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

Overview

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 (p21Cip1). 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.

publication date

  • October 12, 2017

Research

keywords

  • Cyclin-Dependent Kinase Inhibitor p21
  • E2F1 Transcription Factor
  • Enhancer of Zeste Homolog 2 Protein
  • Germinal Center

Identity

PubMed Central ID

  • PMC5638898

Scopus Document Identifier

  • 85031291005

Digital Object Identifier (DOI)

  • 10.1038/nature11606

PubMed ID

  • 29026085

Additional Document Info

volume

  • 8

issue

  • 1