Causal Mechanistic Regulatory Network for Glioblastoma Deciphered Using Systems Genetics Network Analysis

• Published in: Cell systems Vol. 3; no. 2; pp. 172 - 186
• Main Authors: Plaisier, Christopher L., O’Brien, Sofie, Bernard, Brady, Reynolds, Sheila, Simon, Zac, Toledo, Chad M., Ding, Yu, Reiss, David J., Paddison, Patrick J., Baliga, Nitin S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.08.2016
• Subjects: Gene Expression Regulation, Neoplastic; gene regulation; Gene Regulatory Networks; Glioblastoma; glioblastoma multiforme; glioma; Humans; MicroRNAs; network; Oncogenes; systems biology; systems genetics; systems biology; glioblastoma multiforme; systems genetics; glioma; gene regulation; network
• ISSN: 2405-4712; 2405-4720
• DOI: 10.1016/j.cels.2016.06.006

We developed the transcription factor (TF)-target gene database and the Systems Genetics Network Analysis (SYGNAL) pipeline to decipher transcriptional regulatory networks from multi-omic and clinical patient data, and we applied these tools to 422 patients with glioblastoma multiforme (GBM). The resulting gbmSYGNAL network predicted 112 somatically mutated genes or pathways that act through 74 TFs and 37 microRNAs (miRNAs) (67 not previously associated with GBM) to dysregulate 237 distinct co-regulated gene modules associated with patient survival or oncogenic processes. The regulatory predictions were associated to cancer phenotypes using CRISPR-Cas9 and small RNA perturbation studies and also demonstrated GBM specificity. Two pairwise combinations (ETV6-NFKB1 and romidepsin-miR-486-3p) predicted by the gbmSYGNAL network had synergistic anti-proliferative effects. Finally, the network revealed that mutations in NF1 and PIK3CA modulate IRF1-mediated regulation of MHC class I antigen processing and presentation genes to increase tumor lymphocyte infiltration and worsen prognosis. Importantly, SYGNAL is widely applicable for integrating genomic and transcriptomic measurements from other human cohorts. [Display omitted] •A TF-target gene database for 690 human TFs (http://tfbsdb.systemsbiology.net)•SYGNAL pipeline integrates multi-omic data into a mechanistic regulatory network•gbmSYGNAL network: TF and miRNA regulating hallmarks of cancer in GBM•Mutated NF1 and PIK3CA modulate IRF1 to increase tumor lymphocyte infiltration in GBM Plaisier et al. develop the transcription factor (TF)-target gene database and Systems Genetics Network Analysis (SYGNAL) pipeline that converts multi-omic and clinical patient data into mechanistically based transcriptional regulatory networks. They apply the SYGNAL pipeline to the TCGA glioblastoma data and discover synergistic interactions and novel biological insights into the etiology of tumor lymphocyte infiltration.