Journal Article

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

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

2019

Overview

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.

• Publisher: Springer Nature B.V
• Subject: Brain cancer / Brain tumors / Gene expression / Glioma / Histone H3 / Latency / Mutation / Nervous system / Phenotypes / Promoters / Therapeutic applications / Transcription / Xenografts