Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Medical University, Haikou 571199, China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
Theranostics. 2021 Jan 1;11(7):3060-3073. doi: 10.7150/thno.54150. eCollection 2021.
Enhancers are emerging regulatory regions controlling gene expression in diverse cancer types. However, the functions of enhancer regulatory circuit perturbations driven by copy number variations (CNVs) in malignant glioma are unclear. Therefore, we aimed to investigate the comprehensive enhancer regulatory perturbation and identify potential biomarkers in glioma. We performed a meta-analysis of the enhancer centered regulatory circuit perturbations in 683 gliomas by integrating CNVs, gene expression, and transcription factors (TFs) binding. We found widespread CNVs of enhancers during glioma progression, and CNVs were associated with the perturbations of enhancer activities. In particular, the degree of perturbations for amplified enhancers was much greater accompanied by the glioma malignant progression. In addition, CNVs and enhancers cooperatively regulated the expressions of cancer-related genes. Genome-wide TF binding profiles revealed that enhancers were pervasively regulated by TFs. A network-based analysis of TF-enhancer-gene regulatory circuits revealed a core TF-gene module (58 interactions including seven genes and 14 TFs) that was associated survival of patients with glioma (p < 0.001). Finally, we validated this prognosis-associated TF-gene regulatory module in an independent cohort. In summary, our analyses provided new molecular insights for enhancer-centered transcriptional perturbation in glioma therapy. Integrative analysis revealed enhancer regulatory perturbations in glioma and also identified a network module that was associated with patient survival, thereby providing novel insights into enhancer-centered cancer therapy.
增强子是控制多种癌症类型基因表达的新兴调控区域。然而，恶性神经胶质瘤中由拷贝数变异 (CNV) 驱动的增强子调控回路扰动的功能尚不清楚。因此，我们旨在研究胶质母细胞瘤中全面的增强子调控扰动，并鉴定潜在的生物标志物。
我们通过整合 CNV、基因表达和转录因子 (TF) 结合，对 683 例胶质瘤中的增强子为中心的调控回路扰动进行了荟萃分析。我们发现，在胶质母细胞瘤进展过程中，增强子存在广泛的 CNV，并且 CNV 与增强子活性的扰动有关。特别是，扩增增强子的扰动程度随着胶质瘤恶性程度的进展而增大。此外，CNV 和增强子共同调节癌症相关基因的表达。全基因组 TF 结合谱显示，增强子被 TF 广泛调控。基于网络的 TF-增强子-基因调控回路分析揭示了一个核心 TF-基因模块（包含七个基因和 14 个 TF 的 58 个相互作用），与胶质瘤患者的生存相关（p<0.001）。最后，我们在独立队列中验证了这个与预后相关的 TF-基因调控模块。
总之，我们的分析为胶质瘤治疗中的以增强子为中心的转录扰动提供了新的分子见解。综合分析揭示了胶质瘤中的增强子调控扰动，并鉴定了与患者生存相关的网络模块，从而为以增强子为中心的癌症治疗提供了新的见解。
