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

Abstract

Background Glioblastoma (GBM, WHO grade IV) is an aggressive, primary brain tumor. Despite extensive tumor resection followed by radio- and chemotherapy, life expectancy 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. Results We 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, including VIM, FOSL2 or UPP1. Binding of c-Jun to the VIM gene promoter was stronger in GBM-derived cells than in cells derived from benign glioma as evidenced by gel shift and supershift assays. Regulatory regions of the majority of c-Jun targets have distinct DNA methylation patterns in GBMs as compared to benign gliomas, suggesting the contribution of DNA methylation to the c-Jun-dependent gene expression. Conclusions GBM-specific TFs-gene networks identified in GBMs differ from regulatory pathways attributed to benign brain tumors and imply a decisive role of c-Jun in controlling genes that drive glioma growth and invasion as well as a modulatory role of DNA methylation.

Identification of Cholangiocarcinoma (CCA) Subtype-Specific Biomarkers

“…It is made colored). This discovery is consistent with the transcription profiling data reported in various cancer types [30][31][32][33][34], including HCC [31,35]. Recognizing the significant role of TFs in the progression of liver cancers [38][39][40][41][42], we conducted enrichment analyses to unveil the signaling pathways in which the identified TFs are implicated in the context of CCA.…”

“…Hence, mutated or improperly regulated TFs in different cancers serve as clear targets for therapeutic drugs as well as diagnostic and prognostic biomarkers [28,29]. Numerous new prognostic biomarkers or biomarker combinations derived from TFs have been identified through comprehensive omics analyses of transcription profiles across different cancer types [30][31][32][33][34], including HCC [31,35]. As numerous cases of liver cancer arise from chronic health conditions like cirrhosis triggered by hepatitis B or hepatitis C infections [18][19][20]22,23,[36][37][38], alterations in gene expression induced by viruses have been documented at both the DNA and RNA levels [38][39][40][41][42].…”

Novel hepatocellular carcinomas (HCC) Subtype-Specific Biomarkers

“…Using our devised ML/DL-based ESM-TFpredict model [58,69], we have effectively identified 102 transcription factors (TFs) out of the 647 HCC-specific diagnostic and prognostic biomarkers that we previously uncovered (Table 1, Supplementary Table 1). Our findings align with transcription profiling data observed in major cancer types, especially HCC [34,36,38,39,41,72]. Acknowledging the significant influence of transcription factors (TFs) in liver cancer progression [43,51,73], we conducted enrichment analyses to reveal the signaling pathways where the identified TFs play a role within the context of HCC.…”

“…Comprehensive omics analyses of transcription profiles have unveiled novel TF-derived prognostic biomarkers or panels across various cancers, including HCC [34][35][36][37][38][39][40][41]. Liver cancer, particularly HCCs, frequently emerges due to chronic factors such as cirrhosis triggered by hepatitis B or C, leading to its high incidence [25][26][27][28][29]42,43].…”

Navigating the Gene Co-Expression Network and Drug Repurposing Opportunities for Brain Disorders Associated with Neurocognitive Impairment

“…Additionally, elevated levels of the Jun Proto-Oncogene (JUN), the second-ranked hub gene in this module, have been observed in neurodegenerative conditions like Parkinson's and Alzheimer's disease. Primarily recognized as a proto-oncogene, JUN encodes for the c-Jun protein, a component of the AP-1 transcription factor complex that plays a significant role in cell proliferation, differentiation, and apoptosis [85]. Its aberrant expression and mutations have been associated with the promotion of tumorigenic processes, contributing to the progression of glioblastoma [86].…”