Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness

Alexandra Bogeas,Ahmed Idbaïh ,Michèle Goodhardt ,Klaudia Kuranda,François Lejeune ,Stéphanie Rialle,Fanny Burel‐Vandenbos ,Luiz Gustavo Dubois ,Hugues Parrinello,Virgile Delaunay,Thierry Virolle,Ivan Bièche,Jacques Haiech,Matthieu Defrance,Hervé Chneiweiss,Ghislaine Morvan-Dubois,Sylvie Fabrega,Ashwin Narayanan,Salwa Sayd,Elias A El-Habr,Marie Pierre Junier

doi:10.1007/s00401-017-1783-x

Abstract

Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Immunohistochemistry confirmed ARNT2 expression in cell sub-populations within proliferative zones of patients’ glioblastoma. Decreased ARNT2 expression was consistently observed in non-tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a tumorigenic molecular signature at both the tissue level within the tumor core and at the single cell level in the patients’ tumors. We found that ARNT2 knockdown decreased the expression of SOX9, POU3F2 and OLIG2, transcription factors implicated in glioblastoma cell tumorigenicity, and repressed glioblastoma stem-like cell tumorigenic properties in vivo. Our results reveal ARNT2 as a pivotal component of the glioblastoma cell tumorigenic signature, located at a node of a transcription factor network controlling glioblastoma cell aggressiveness.

Highlights

De novo glioblastoma, the most common and malignant primary brain tumor in adults, is a paradigmatic exampleHervé Chneiweiss and Marie-Pierre Junier are co-seniors.Ghislaine Morvan-Dubois and Elias A
We identified changes in the chromatin state of transcription factors, which accompany the passage of GBM stem-like cells from a highly aggressive to a poorly tumorigenic state
We uncovered a novel transcription factor controlling glioblastoma cell tumorigenicity, which is localized at a node of a transcription factor network controlling glioblastoma cell aggressiveness, and which clusters with a tumorigenic/stem signature of glioblastoma cells at both tissue and single cell levels

Summary

Introduction

The most common and malignant primary brain tumor in adults, is a paradigmatic exampleHervé Chneiweiss and Marie-Pierre Junier are co-seniors.Ghislaine Morvan-Dubois and Elias A. Extended author information available on the last page of the article of heterogeneous tumors [11, 49, 54, 64]. This heterogeneity stems from clonal selection of genomic and phenotypic variants, which arises from the accumulation of mutations and from dynamic changes in cell states [27, 28]. Understanding the basis for this heterogeneity is of importance to efficiently target pivotal tumor cells, especially in glioblastoma that exhibits a dismal prognosis despite aggressive therapies

Methods

Results

Conclusion