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

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^Cip1). 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

SUBMITTER: Beguelin W 

PROVIDER: S-EPMC5638898 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature