Format

Send to

Choose Destination
Acta Neuropathol. 2018 Feb;135(2):267-283. doi: 10.1007/s00401-017-1783-x. Epub 2017 Nov 17.

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

Author information

1
CNRS UMR8246, Inserm U1130, Neuroscience Paris Seine-IBPS, UPMC, Sorbonne Universités, Paris, France.
2
CNRS, UMR 8256, Laboratory of Neuronal Cell Biology and Pathology-IBPS, UPMC, Sorbonne Universités, Paris, France.
3
Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles, Brussels, Belgium.
4
UMRS-1126, Université Paris Diderot, Paris 7, Institut Universitaire d'Hématologie, EPHE, Paris, France.
5
CNRS UMR7277, INSERM U1091, Institut de Biologie Valrose, Université Nice-Sophia Antipolis, Université côte d'azur Nice, Nice, France.
6
Laboratoire Central d'Anatomie Pathologique, Hôpital Pasteur, Université Nice-Sophia Antipolis, Nice, France.
7
MGX-Montpellier GenomiX, c/o Institut de Génomique Fonctionnelle, Université Montpellier, Montpellier, France.
8
Plateforme Vecteurs Viraux et Transfert de Gènes, Université Paris Descartes-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, 75014, Paris, France.
9
Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, 75013, Paris, France.
10
Laboratoire d'Excellence Medalis, Université de Strasbourg, CNRS, LIT UMR 7200, Strasbourg, France.
11
Pharmacogenomics Unit, Department of Genetics, Institut Curie Hospital, 75005, Paris, France.
12
CNRS UMR8246, Inserm U1130, Neuroscience Paris Seine-IBPS, UPMC, Sorbonne Universités, Paris, France. herve.chneiweiss@inserm.fr.
13
CNRS UMR8246, Inserm U1130, Neuroscience Paris Seine-IBPS, UPMC, Sorbonne Universités, Paris, France. marie-pierre.junier@inserm.fr.

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.

KEYWORDS:

Brain cancer; ChIP; Glioma; Xenograft

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center