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

Clinical Epigenetics

Research

Michal J. Dabrowski¹  Katarzyna Poleszak²  Karolina Stepniak²  Iwona A. Ciechomska²  Kamil Wojnicki²  Bozena Kaminska²  Adria-Jaume Roura²  Aleksandra Ellert-Miklaszewska²  Bartosz Wojtas³  Paulina Szadkowska⁴ 

[1] Institute of Computer Science of the Polish Academy of Sciences, Warsaw, Poland;Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland;Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland;Laboratory of Sequencing, Nencki Institute of Experimental Biology, ul. Ludwika Pasteura 3, 02-093, Warsaw, Poland;Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland;Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland;

关键词: Glioblastoma;    Transcriptional deregulation;    Transcription factors;    Gene expression;    Chromatin accessibility;    DNA binding;    DNA methylation;   

DOI  :  10.1186/s13148-023-01446-4

 received in 2022-11-10, accepted in 2023-02-13,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundGlioblastoma (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.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, 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.ConclusionsGBM-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.

【 授权许可】

CC BY   
© The Author(s) 2023

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