Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications

Abstract

BackgroundGlioblastoma (GBM, WHO grade IV) is an aggressive, primary brain tumor. Despite gross surgery and forceful radio- and chemotherapy, survival of GBM patients did not improve over decades. Several studies reported transcription deregulation in GBMs but regulatory mechanisms driving overexpression of GBM-specific genes remain largely unknown. Transcription in open chromatin regions is directed by transcription factors (TFs) that bind to specific motifs, recruit co-activators/repressors and the transcriptional machinery. Identification of GBM-related TFs-gene regulatory networks may reveal new and targetable mechanisms of gliomagenesis.ResultsWe predicted TFs-regulated networks in GBMs in silico and intersected them with putative TF binding sites identified in the accessible chromatin in human glioma cells and GBM patient samples. The Cancer Genome Atlas and Glioma Atlas datasets (DNA methylation, H3K27 acetylation, transcriptomic profiles) were explored to elucidate TFs-gene regulatory networks and effects of the epigenetic background. In contrast to the majority of tumors, c-Jun expression was higher in GBMs than in normal brain and c-Jun binding sites were found in multiple genes overexpressed in GBMs such as VIM, FOSL2 or UPP1. Binding of c-Jun to the VIM gene promoter is stronger in GBM cells than in cells derived from benign glioma as evidenced by gel shift and supershift assays. Regulatory regions of a majority of the c-Jun targets have distinct DNA methylation in GBMs suggesting the contribution of DNA methylation to the c-Jun-dependent regulation.ConclusionsWe identified distinct TFs-gene networks in GBMs compared to benign gliomas, a predominant role of c-Jun in controlling genes driving gliomagenesis and a modulatory role of DNA methylation.

Exploring Responses of Glioblastoma Patient-Derived Cell Cultures to Drugs Reveals New Therapeutic Opportunities

“…Our data indicate that GBMderived spheres represent a lineage-restricted progeny that expressed neural stem and precursor markers (NESTIN, SOX2 and OLIG2), but without expression of NANOG and OCT4A, an essential transcription factors that regulate self-renewal and pluripotency of embryonic stem cells [78], which is in agreement with recent findings [24,80,105]. Interestingly, we generated two cell lines from a WHO grade 1 tumor, and two cell lines from a grade WHO 2/3 tumor [106]. Creating patient-derived models of lower-grade gliomas (LGG) is challenging [107].…”