title: OTX2 Activity at Distal Regulatory Elements Shapes the Chromatin Landscape of Group 3 Medulloblastoma.
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 toOTX2andNEUROD1knockdown and could also be generatedde novoupon ectopicOTX2expression 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.
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Gaylor
authors.initials: G
authors.lastname: Boulay
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Awad
authors.affiliation: Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nicolo
authors.initials: N
authors.lastname: Riggi
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Tenley C
authors.initials: TC
authors.lastname: Archer
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sowmya
authors.initials: S
authors.lastname: Iyer
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Wannaporn E
authors.initials: WE
authors.lastname: Boonseng
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Nikki E
authors.initials: NE
authors.lastname: Rossetti
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Beverly
authors.initials: B
authors.lastname: Naigles
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Shruthi
authors.initials: S
authors.lastname: Rengarajan
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.|Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Volorio
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: James C
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, Massachusetts.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Pomeroy
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Aryee
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. mnrivera@mgh.harvard.edu.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000502:physiology; D000072379:NIMA-Related Kinases / Q000235:genetics / Q000378:metabolism; D051857:Otx Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D000072379:NIMA-Related Kinases; D051857:Otx Transcription Factors; C093970:NEUROD1 protein, human; C497659:OTX2 protein, human; C089441:NEK2 protein, human