biomining process, such as heavy metal transport, DNA damage, replication and repair, and membrane biogenesis. The method also provided indications for the role of several uncharacterized proteins by the inferred connection in their network context.ConclusionsThe combination of fast algorithms with high-performance computing allowed the simulation of a multitude of gene regulatory networks and their comparison to experimentally measured OMICs data through approximate Bayesian computation, enabling the probabilistic inference of causality in gene regulatory networks of a multispecies bacterial system involved in biomining without need of single-cell or multiple perturbation experiments. This information can be used to influence biological functions and control specific processes in biotechnology applications.

Predicting gene regulatory interactions based on spatial gene expression data and deep learning.

Reverse engineering of gene regulatory networks (GRNs) is a central task in systems biology. Most of the existing methods for GRN inference rely on gene co-expression analysis or TF-target binding information, where the determination of co-expression is often unreliable merely based on gene expression levels, and the TF-target binding data from high-throughput experiments may be noisy, leading to a high ratio of false links and missed links, especially for large-scale networks. In recent years, the microscopy images recording spatial gene expression have become a new resource in GRN reconstruction, as the spatial and temporal expression patterns contain much abundant gene interaction information. Till now, the spatial expression resources have been largely underexploited, and only a few traditional image processing methods have been employed in the image-based GRN reconstruction. Moreover, co-expression analysis using conventional measurements based on image similarity may be inaccurate, because it is the local-pattern consistency rather than global-image-similarity that determines gene-gene interactions. Here we present GripDL (Gene regulatory interaction prediction via Deep Learning), which incorporates high-confidence TF-gene regulation knowledge from previous studies, and constructs GRNs for Drosophila eye development based on Drosophila embryonic gene expression images. Benefitting from the powerful representation ability of deep neural networks and the supervision information of known interactions, the new method outperforms traditional methods with a large margin and reveals new intriguing knowledge about Drosophila eye development.

Parametric and non-parametric gradient matching for network inference: a comparison

BackgroundReverse engineering of gene regulatory networks from time series gene-expression data is a challenging problem, not only because of the vast sets of candidate interactions but also due to the stochastic nature of gene expression. We limit our analysis to nonlinear differential equation based inference methods. In order to avoid the computational cost of large-scale simulations, a two-step Gaussian process interpolation based gradient matching approach has been proposed to solve differential equations approximately.ResultsWe apply a gradient matching inference approach to a large number of candidate models, including parametric differential equations or their corresponding non-parametric representations, we evaluate the network inference performance under various settings for different inference objectives. We use model averaging, based on the Bayesian Information Criterion (BIC), to combine the different inferences. The performance of different inference approaches is evaluated using area under the precision-recall curves.ConclusionsWe found that parametric methods can provide comparable, and often improved inference compared to non-parametric methods; the latter, however, require no kinetic information and are computationally more efficient.

Modified Half-System Based Method for Reverse Engineering of Gene Regulatory Networks.

The accurate reconstruction of gene regulatory networks for proper understanding of the intricacies of complex biological mechanisms still provides motivation for researchers. Due to accessibility of various gene expression data, we can now attempt to computationally infer genetic interactions. Among the established network inference techniques, S-system is preferred because of its efficiency in replicating biological systems though it is computationally more expensive. This provides motivation for us to develop a similar system with lesser computational load. In this work, we have proposed a novel methodology for reverse engineering of gene regulatory networks based on a new technique: half-system. Half-systems use half the number of parameters compared to S-systems and thus significantly reduce the computational complexity. We have implemented our proposed technique for reconstructing four benchmark networks from their corresponding temporal expression profiles: an 8-gene, a 10-gene, and two 20-gene networks. Being a new technique, to the best of our knowledge, there are no comparable results for this in the contemporary literature. Therefore, we have compared our results with those obtained from the contemporary literature using other methodologies, including the state-of-the-art method, GENIE3. The results obtained in this work stack favourably against the competition, even showing quantifiable improvements in some cases.

