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Updated: Oct 27, 2025

Isolation and Cultivation of Neural Progenitors Followed by Chromatin-Immunoprecipitation of Histone 3 Lysine 79 Dimethylation Mark
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Simultaneous disruption of PRC2 and enhancer function underlies histone H3.3-K27M oncogenic activity in human

Gerard L Brien1, Raul Bardini Bressan2,3,4, Craig Monger5

  • 1Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland. gbrien@tcd.ie.

Nature Genetics
|July 23, 2021
PubMed

Insights

Histone H3-K27M mutations in pediatric brain tumors disrupt enhancer function and chromatin accessibility. This locks cells in an immature state, driving tumorigenesis by altering epigenetic regulation.

Area of Science:

  • Epigenetics and Molecular Biology
  • Pediatric Oncology
  • Developmental Neurobiology

Background:

  • Driver mutations in histone H3 genes, specifically p.Lys27Met substitutions (H3-K27M), are prevalent in pediatric midline brain tumors.
  • The exact mechanisms by which H3-K27M mutations initiate these tumors are not fully understood.

Purpose of the Study:

  • To model the epigenomic consequences of H3.3-K27M mutations in human hindbrain neural stem cells.
  • To elucidate the role of H3.3-K27M in tumor initiation within a relevant developmental context.

Main Methods:

  • Genome-wide mapping of epitope-tagged wild-type and H3.3-K27M mutant histone incorporation.
  • Analysis of chromatin accessibility, histone modifications (H3K27ac), and gene expression.
  • Assessment of Polycomb repressive complex 2 (PRC2) and PRC1 binding dynamics.

Main Results:

  • H3.3-K27M incorporates at active enhancers and promoters, causing H3K27ac loss, reduced chromatin accessibility, and decreased expression of neurodevelopmental genes.
  • H3.3-K27M deposition at PRC2 target genes increases PRC2 and PRC1 binding, leading to enhanced transcriptional repression.
  • The repressive effects of H3.3-K27M can be partially reversed by PRC2 inhibitors.

Conclusions:

  • H3.3-K27M drives tumorigenesis not by creating new transcriptional programs, but by impairing enhancer function and PRC2 activity.
  • This disruption locks neural stem cells in an immature epigenomic state, contributing to pediatric brain tumor initiation.
  • Targeting PRC2 may offer a therapeutic strategy for H3-K27M-driven pediatric brain tumors.

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