Dataset Information

Generating Ensembles of Gene Regulatory Networks to Assess Robustness of Disease Modules.

ABSTRACT: The use of biological networks such as protein-protein interaction and transcriptional regulatory networks is becoming an integral part of genomics research. However, these networks are not static, and during phenotypic transitions like disease onset, they can acquire new "communities" (or highly interacting groups) of genes that carry out cellular processes. Disease communities can be detected by maximizing a modularity-based score, but since biological systems and network inference algorithms are inherently noisy, it remains a challenge to determine whether these changes represent real cellular responses or whether they appeared by random chance. Here, we introduce Constrained Random Alteration of Network Edges (CRANE), a method for randomizing networks with fixed node strengths. CRANE can be used to generate a null distribution of gene regulatory networks that can in turn be used to rank the most significant changes in candidate disease communities. Compared to other approaches, such as consensus clustering or commonly used generative models, CRANE emulates biologically realistic networks and recovers simulated disease modules with higher accuracy. When applied to breast and ovarian cancer networks, CRANE improves the identification of cancer-relevant GO terms while reducing the signal from non-specific housekeeping processes.

SUBMITTER: Lim JT

PROVIDER: S-EPMC7841433 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Generating Ensembles of Gene Regulatory Networks to Assess Robustness of Disease Modules.

Lim James T JT Chen Chen C Grant Adam D AD Padi Megha M

Frontiers in genetics 20210114

The use of biological networks such as protein-protein interaction and transcriptional regulatory networks is becoming an integral part of genomics research. However, these networks are not static, and during phenotypic transitions like disease onset, they can acquire new "communities" (or highly interacting groups) of genes that carry out cellular processes. Disease communities can be detected by maximizing a modularity-based score, but since biological systems and network inference algorithms ...[more]

PMID: 33519907

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Project description:Current experimental evidence indicates that functionally related genes show coordinated expression in order to perform their cellular functions. In this way, the cell transcriptional machinery can respond optimally to internal or external stimuli. This provides a research opportunity to identify and study co-expressed gene modules whose transcription is controlled by shared gene regulatory networks.We developed and integrated a set of computational methods of differential gene expression analysis, gene clustering, gene network inference, gene function prediction, and DNA motif identification to automatically identify differentially co-expressed gene modules, reconstruct their regulatory networks, and validate their correctness. We tested the methods using microarray data derived from soybean cells grown under various stress conditions. Our methods were able to identify 42 coherent gene modules within which average gene expression correlation coefficients are greater than 0.8 and reconstruct their putative regulatory networks. A total of 32 modules and their regulatory networks were further validated by the coherence of predicted gene functions and the consistency of putative transcription factor binding motifs. Approximately half of the 32 modules were partially supported by the literature, which demonstrates that the bioinformatic methods used can help elucidate the molecular responses of soybean cells upon various environmental stresses.The bioinformatics methods and genome-wide data sources for gene expression, clustering, regulation, and function analysis were integrated seamlessly into one modular protocol to systematically analyze and infer modules and networks from only differential expression genes in soybean cells grown under stress conditions. Our approach appears to effectively reduce the complexity of the problem, and is sufficiently robust and accurate to generate a rather complete and detailed view of putative soybean gene transcription logic potentially underlying the responses to the various environmental challenges. The same automated method can also be applied to reconstruct differentially co-expressed gene modules and their regulatory networks from gene expression data of any other transcriptome.

Dataset Information

Generating Ensembles of Gene Regulatory Networks to Assess Robustness of Disease Modules.

Publications

Generating Ensembles of Gene Regulatory Networks to Assess Robustness of Disease Modules.

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