Reconstruction of gene regulatory networks using S-system with a genetic algorithm and flower pollination algorithm hybrid

Accurate reconstruction of gene regulatory networks from time-series gene expression data is a significant challenge for computer scientists. In this paper, we have proposed a genetic algorithm and flower pollination algorithm hybrid for the reverse engineering of gene regulatory network based on decoupled S-systems. Here, genetic algorithm has been used to select the best combination of genes, which act as regulators in the network. Flower pollination algorithm has been used to calculate the best possible S-system parameters for which the training error is minimal for those regulators. The proposed method has been tested on small-scale and medium-scale; synthetic benchmark networks and in-slico benchmark networks extracted from the GeneNetWeaver database, as well as the real-world experimental datasets of the yeast IMRA and DNA SOS repair network of Escherichia coli. The experiments reveal that the proposed hybrid methodology is capable of inferring gene regulatory networks more accurately with lesser training data and in lesser computational time compared to other existing methods.

New algorithms for inferring gene regulatory networks from time-series expression data on Apache Spark

Gene regulatory networks (GRNs) are crucial to understand the inner workings of the cell and the complexity of gene interactions. Numerous algorithms have been developed to infer GRNs from gene expression data. As the number of identified genes increases and the complexity of their interactions is uncovered, gene networks become cumbersome to test. Furthermore, prodding through experimental results requires an enormous amount of computation, resulting in slow data processing. Therefore, new approaches are needed to analyse copious amounts of experimental data from cellular GRNs. To meet this need, cloud computing is promising as reported in the literature. Here we present two new algorithms for reverse engineering GRNs in a cloud environment. The algorithms, implemented in Spark, employ an information-theoretic approach to infer GRNs from time-series gene expression data. Experimental results show that one of our new algorithms is faster than, yet as accurate as, two existing cloud-based GRN inference methods.

Identification of self-regulatory network motifs in reverse engineering gene regulatory networks using microarray gene expression data.

Gene Regulatory Networks (GRNs) are reconstructed from the microarray gene expression data through diversified computational approaches. This process ensues in symmetric and diagonal interaction of gene pairs that cannot be modelled as direct activation, inhibition, and self-regulatory interactions. The values of gene co-expressions could help in identifying co-regulations among them. The proposed approach aims at computing the differences in variances of co-expressed genes rather than computing differences in values of mean expressions across experimental conditions. It adopts multivariate co-variances using principal component analysis (PCA) to predict an asymmetric and non-diagonal gene interaction matrix, to select only those gene pair interactions that exhibit the maximum variances in gene regulatory expressions. The asymmetric gene regulatory interactions help in identifying the controlling regulatory agents, thus lowering the false positive rate by minimizing the connections between previously unlinked network components. The experimental results on real as well as in silico datasets including time-series RTX therapy, Arabidopsis thaliana, DREAM-3, and DREAM-8 datasets, in comparison with existing state-of-the-art approaches demonstrated the enhanced performance of the proposed approach for predicting positive and negative feedback loops and self-regulatory interactions. The generated GRNs hold the potential in determining the real nature of gene pair regulatory interactions.

Hierarchical parameter estimation of GRN based on topological analysis.

Reverse engineering of gene regulatory network (GRN) is an important and challenging task in systems biology. Existing parameter estimation approaches that compute model parameters with the same importance are usually computationally expensive or infeasible, especially in dealing with complex biological networks.In order to improve the efficiency of computational modeling, the paper applies a hierarchical estimation methodology in computational modeling of GRN based on topological analysis. This paper divides nodes in a network into various priority levels using the graph-based measure and genetic algorithm. The nodes in the first level, that correspond to root strongly connected components(SCC) in the digraph of GRN, are given top priority in parameter estimation. The estimated parameters of vertices in the previous priority level ARE used to infer the parameters for nodes in the next priority level. The proposed hierarchical estimation methodology obtains lower error indexes while consuming less computational resources compared with single estimation methodology. Experimental outcomes with insilico networks and a realistic network show that gene networks are decomposed into no more than four levels, which is consistent with the properties of inherent modularity for GRN. In addition, the proposed hierarchical parameter estimation achieves a balance between computational efficiency and accuracy.

