Systematic analysis of enhancer regulatory circuit perturbation driven by copy number variations in malignant glioma

Abstract

Background: 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. Results: 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. Conclusion: 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.

Integration of Multi-omics Data Revealed the Orphan CpG Islands and Enhancer-dominated Cis-regulatory Network in Glioma

“…Enhancers, as distal cis-regulatory elements, are different from proximal regulatory elements such as promoters. They rely on the 3D structure of chromosomes to achieve long-range regulation, thereby playing a pivotal role in the intricate regulatory network of glioma 12,13 . Compared to the high density of CGIs in the promoter regions, CGIs are relatively sparse within enhancers.…”

Integrative analysis of genomic and epigenomic regulation reveals miRNA mediated tumor heterogeneity and immune evasion in lower grade glioma

“…As a key genomic regulator that contribute to gene expression dysregulation via modulating mRNA levels and by influencing transcriptional regulation, CNV is significantly correlated with certain pathological processes such as cancer 21 . Transcriptional disorders caused by CNV changes have been identified as driving events in LGG progression 22 . In addition, gene expression regulation via DNA methylation at the epigenetic level also exerts a crucial part in the behaviors of LGG.…”

G protein inhibitory α subunit 2 is a molecular oncotarget of human glioma

“…Current traditional treatments have very limited effects on improving survival of glioblastoma (GBM) and other high-grade glioma (HGG) [1][2][3]. Multiple signaling cascades are dysregulated in glioma, including EGFR, the type III mutations, VEGFR and CDK, which are essential for the uncontrolled glioma growth and malignant progression [4][5][6][7][8]. Targeted therapies for specific molecules on the signaling pathways have become the research hotspot for glioma [4][5][6]9].…”