EZH2 Regulates the Developmental Timing of Effectors of the Pre–Antigen Receptor Checkpoints

Abstract

The histone methyltransferase EZH2 is required for B and T cell development; however, the molecular mechanisms underlying this requirement remain elusive. In a murine model of lymphoid-specific EZH2 deficiency we found that EZH2 was required for proper development of adaptive, but not innate, lymphoid cells. In adaptive lymphoid cells EZH2 prevented the premature expression of <i>Cdkn2a</i> and the consequent stabilization of p53, an effector of the pre-Ag receptor checkpoints. Deletion of <i>Cdkn2a</i> in EZH2-deficient lymphocytes prevented p53 stabilization, extended lymphocyte survival, and restored differentiation resulting in the generation of mature B and T lymphocytes. Our results uncover a crucial role for EZH2 in adaptive lymphocytes to control the developmental timing of effectors of the pre-Ag receptor checkpoints.