MICRAT: a novel algorithm for inferring gene regulatory networks using time series gene expression data

BackgroundReconstruction of gene regulatory networks (GRNs), also known as reverse engineering of GRNs, aims to infer the potential regulation relationships between genes. With the development of biotechnology, such as gene chip microarray and RNA-sequencing, the high-throughput data generated provide us with more opportunities to infer the gene-gene interaction relationships using gene expression data and hence understand the underlying mechanism of biological processes. Gene regulatory networks are known to exhibit a multiplicity of interaction mechanisms which include functional and non-functional, and linear and non-linear relationships. Meanwhile, the regulatory interactions between genes and gene products are not spontaneous since various processes involved in producing fully functional and measurable concentrations of transcriptional factors/proteins lead to a delay in gene regulation. Many different approaches for reconstructing GRNs have been proposed, but the existing GRN inference approaches such as probabilistic Boolean networks and dynamic Bayesian networks have various limitations and relatively low accuracy. Inferring GRNs from time series microarray data or RNA-sequencing data remains a very challenging inverse problem due to its nonlinearity, high dimensionality, sparse and noisy data, and significant computational cost, which motivates us to develop more effective inference methods.ResultsWe developed a novel algorithm, MICRAT (Maximal Information coefficient with Conditional Relative Average entropy and Time-series mutual information), for inferring GRNs from time series gene expression data. Maximal information coefficient (MIC) is an effective measure of dependence for two-variable relationships. It captures a wide range of associations, both functional and non-functional, and thus has good performance on measuring the dependence between two genes. Our approach mainly includes two procedures. Firstly, it employs maximal information coefficient for constructing an undirected graph to represent the underlying relationships between genes. Secondly, it directs the edges in the undirected graph for inferring regulators and their targets. In this procedure, the conditional relative average entropies of each pair of nodes (or genes) are employed to indicate the directions of edges. Since the time delay might exist in the expression of regulators and target genes, time series mutual information is combined to cooperatively direct the edges for inferring the potential regulators and their targets. We evaluated the performance of MICRAT by applying it to synthetic datasets as well as real gene expression data and compare with other GRN inference methods. We inferred five 10-gene and five 100-gene networks from the DREAM4 challenge that were generated using the gene expression simulator GeneNetWeaver (GNW). MICRAT was also used to reconstruct GRNs on real gene expression data including part of the DNA-damaged response pathway (SOS DNA repair network) and experimental dataset in E. Coli. The results showed that MICRAT significantly improved the inference accuracy, compared to other inference methods, such as TDBN, etc.ConclusionIn this work, a novel algorithm, MICRAT, for inferring GRNs from time series gene expression data was proposed by taking into account dependence and time delay of expressions of a regulator and its target genes. This approach employed maximal information coefficients for reconstructing an undirected graph to represent the underlying relationships between genes. The edges were directed by combining conditional relative average entropy with time course mutual information of pairs of genes. The proposed algorithm was evaluated on the benchmark GRNs provided by the DREAM4 challenge and part of the real SOS DNA repair network in E. Coli. The experimental study showed that our approach was comparable to other methods on 10-gene datasets and outperformed other methods on 100-gene datasets in GRN inference from time series datasets.

Reverse engineering gene regulatory networks by modular response analysis - a benchmark.

