EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains.

Détails

ID Serval
serval:BIB_32717C0BB8B8
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains.
Périodique
Nature genetics
Auteur(s)
Donaldson-Collier M.C., Sungalee S., Zufferey M., Tavernari D., Katanayeva N., Battistello E., Mina M., Douglass K.M., Rey T., Raynaud F., Manley S., Ciriello G., Oricchio E.
ISSN
1546-1718 (Electronic)
ISSN-L
1061-4036
Statut éditorial
Publié
Date de publication
03/2019
Peer-reviewed
Oui
Volume
51
Numéro
3
Pages
517-528
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Chromatin is organized into topologically associating domains (TADs) enriched in distinct histone marks. In cancer, gain-of-function mutations in the gene encoding the enhancer of zeste homolog 2 protein (EZH2) lead to a genome-wide increase in histone-3 Lys27 trimethylation (H3K27me3) associated with transcriptional repression. However, the effects of these epigenetic changes on the structure and function of chromatin domains have not been explored. Here, we found a functional interplay between TADs and epigenetic and transcriptional changes mediated by mutated EZH2. Altered EZH2 (p.Tyr646* (EZH2 <sup>Y646X</sup> )) led to silencing of entire domains, synergistically inactivating multiple tumor suppressors. Intra-TAD gene silencing was coupled with changes of interactions between gene promoter regions. Notably, gene expression and chromatin interactions were restored by pharmacological inhibition of EZH2 <sup>Y646X</sup> . Our results indicate that EZH2 <sup>Y646X</sup> alters the topology and function of chromatin domains to promote synergistic oncogenic programs.
Mots-clé
Animals, Cell Line, Tumor, Chromatin/genetics, DNA Methylation/genetics, Enhancer of Zeste Homolog 2 Protein/genetics, Epigenesis, Genetic/genetics, Epigenomics/methods, Gene Expression Regulation, Neoplastic/genetics, Gene Silencing/physiology, Histones/genetics, Humans, Mice, Mutation/genetics, Promoter Regions, Genetic/genetics, Transcription, Genetic/genetics
Pubmed
Web of science
Création de la notice
14/03/2019 8:36
Dernière modification de la notice
20/08/2019 13:18
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