EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition - Sorbonne Université Access content directly
Journal Articles Nature Communications Year : 2024

EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition

Laia Richart
  • Function : relator_co_first_author
Samuel Le Cam

Abstract

Mutations in chromatin regulators are widespread in cancer. Among them, the histone H3 lysine 27 methyltransferase Polycomb Repressive Complex 2 (PRC2) shows distinct alterations according to tumor type. This specificity is poorly understood. Here, we model several PRC2 alterations in one isogenic system to reveal their comparative effects. Focusing then on lymphoma-associated EZH2 mutations, we show that Ezh2 Y641F induces aberrant H3K27 methylation patterns even without wild-type Ezh2 , which are alleviated by partial PRC2 inhibition. Remarkably, Ezh2 Y641F rewires the response to PRC2 inhibition, leading to induction of antigen presentation genes. Using a unique longitudinal follicular lymphoma cohort, we further link EZH2 status to abnormal H3K27 methylation. We also uncover unexpected variability in the mutational landscape of successive biopsies, pointing to frequent co-existence of different clones and cautioning against stratifying patients based on single sampling. Our results clarify how oncogenic PRC2 mutations disrupt chromatin and transcription, and the therapeutic vulnerabilities this creates.

Domains

Cancer
Fichier principal
Vignette du fichier
Romero_Richart_2024.pdf (13.26 Mo) Télécharger le fichier
Origin Publication funded by an institution

Dates and versions

hal-04561230 , version 1 (26-04-2024)

Identifiers

Cite

Pierre Romero, Laia Richart, Setareh Aflaki, Ambre Petitalot, Megan Burton, et al.. EZH2 mutations in follicular lymphoma distort H3K27me3 profiles and alter transcriptional responses to PRC2 inhibition. Nature Communications, 2024, 15 (1), pp.3452. ⟨10.1038/s41467-024-47701-x⟩. ⟨hal-04561230⟩
7 View
3 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More