OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma.

Détails

ID Serval
serval:BIB_22D17126749C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma.
Périodique
Cancer discovery
Auteur(s)
Boulay G., Awad M.E., Riggi N., Archer T.C., Iyer S., Boonseng W.E., Rossetti N.E., Naigles B., Rengarajan S., Volorio A., Kim J.C., Mesirov J.P., Tamayo P., Pomeroy S.L., Aryee M.J., Rivera M.N.
ISSN
2159-8290 (Electronic)
ISSN-L
2159-8274
Statut éditorial
Publié
Date de publication
03/2017
Peer-reviewed
Oui
Volume
7
Numéro
3
Pages
288-301
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Medulloblastoma is the most frequent malignant pediatric brain tumor and is divided into at least four subgroups known as WNT, SHH, Group 3, and Group 4. Here, we characterized gene regulation mechanisms in the most aggressive subtype, Group 3 tumors, through genome-wide chromatin and expression profiling. Our results show that most active distal sites in these tumors are occupied by the transcription factor OTX2. Highly active OTX2-bound enhancers are often arranged as clusters of adjacent peaks and are also bound by the transcription factor NEUROD1. These sites are responsive to OTX2 and NEUROD1 knockdown and could also be generated de novo upon ectopic OTX2 expression in primary cells, showing that OTX2 cooperates with NEUROD1 and plays a major role in maintaining and possibly establishing regulatory elements as a pioneer factor. Among OTX2 target genes, we identified the kinase NEK2, whose knockdown and pharmacologic inhibition decreased cell viability. Our studies thus show that OTX2 controls the regulatory landscape of Group 3 medulloblastoma through cooperative activity at enhancer elements and contributes to the expression of critical target genes.Significance: The gene regulation mechanisms that drive medulloblastoma are not well understood. Using chromatin profiling, we find that the transcription factor OTX2 acts as a pioneer factor and, in cooperation with NEUROD1, controls the Group 3 medulloblastoma active enhancer landscape. OTX2 itself or its target genes, including the mitotic kinase NEK2, represent attractive targets for future therapies. Cancer Discov; 7(3); 288-301. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 235.

Mots-clé
Basic Helix-Loop-Helix Transcription Factors/genetics, Basic Helix-Loop-Helix Transcription Factors/metabolism, Cell Line, Tumor, Cell Survival/genetics, Cerebellar Neoplasms/genetics, Cerebellar Neoplasms/pathology, Chromatin/genetics, Chromatin/metabolism, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Humans, Medulloblastoma/genetics, Medulloblastoma/pathology, Mesenchymal Stromal Cells/physiology, NIMA-Related Kinases/genetics, NIMA-Related Kinases/metabolism, Otx Transcription Factors/genetics, Otx Transcription Factors/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/02/2017 19:21
Dernière modification de la notice
20/08/2019 13:00
Données d'usage