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

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2019 Oct 8

PMID 31588023

Citations 85

Authors

Surya Nagaraja

Michael A Quezada

Shawn M Gillespie

Marlene Arzt

James J Lennon

Pamelyn J Woo

Volker Hovestadt

Madhuri Kambhampati

Mariella G Filbin

Mario L Suva

Javad Nazarian

Michelle Monje

Affiliations

Soon will be listed here.

Abstract

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.

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