Gene regulatory networks control the cellular phenotype by changing the RNA and protein composition. Despite its importance, the gene regulatory network in higher organisms is only partly mapped out. Here, we investigate the potential of reverse engineering methods to unravel the structure of these networks. Particularly, we focus on modular response analysis (MRA), a method that can disentangle networks from perturbation data. We benchmark a version of MRA that was previously successfully applied to reconstruct a signalling-driven genetic network, termed MLMSMRA, to test cases mimicking various aspects of gene regulatory networks. We then investigate the performance in comparison with other MRA realisations and related methods. The benchmark shows that MRA has the potential to predict functional interactions, but also shows that successful application of MRA is restricted to small sparse networks and to data with a low signal-to-noise ratio.

Towards precise reconstruction of gene regulatory networks by data integration

BackgroundMore and more high‐throughput datasets are available from multiple levels of measuring gene regulations. The reverse engineering of gene regulatory networks from these data offers a valuable research paradigm to decipher regulatory mechanisms. So far, numerous methods have been developed for reconstructing gene regulatory networks.ResultsIn this paper, we provide a review of bioinformatics methods for inferring gene regulatory network from omics data. To achieve the precision reconstruction of gene regulatory networks, an intuitive alternative is to integrate these available resources in a rational framework. We also provide computational perspectives in the endeavors of inferring gene regulatory networks from heterogeneous data. We highlight the importance of multi‐omics data integration with prior knowledge in gene regulatory network inferences.ConclusionsWe provide computational perspectives of inferring gene regulatory networks from multiple omics data and present theoretical analyses of existing challenges and possible solutions. We emphasize on prior knowledge and data integration in network inferences owing to their abilities of identifying regulatory causality.

An approach for reduction of false predictions in reverse engineering of gene regulatory networks

A gene regulatory network discloses the regulatory interactions amongst genes, at a particular condition of the human body. The accurate reconstruction of such networks from time-series genetic expression data using computational tools offers a stiff challenge for contemporary computer scientists. This is crucial to facilitate the understanding of the proper functioning of a living organism. Unfortunately, the computational methods produce many false predictions along with the correct predictions, which is unwanted. Investigations in the domain focus on the identification of as many correct regulations as possible in the reverse engineering of gene regulatory networks to make it more reliable and biologically relevant. One way to achieve this is to reduce the number of incorrect predictions in the reconstructed networks. In the present investigation, we have proposed a novel scheme to decrease the number of false predictions by suitably combining several metaheuristic techniques. We have implemented the same using a dataset ensemble approach (i.e. combining multiple datasets) also. We have employed the proposed methodology on real-world experimental datasets of the SOS DNA Repair network of Escherichia coli and the IMRA network of Saccharomyces cerevisiae. Subsequently, we have experimented upon somewhat larger, in silico networks, namely, DREAM3 and DREAM4 Challenge networks, and 15-gene and 20-gene networks extracted from the GeneNetWeaver database. To study the effect of multiple datasets on the quality of the inferred networks, we have used four datasets in each experiment. The obtained results are encouraging enough as the proposed methodology can reduce the number of false predictions significantly, without using any supplementary prior biological information for larger gene regulatory networks. It is also observed that if a small amount of prior biological information is incorporated here, the results improve further w.r.t. the prediction of true positives.

A Simple Approach for Representation of Gene Regulatory Networks (GRN)

Gene expressions are controlled by a series of processes known as Gene Regulation, and their abstract mapping is represented by Gene Regulatory Network (GRN) which is a descriptive model of gene interactions. Reverse engineering GRNs can reveal the complexity of gene interactions whose comprehension can lead to several other details. RNA-seq data provides better measurement of gene expressions, however it is difficult to infer GRNs using it because of its discreteness. Multiple other methods have already been proposed to infer GRN using RNA-seq data, but these methodologies are difficult to grasp. In this paper, a simple model is presented to infer GRNs, using RNA-seq based coexpression map provided by GeneFriends database, and a graph-based database tool is used to create regulatory network. The obtained results show that it is convenient to use graph database tools to work with regulatory networks instead of developing a new model from scratch.