Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Wolstein Research Building, 2103 Cornell Road, Suite 1-314, Cleveland, OH, 44106-7295, USA.
Systems Biology and Bioinformatics Program, Case Western Reserve University, Cleveland, OH, USA.
BMC Bioinformatics. 2021 Jan 12;22(1):22. doi: 10.1186/s12859-020-03929-0.
In this study, we demonstrate that our modified Gene Set Enrichment Analysis (GSEA) method, drug perturbation GSEA (dpGSEA), can detect phenotypically relevant drug targets through a unique transcriptomic enrichment that emphasizes biological directionality of drug-derived gene sets.
We detail our dpGSEA method and show its effectiveness in detecting specific perturbation of drugs in independent public datasets by confirming fluvastatin, paclitaxel, and rosiglitazone perturbation in gastroenteropancreatic neuroendocrine tumor cells. In drug discovery experiments, we found that dpGSEA was able to detect phenotypically relevant drug targets in previously published differentially expressed genes of CD4+T regulatory cells from immune responders and non-responders to antiviral therapy in HIV-infected individuals, such as those involved with virion replication, cell cycle dysfunction, and mitochondrial dysfunction. dpGSEA is publicly available at https://github.com/sxf296/drug_targeting .
dpGSEA is an approach that uniquely enriches on drug-defined gene sets while considering directionality of gene modulation. We recommend dpGSEA as an exploratory tool to screen for possible drug targeting molecules.
在这项研究中，我们证明了我们改进的基因集富集分析（GSEA）方法，即药物扰动 GSEA（dpGSEA），可以通过强调药物衍生基因集的生物学方向性的独特转录组富集来检测表型相关的药物靶点。
我们详细介绍了我们的 dpGSEA 方法，并通过在独立的公共数据集确认氟伐他汀、紫杉醇和罗格列酮对胃肠胰腺神经内分泌肿瘤细胞的扰动，展示了其在检测特定药物扰动方面的有效性。在药物发现实验中，我们发现 dpGSEA 能够检测到 HIV 感染个体中抗病毒治疗免疫应答者和无应答者的 CD4+T 调节细胞中先前发表的差异表达基因中的表型相关药物靶点，例如与病毒复制、细胞周期功能障碍和线粒体功能障碍相关的靶点。dpGSEA 可在 https://github.com/sxf296/drug_targeting 上公开获取。
dpGSEA 是一种独特的富集药物定义基因集的方法，同时考虑基因调控的方向性。我们建议将 dpGSEA 作为一种探索性工具，用于筛选可能的药物靶向分子。
