Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation

Benjamin A. Nacev, Yakshi Dabas, Matthew R. Paul, Christian Pacheco, Michelle Mitchener, Yekaterina Perez, Yan Fang, Alexey A. Soshnev, Douglas Barrows, Thomas Carroll, Nicholas D. Socci, Samantha C. St. Jean, Sagarika Tiwari, Michael J. Gruss, Sebastien Monette, William D. Tap, Benjamin A. Garcia, Tom Muir, C. David Allis

Research output: Contribution to journalArticlepeer-review

Abstract

Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, the same mutants recurrently disrupt broad H3K27me3 domains in the chromatin context, including near developmentally regulated promoters. H3K27me3 loss leads to de-repression of differentiation pathways, with concordant effects between H3R2 and H3R26 mutants despite different proximity to the PRC2 substrate, H3K27. Functionally, H3R26C-expressing mesenchymal progenitor cells and murine embryonic stem cell-derived teratomas demonstrate impaired differentiation. Collectively, these data show that cancer-associated H3 N-terminal arginine mutations reduce PRC2 activity and disrupt chromatin-dependent developmental functions, a cancer-relevant phenotype.

Original languageEnglish (US)
Article number5155
JournalNature communications
Volume15
Issue number1
DOIs
StatePublished - Dec 2024

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

Fingerprint

Dive into the research topics of 'Cancer-associated Histone H3 N-terminal arginine mutations disrupt PRC2 activity and impair differentiation'. Together they form a unique fingerprint.

Cite this