Dataset Information

A Bayesian gene network reveals insight into the JAK-STAT pathway in systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic, remitting, and relapsing, inflammatory disease involving multiple organs, which exhibits abnormalities of both the innate and adaptive immune responses. A limited number of transcriptomic studies have characterized the gene pathways involved in SLE in an attempt to identify the key pathogenic drivers of the disease. In order to further advance our understanding of the pathogenesis of SLE, we used a novel Bayesian network algorithm to hybridize knowledge- and data-driven methods, and then applied the algorithm to build an SLE gene network using transcriptomic data from 1,760 SLE patients' RNA from the two tabalumab Phase III trials (ILLUMINATE-I & -II), the largest SLE RNA dataset to date. Further, based on the gene network, we carried out hub- and key driver-gene analyses for gene prioritization. Our analyses identified that the JAK-STAT pathway genes, including JAK2, STAT1, and STAT2, played essential roles in SLE pathogenesis, and reaffirmed the recent discovery of pathogenic relevance of JAK-STAT signaling in SLE. Additionally, we showed that other genes, such as IRF1, IRF7, PDIA4, FAM72C, TNFSF10, DHX58, SIGLEC1, and PML, may be also important in SLE and serve as potential therapeutic targets for SLE. In summary, using a hybridized network construction approach, we systematically investigated gene-gene interactions based on their transcriptomic profiles, prioritized genes based on their importance in the network structure, and revealed new insights into SLE activity.

SUBMITTER: Li Y

PROVIDER: S-EPMC6886858 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Bayesian gene network reveals insight into the JAK-STAT pathway in systemic lupus erythematosus.

Li Yupeng Y Higgs Richard E RE Hoffman Robert W RW Dow Ernst R ER Liu Xiong X Petri Michelle M Wallace Daniel J DJ Dörner Thomas T Eastwood Brian J BJ Miller Bradley B BB Liu Yushi Y

PloS one 20191202 12

Systemic lupus erythematosus (SLE) is a chronic, remitting, and relapsing, inflammatory disease involving multiple organs, which exhibits abnormalities of both the innate and adaptive immune responses. A limited number of transcriptomic studies have characterized the gene pathways involved in SLE in an attempt to identify the key pathogenic drivers of the disease. In order to further advance our understanding of the pathogenesis of SLE, we used a novel Bayesian network algorithm to hybridize kno ...[more]

PMID: 31790472

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Project description:BackgroundA comprehensive intuition of the systemic lupus erythematosus (SLE), as a complex and multifactorial disease, is a biological challenge. Dealing with this challenge needs employing sophisticated bioinformatics algorithms to discover the unknown aspects. This study aimed to underscore key molecular characteristics of SLE pathogenesis, which may serve as effective targets for therapeutic intervention.MethodsIn the present study, the human peripheral blood mononuclear cell (PBMC) microarray datasets (n = 6), generated by three platforms, which included SLE patients (n = 220) and healthy control samples (n = 135) were collected. Across each platform, we integrated the datasets by cross-platform normalization (CPN). Subsequently, through BNrich method, the structures of Bayesian networks (BNs) were extracted from KEGG-indexed SLE, TCR, and BCR signaling pathways; the values of the node (gene) and edge (intergenic relationships) parameters were estimated within each integrated datasets. Parameters with the FDR < 0.05 were considered significant. Finally, a mixture model was performed to decipher the signaling pathway alterations in the SLE patients compared to healthy controls.ResultsIn the SLE signaling pathway, we identified the dysregulation of several nodes involved in the (1) clearance mechanism (SSB, MACROH2A2, TRIM21, H2AX, and C1Q gene family), (2) autoantigen presentation by MHCII (HLA gene family, CD80, IL10, TNF, and CD86), and (3) end-organ damage (FCGR1A, ELANE, and FCGR2A). As a remarkable finding, we demonstrated significant perturbation in CD80 and CD86 to CD28, CD40LG to CD40, C1QA and C1R to C2, and C1S to C4A edges. Moreover, we not only replicated previous studies regarding alterations of subnetworks involved in TCR and BCR signaling pathways (PI3K/AKT, MAPK, VAV gene family, AP-1 transcription factor) but also distinguished several significant edges between genes (PPP3 to NFATC gene families). Our findings unprecedentedly showed that different parameter values assign to the same node based on the pathway topology (the PIK3CB parameter values were 1.7 in TCR vs - 0.5 in BCR signaling pathway).ConclusionsApplying the BNrich as a hybridized network construction method, we highlight under-appreciated systemic alterations of SLE, TCR, and BCR signaling pathways in SLE. Consequently, having such a systems biology approach opens new insights into the context of multifactorial disorders.

Dataset Information

A Bayesian gene network reveals insight into the JAK-STAT pathway in systemic lupus erythematosus.

Publications

A Bayesian gene network reveals insight into the JAK-STAT pathway in systemic lupus erythematosus.

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