Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State

Development of effective targeted cancer therapies is fundamentally limited by our molecular understanding of disease pathogenesis. Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique substitution to methionine in histone H3 at lysine 27 (H3K...

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Published in:	Molecular cell 2019-12, Vol.76 (6), p.965-980.e12
Main Authors:	Nagaraja, Surya, Quezada, Michael A., Gillespie, Shawn M., Arzt, Marlene, Lennon, James J., Woo, Pamelyn J., Hovestadt, Volker, Kambhampati, Madhuri, Filbin, Mariella G., Suva, Mario L., Nazarian, Javad, Monje, Michelle
Format:	Article
Language:	eng
Subjects:	active enhancers Brain - pathology Brain Neoplasms - genetics Cellular Reprogramming - genetics Diffuse Intrinsic Pontine Glioma - genetics Diffuse Intrinsic Pontine Glioma - metabolism DIPG Enhancer Elements, Genetic - genetics Epigenesis, Genetic - genetics Epigenomics Gene Expression Profiling Gene Expression Regulation, Neoplastic - genetics glioma Glioma - genetics Glioma - metabolism H3.3 H3K27Ac H3K27M H3K27me3 histone variant Histones - genetics Humans Lysine - genetics Mutation - genetics oligodendrocyte precursor cell Pons - metabolism PRC2 Signal Transduction Transcriptome - physiology
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Summary:	Development of effective targeted cancer therapies is fundamentally limited by our molecular understanding of disease pathogenesis. Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique substitution to methionine in histone H3 at lysine 27 (H3K27M) that results in globally altered epigenetic marks and oncogenic transcription. Through primary DIPG tumor characterization and isogenic oncohistone expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending upon both the variant of histone H3 and the cell context in which the mutation occurs. Compared with non-malignant pediatric pontine tissue, we identify and functionally validate both shared and variant-specific pathophysiology. Altogether, we provide a powerful resource of epigenomic data in 25 primary DIPG samples and 5 rare normal pediatric pontine tissue samples, revealing clinically relevant functional distinctions previously unidentified in DIPG. [Display omitted] •H3.3K27M and H3.1K27M DIPG tumors exhibit distinct active enhancer profiles•Extensive chromatin studies in primary H3K27M samples reveal oncogenic signaling•Disparate genomic locations of each H3K27M variant disrupt different PRC2 targets•H3K27M remodeling differs between NPCs and OPCs Diffuse intrinsic pontine glioma is a lethal pediatric brain cancer characterized by H3K27M histone mutation. Nagaraja et al. characterize a large cohort of rare primary tumors and normal pontine tissue to reveal active regulatory element heterogeneity dependent upon the histone variant and cell context in which the mutation occurs.
ISSN:	1097-2765 1097-4164