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H3.1K27M-induced misregulation of the TONSOKU-H3.1 pathway causes genomic instability

Author

Listed:
  • Wenxin Yuan

    (Faculty of Arts and Sciences, Yale University)

  • Yi-Chun Huang

    (Faculty of Arts and Sciences, Yale University)

  • Chantal LeBlanc

    (Faculty of Arts and Sciences, Yale University)

  • Axel Poulet

    (Faculty of Arts and Sciences, Yale University
    Yale School of Medicine
    Yale School of Medicine)

  • Francisca N. Luna Vitorino

    (Washington University School of Medicine)

  • Devisree Valsakumar

    (University of Edinburgh
    Babraham Institute)

  • Renee Dean

    (Washington University School of Medicine)

  • Benjamin A. Garcia

    (Washington University School of Medicine)

  • Josien C. Wolfswinkel

    (Faculty of Arts and Sciences, Yale University
    Yale School of Medicine
    Yale School of Medicine)

  • Philipp Voigt

    (Babraham Institute)

  • Yannick Jacob

    (Faculty of Arts and Sciences, Yale University
    Yale School of Medicine)

Abstract

The oncomutation lysine 27-to-methionine in histone H3 (H3K27M) is frequently identified in tumors of patients with diffuse midline glioma-H3K27 altered (DMG-H3K27a). H3K27M inhibits the deposition of the histone mark H3K27me3, which affects the maintenance of transcriptional programs and cell identity. Cells expressing H3K27M are also characterized by defects in genome integrity, but the mechanisms linking expression of the oncohistone to DNA damage remain mostly unknown. In this study, we demonstrate that expression of H3.1K27M in the model plant Arabidopsis thaliana interferes with post-replicative chromatin maturation mediated by the H3.1K27 methyltransferases ATXR5 and ATXR6. As a result, H3.1 variants on nascent chromatin remain unmethylated at K27 (H3.1K27me0), leading to ectopic activity of TONSOKU (TSK/TONSL), which induces DNA damage and genomic alterations. Elimination of TSK activity suppresses the genome stability defects associated with H3.1K27M expression, while inactivation of specific DNA repair pathways prevents survival of H3.1K27M-expressing plants. Overall, our results suggest that H3.1K27M disrupts the chromatin-based mechanisms regulating TSK activity, which causes genomic instability and may contribute to the etiology of DMG-H3K27a.

Suggested Citation

  • Wenxin Yuan & Yi-Chun Huang & Chantal LeBlanc & Axel Poulet & Francisca N. Luna Vitorino & Devisree Valsakumar & Renee Dean & Benjamin A. Garcia & Josien C. Wolfswinkel & Philipp Voigt & Yannick Jacob, 2025. "H3.1K27M-induced misregulation of the TONSOKU-H3.1 pathway causes genomic instability," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58892-2
    DOI: 10.1038/s41467-025-58892-2
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