Single-cell epigenetic analysis reveals principles of chromatin states in H3.3-K27M gliomas

Nofar Harpaz, Tamir Mittelman, Olga Beresh, Ofir Griess, Noa Furth, Tomer Meir Salame, Roni Oren, Liat Fellus-Alyagor, Alon Harmelin, Sanda Alexandrescu, Joana Graca Marques, Mariella G. Filbin, Guy Ron, Efrat Shema*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Cancer cells are highly heterogeneous at the transcriptional level and epigenetic state. Methods to study epigenetic heterogeneity are limited in throughput and information obtained per cell. Here, we adapted cytometry by time-of-flight (CyTOF) to analyze a wide panel of histone modifications in primary tumor-derived lines of diffused intrinsic pontine glioma (DIPG). DIPG is a lethal glioma, driven by a histone H3 lysine 27 mutation (H3-K27M). We identified two epigenetically distinct subpopulations in DIPG, reflecting inherent heterogeneity in expression of the mutant histone. These two subpopulations are robust across tumor lines derived from different patients and show differential proliferation capacity and expression of stem cell and differentiation markers. Moreover, we demonstrate the use of these high-dimensional data to elucidate potential interactions between histone modifications and epigenetic alterations during the cell cycle. Our work establishes new concepts for the analysis of epigenetic heterogeneity in cancer that could be applied to diverse biological systems.

Original languageAmerican English
Pages (from-to)2696-2713.e9
JournalMolecular Cell
Volume82
Issue number14
DOIs
StatePublished - 21 Jul 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • CyTOF
  • DIPG
  • H3-K27M
  • cancer heterogeneity
  • chromatin
  • epigenetic heterogeneity
  • glioma
  • histone modifications
  • oncohistone
  • single-cell

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