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

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 and Yannick Jacob ()
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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
Francisca N. Luna Vitorino: Washington University School of Medicine
Devisree Valsakumar: University of Edinburgh
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
Philipp Voigt: Babraham Institute
Yannick Jacob: Faculty of Arts and Sciences, Yale University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58892-2

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