Code for analyses presented in "Regulatory networks driving expression of genes critical for glioblastoma are controlled by the transcription factor c-Jun and the pre-existing epigenetic modifications".
Processed data is available at https://www.synapse.org/TFBSglioma
Glioblastoma (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 a transcriptional machinery. Identification of GBM-related TFs-gene regulatory networks may reveal new, targetable mechanisms of gliomagenesis.We predicted TFs-regulated networks in GBMs in silico and intersected them with putative TF binding sites identified in accessible chromatin in human glioma cells and GBMs. The Cancer Genome Atlas and gliomaAtlas datasets (DNA methylation, H3K27 acetylation, transcriptomic profiles) were explored to elucidate TFs-gene regulatory networks and effects of the epigenetic background. In contrast to majority of tumors, c-Jun expression was higher in GBMs that in normal brain and c-Jun binding sites were found in multiple genes overexpressed in GBMs such as VIMENTIN, FOSL2 or UPP1. Binding of c-Jun to the VIMENTIN gene promoter is stronger in GBM 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 contribution of DNA methylation in the c-Jun-dependent regulation.We 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.
Contact for data and materials availability: Adria-Jaume Roura.
Analysis performed by: Adria-Jaume Roura, Bartosz Wojtas and Michal J. Dabrowski.