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 Cdkn2a and the consequent stabilization of p53, an effector of the pre-antigen receptor checkpoints. Deletion of Cdkn2a 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-antigen receptor checkpoints.

EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody-Secreting Cell Metabolism and Antibody Production

“…Following tamoxifen treatment, we observed genomic rearrangement of the Ezh2 locus in splenic B cells and a significant reduction in Ezh2 transcripts and protein was observed (Supplemental Figure 1C-E). Ezh2 is essential for B cell development (26, 51); however, it is dispensable for peripheral B cell homeostasis (26). Consistent with previous findings, following tamoxifen induced deletion of Ezh2 , a block in B cell development at the pre-B stage was observed (Supplemental Figure 1F).…”

Polycomb repressive complex 2 is a critical mediator of allergic inflammation

“…This effect may be due to global destabilization of H3K27me3-dependent heterochromatin, which may affect cell viability as the genome is placed in a unique position of stress through the process of rapid and massive clonal expansion (33). Alternatively, loss of PRC2 function may cause dysregulated transcription of key target genes such as Cdkn2a, a known target of Ezh2 in multiple cell types (34) that is involved in the stabilization of p53 regulating cell cycle progression (35), and furthermore has been shown to regulate lymphoid cell survival (36). These effects on dividing T cells might somewhat blunt adaptive responses; however, innate responses would likely remain intact.…”

BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis

“…Some TFs important for B lymphopoiesis, including E2A, Pax, and STAT5, can modulate enhancer accessibility through the recruitment of histone modifying and remodeling complexes 11 , 26 , 27 . Furthermore, EZH2, which generates H3K27me3, plays important roles in both repressing Igk accessibility 11 and regulating p53 28 . Recruitment of the RAG proteins, and assembly of the recombination center 2 , requires H3K4me3.…”