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

Cancer Discov. 2017 Mar;7(3):288-301. doi: 10.1158/2159-8290.CD-16-0844. Epub 2017 Feb 17.

Abstract

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.

MeSH terms

  • 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 Stem Cells / physiology
  • NIMA-Related Kinases / genetics
  • NIMA-Related Kinases / metabolism
  • Otx Transcription Factors / genetics*
  • Otx Transcription Factors / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • NEUROD1 protein, human
  • OTX2 protein, human
  • Otx Transcription Factors
  • NEK2 protein, human
  • NIMA-Related Kinases