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Acta Neuropathologica

, Volume 137, Issue 4, pp 637–655 | Cite as

H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo

  • André B. Silveira
  • Lawryn H. Kasper
  • Yiping Fan
  • Hongjian Jin
  • Gang Wu
  • Timothy I. Shaw
  • Xiaoyan Zhu
  • Jon D. Larson
  • John Easton
  • Ying Shao
  • Donald A. Yergeau
  • Celeste Rosencrance
  • Kristy Boggs
  • Michael C. Rusch
  • Liang Ding
  • Junyuan Zhang
  • David Finkelstein
  • Rachel M. Noyes
  • Brent L. Russell
  • Beisi Xu
  • Alberto Broniscer
  • Cynthia Wetmore
  • Stanley B. Pounds
  • David W. Ellison
  • Jinghui Zhang
  • Suzanne J. BakerEmail author
Original Paper

Abstract

Histone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Comparisons of matched DIPG xenografts with and without K27M knockdown allowed identification of mutation-specific effects on the transcriptome and epigenome. The resulting transcriptional changes recapitulate expression signatures from K27M primary DIPG tumors and are strongly enriched for genes associated with nervous system development. Integrated analysis of ChIP-seq and expression data showed that genes upregulated by the mutation are overrepresented in apparently bivalent promoters. Many of these targets are associated with more immature differentiation states. Expression profiles indicate K27M knockdown decreases proliferation and increases differentiation within lineages represented in DIPG. These data suggest that K27M-mediated loss of H3K27me3 directly regulates a subset of genes by releasing poised promoters, and contributes to tumor phenotype and growth by limiting differentiation. The delayed tumor growth associated with knockdown of H3 K27M provides evidence that this highly recurrent mutation is a relevant therapeutic target.

Keywords

Histone H3K27M DIPG Glioma Epigenetic H3K27me3 Bivalent Oncohistone Isogenic knockdown Differentiation Stemness 

Notes

Acknowledgements

We thank Michelle Monje for sharing SUDIPG-VI cells. Surgeries and preclinical imaging were performed by the Center for In Vivo Imaging and Therapeutics which is supported by SJCRH and NCI grants P30CA021765 and R50CA211481. This work was supported by NIH grants CA096832 and CA188516 (SJB), R25CA23944 (RMN), the NCI Cancer Center Support Grant CA21765, the St Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project, and ALSAC.

Author contributions

Conceptualization: ABS, LHK, and SJB. Methodology: ABS, LHK, XZ, JDL, and SJB. Software: MCR and LD. Formal analysis: ABS, LHK, YF, HJ, GW, TIS, DF, BX, and SBP. Investigation and validation: ABS, LHK, XZ, JDL, JE, YS, DAY, CR, KB, JZ, RMN, and BLR. Resources: AB and CW. Data curation: ABS, LHK, YF, HJ, and GW. Writing—original draft: ABS, LHK, and SJB. Writing—review and editing: ABS, LHK, SJB, GW, HJ, JE, and DWE. Visualization: ABS, LHK, HJ, GW, TIS, and DF. Supervision: SJB, JE, SBP, DWE, and JZ. Funding acquisition: SJB and JZ.

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.

Supplementary material

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Supplementary material 1 (DOCX 14 kb)
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Supplementary material 2 (PDF 4525 kb)
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Supplementary material 3 (XLSX 273 kb)
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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • André B. Silveira
    • 1
  • Lawryn H. Kasper
    • 1
  • Yiping Fan
    • 2
  • Hongjian Jin
    • 2
  • Gang Wu
    • 2
  • Timothy I. Shaw
    • 2
  • Xiaoyan Zhu
    • 1
  • Jon D. Larson
    • 1
  • John Easton
    • 2
  • Ying Shao
    • 2
  • Donald A. Yergeau
    • 2
  • Celeste Rosencrance
    • 2
  • Kristy Boggs
    • 2
  • Michael C. Rusch
    • 2
  • Liang Ding
    • 2
  • Junyuan Zhang
    • 1
  • David Finkelstein
    • 2
  • Rachel M. Noyes
    • 1
  • Brent L. Russell
    • 1
  • Beisi Xu
    • 2
  • Alberto Broniscer
    • 5
  • Cynthia Wetmore
    • 6
  • Stanley B. Pounds
    • 3
  • David W. Ellison
    • 4
  • Jinghui Zhang
    • 2
  • Suzanne J. Baker
    • 1
    Email author
  1. 1.Department of Developmental NeurobiologySt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Department of Computational BiologySt. Jude Children’s Research HospitalMemphisUSA
  3. 3.Department of BiostatisticsSt. Jude Children’s Research HospitalMemphisUSA
  4. 4.Department of PathologySt. Jude Children’s Research HospitalMemphisUSA
  5. 5.Department of PediatricsUPMC Children’s Hospital of PittsburghPittsburghUSA
  6. 6.Center for Cancer and Blood DisordersPhoenix Children’s HospitalPhoenixUSA

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