Dataset Information

Reconciling differential gene expression data with molecular interaction networks.

ABSTRACT:

Motivation

Many techniques have been developed to compute the response network of a cell. A recent trend in this area is to compute response networks of small size, with the rationale that only part of a pathway is often changed by disease and that interpreting small subnetworks is easier than interpreting larger ones. However, these methods may not uncover the spectrum of pathways perturbed in a particular experiment or disease.

Results

To avoid these difficulties, we propose to use algorithms that reconcile case-control DNA microarray data with a molecular interaction network by modifying per-gene differential expression P-values such that two genes connected by an interaction show similar changes in their gene expression values. We provide a novel evaluation of four methods from this class of algorithms. We enumerate three desirable properties that this class of algorithms should address. These properties seek to maintain that the returned gene rankings are specific to the condition being studied. Moreover, to ease interpretation, highly ranked genes should participate in coherent network structures and should be functionally enriched with relevant biological pathways. We comprehensively evaluate the extent to which each algorithm addresses these properties on a compendium of gene expression data for 54 diverse human diseases. We show that the reconciled gene rankings can identify novel disease-related functions that are missed by analyzing expression data alone.

Availability

C++ software implementing our algorithms is available in the NetworkReconciliation package as part of the Biorithm software suite under the GNU General Public License: http://bioinformatics.cs.vt.edu/?murali/software/biorithm-docs.

SUBMITTER: Poirel CL

PROVIDER: S-EPMC3582271 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Publications

Reconciling differential gene expression data with molecular interaction networks.

Poirel Christopher L CL Rahman Ahsanur A Rodrigues Richard R RR Krishnan Arjun A Addesa Jacqueline R JR Murali T M TM

Bioinformatics (Oxford, England) 20130112 5

<h4>Motivation</h4>Many techniques have been developed to compute the response network of a cell. A recent trend in this area is to compute response networks of small size, with the rationale that only part of a pathway is often changed by disease and that interpreting small subnetworks is easier than interpreting larger ones. However, these methods may not uncover the spectrum of pathways perturbed in a particular experiment or disease.<h4>Results</h4>To avoid these difficulties, we propose to ...[more]

PMID: 23314326

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Project description:BackgroundKanglaite injection (KLTi) has shown good clinical efficacy in the treatment of pancreatic ductal adenocarcinoma (PDAC). While previous studies have demonstrated the antitumor effects of the oil compounds in KLTi, it is unclear whether the unsaponifiable matter (USM) also has antitumor effects. This study used network pharmacology, molecular docking, and database verification methods to investigate the molecular biological mechanisms of USM.MethodsCompounds of USM were obtained from GC-MS, and targets from DrugBank. Next, the GEO database was searched for differentially expressed genes in cancerous tissues and healthy tissues of PDAC to identify targets. Subsequently, the protein-protein interaction of USM and PDAC targets was constructed by BisoGenet to extract candidate genes. The candidate genes were enriched using GO and KEGG by Metascape, and the gene-pathway network was constructed to screen the key genes. Molecular docking and molecular dynamic simulations of core compound targets were finally performed and to explore the diagnostic, survival, and prognosis value of targets.ResultsA total of 10 active compounds and 36 drug targets were screened for USM, 919 genes associated with PDAC, and 139 USM candidate genes against PDAC were excavated. The enrichment predicted USM by acting on RELA, NFKB1, IKBKG, JUN, MAPK1, TP53, and AKT1. Molecular docking and dynamic simulations confirmed the screened core targets had good affinity and stability with the corresponding compounds. In diagnostic ROC validation, the above targets have certain accuracy for diagnosing PDAC, and the combined diagnosis is more advantageous. As the most diagnostic value of RELA, it is equally significant in predicting disease-specific survival and progression-free interval.ConclusionsUSM in KLTi plays an anti-PDAC role by intervening in the cell cycle, inducing apoptosis, and downregulating the NF-κB, MAPK, and PI3K-Akt pathways. It might participate in the pancreatic cancer pathway, and core target groups have diagnostic, survival, and prognosis value biomarker significance.

Project description:BackgroundPathway alterations reflected as changes in gene expression regulation and gene interaction can result from cellular exposure to toxicants. Such information is often used to elucidate toxicological modes of action. From a risk assessment perspective, alterations in biological pathways are a rich resource for setting toxicant thresholds, which may be more sensitive and mechanism-informed than traditional toxicity endpoints. Here we developed a novel differential networks (DNs) approach to connect pathway perturbation with toxicity threshold setting.MethodsOur DNs approach consists of 6 steps: time-series gene expression data collection, identification of altered genes, gene interaction network reconstruction, differential edge inference, mapping of genes with differential edges to pathways, and establishment of causal relationships between chemical concentration and perturbed pathways. A one-sample Gaussian process model and a linear regression model were used to identify genes that exhibited significant profile changes across an entire time course and between treatments, respectively. Interaction networks of differentially expressed (DE) genes were reconstructed for different treatments using a state space model and then compared to infer differential edges/interactions. DE genes possessing differential edges were mapped to biological pathways in databases such as KEGG pathways.ResultsUsing the DNs approach, we analyzed a time-series Escherichia coli live cell gene expression dataset consisting of 4 treatments (control, 10, 100, 1000 mg/L naphthenic acids, NAs) and 18 time points. Through comparison of reconstructed networks and construction of differential networks, 80 genes were identified as DE genes with a significant number of differential edges, and 22 KEGG pathways were altered in a concentration-dependent manner. Some of these pathways were perturbed to a degree as high as 70% even at the lowest exposure concentration, implying a high sensitivity of our DNs approach.ConclusionsFindings from this proof-of-concept study suggest that our approach has a great potential in providing a novel and sensitive tool for threshold setting in chemical risk assessment. In future work, we plan to analyze more time-series datasets with a full spectrum of concentrations and sufficient replications per treatment. The pathway alteration-derived thresholds will also be compared with those derived from apical endpoints such as cell growth rate.

Dataset Information

Reconciling differential gene expression data with molecular interaction networks.

Motivation

Results

Availability

Publications

Reconciling differential gene expression data with molecular interaction networks.

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