EZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop.

TitleEZH2 enables germinal centre formation through epigenetic silencing of CDKN1A and an Rb-E2F1 feedback loop.
Publication TypeJournal Article
Year of Publication2017
AuthorsB├ęguelin W, Rivas MA, Fernandez MTCalvo, Teater M, Purwada A, Redmond D, Shen H, Challman MF, Elemento O, Singh A, Melnick AM
JournalNat Commun
Volume8
Issue1
Pagination877
Date Published2017 10 12
ISSN2041-1723
KeywordsAnimals, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, E2F1 Transcription Factor, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Feedback, Physiological, G1 Phase Cell Cycle Checkpoints, Gene Silencing, Germinal Center, Mice
Abstract

The EZH2 histone methyltransferase is required for B cells to form germinal centers (GC). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A (p21). Deletion of Cdkn1a rescues the GC reaction in Ezh2 mice. Using a 3D B cell follicular organoid system that mimics the GC reaction, we show that depletion of EZH2 suppresses G1 to S phase transition of GC B cells in a Cdkn1a-dependent manner. GC B cells of Cdkn1a Ezh2 mice have high levels of phospho-Rb, indicating that loss of Cdkn1a enables progression of cell cycle. Moreover, the transcription factor E2F1 induces EZH2 during the GC reaction. E2f1 mice manifest impaired GC responses, which is rescued by restoring EZH2 expression, thus defining a positive feedback loop in which EZH2 controls GC B cell proliferation by suppressing CDKN1A, enabling cell cycle progression with a concomitant phosphorylation of Rb and release of E2F1.The histone methyltransferase EZH2 silences genes by generating H3K27me3 marks. Here the authors use a 3D GC organoid and show EZH2 mediates germinal centre (GC) formation through epigenetic silencing of CDKN1A and release of cell cycle checkpoints.

DOI10.1038/s41467-017-01029-x
Alternate JournalNat Commun
PubMed ID29026085
PubMed Central IDPMC5638898
Grant ListR01 CA187109 / CA / NCI NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States
R33 CA212968 / CA / NCI NIH HHS / United States