Doostparast Torshizi Abolfazl, Wang Kai
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, 10032, USA.
Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, 10032, USA.
Sci Rep. 2017 Nov 3;7(1):14486. doi: 10.1038/s41598-017-15221-y.
Post-Traumatic Stress Disorder (PTSD) is a psychiatric disorder that develops in individuals experiencing a shocking incident, but the underlying disease susceptibility gene networks remain poorly understood. Breen et al. conducted a Weighted Gene Co-expression Network Analysis on PTSD, and identified a dysregulated innate immune module associated with PTSD development. To further identify the Master Regulators (MRs) driving the network function, here we deconvoluted the transcriptional networks on the same datasets using ARACNe (Algorithm for Reconstruction of Accurate Cellular Networks) followed by protein activity analysis. We successfully identified several MRs including SOX3, TNFAIP3, TRAFD1, POU3F3, STAT2, and PML that govern the expression of a large collection of genes. Transcription factor binding site enrichment analysis verified the binding of these MRs to their predicted targets. Notably, the sub-networks regulated by TNFAIP3, TRAFD1 and PML are involved in innate immune response, suggesting that these MRs may correlate with the innate immune module identified by Breen et al. These findings were replicated in an independent dataset generated on expression microarrays. In conclusion, our analysis corroborated previous findings that innate immunity may be involved in the progression of PTSD, yet also identified candidate MRs driving the disease progression in the innate immunity pathways.
创伤后应激障碍（PTSD）是一种在经历令人震惊事件的个体中出现的精神障碍，但其潜在的疾病易感性基因网络仍知之甚少。Breen等人对PTSD进行了加权基因共表达网络分析，并确定了一个与PTSD发展相关的失调的先天免疫模块。为了进一步识别驱动网络功能的主调控因子（MRs），我们在此使用ARACNe（精确细胞网络重建算法）对相同数据集的转录网络进行反卷积，随后进行蛋白质活性分析。我们成功识别了几个MRs，包括SOX3、TNFAIP3、TRAFD1、POU3F3、STAT2和PML，它们控制着大量基因的表达。转录因子结合位点富集分析验证了这些MRs与其预测靶点的结合。值得注意的是，由TNFAIP3、TRAFD1和PML调控的子网络参与先天免疫反应，这表明这些MRs可能与Breen等人识别的先天免疫模块相关。这些发现在通过表达微阵列生成的独立数据集中得到了重复。总之，我们的分析证实了先前的发现，即先天免疫可能参与PTSD的进展，但也识别出了在先天免疫途径中驱动疾病进展的候选MRs。
