Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109-5234, USA.
Cell Syst. 2016 Aug;3(2):172-186. doi: 10.1016/j.cels.2016.06.006. Epub 2016 Jul 14.
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.
我们开发了转录因子 (TF)-靶基因数据库和系统遗传学网络分析 (SYGNAL) 管道，以从多组学和临床患者数据中破译转录调控网络，并将这些工具应用于 422 名多形性胶质母细胞瘤 (GBM) 患者。由此产生的 gbmSYGNAL 网络预测了 112 个体细胞突变基因或途径，这些基因或途径通过 74 个 TF 和 37 个 microRNAs (miRNAs)（以前与 GBM 无关的 67 个）来失调与患者生存或致癌过程相关的 237 个不同的共同调节基因模块。使用 CRISPR-Cas9 和小 RNA 扰动研究对这些调控预测与癌症表型进行了关联，并且还证明了 GBM 的特异性。gbmSYGNAL 网络预测的两个成对组合（ETV6-NFKB1 和 romidepsin-miR-486-3p）具有协同的抗增殖作用。最后，该网络揭示 NF1 和 PIK3CA 的突变调节了 MHC 类 I 抗原加工和呈递基因的 IRF1 介导的调节，以增加肿瘤淋巴细胞浸润并恶化预后。重要的是，SYGNAL 广泛适用于整合来自其他人类队列的基因组和转录组测量值。
