Polycomb repressive complex 2 (PRC2) suppresses Em-myc lymphoma

Polycomb group (PcG) proteins are global transcriptional repressors first identified in Drosophila as silencers of Hox genes during development. Subsequent genomewide studies showed that PcG proteins regulate genes involved in diverse cellular functions. PcG proteins exist in 2 distinct protein complexes called polycomb repressive complex 1 (PRC1) and 2 (PRC2). Mammalian PRC1 components include Bmi1, Mel18, Cbx2, 4, 7, and 8, Scmh1 and 2, Phc1/Rae28, Phc2 and 3, Ring1A, andRing1B; the complex is highly heterogeneous, and its precise makeup varies depending on the cellular and developmental context. Although Bmi1 is crucial for augmenting PRC1 activity, Ring1B is the enzyme that monoubiquitinates histone H2A at lysine 119 (H2AK119ub), a mark associated with transcriptional repression. PRC2 mediates tri-methylation of histone H3 at lysine 27 (H3K27me3), another repressive mark. The main components in PRC2 are Suz12, Eed, and the enzymatic components Ezh2 and/or Ezh1. Eed and Suz12 are essential for PRC2 complex stability, whereas accessory factors Jarid2, Rbbp4 and 7, Phf1, and Mtf2 are required to modulate PRC2 function. PRC1 and PRC2 interact to control transcriptional activity at target loci. In the hierarchical-recruitment model, PRC2-mediated H3K27me3 recruits PRC1 via the chromodomain of Cbx proteins, leading to H2AK119ub-induced transcriptional silencing. Studies have correlated PRC2 activity and H3K27me3 with PRC1 occupancy at target genes, providing support for a role of PRC2/ H3K27me3 in recruiting PRC1.However, other observations suggest that the hierarchical model may not always hold. For example, PRC1 can bind nucleosomes lacking N-terminal histone tails in vitro and can be recruited to targets in the absence of PRC2. Moreover, mice with a heterozygous loss-of-function mutation in Suz12 display enhanced hematopoietic stem cell (HSC) activity, whereas mice lacking PRC1 components have functionally compromisedHSCs. PcG genes are deregulated in many human cancers. EZH2 and BMI1 are overexpressed in some breast cancers and colon cancers, and increased expression of EZH2 is associated with more aggressive disease in prostate cancers. Discovery of a gain-of-functionmutation in EZH2 in follicular and diffuse large B-cell lymphoma strengthened the argument that PcG genes are oncogenic. Conversely, loss-offunctionmutations and deletions inEZH2, EED, and SUZ12 have been described in myelodysplastic syndromes and T-cell acute lymphoblastic leukemia (T-ALL). This suggests that PRC2 has a tumor suppressor role in specific hematological malignancies, a hypothesis supported in a mouse model whereEzh2 inactivation resulted in T-cell lymphoma. These studies suggest that aberrant PRC2 function contributes to tumorigenesis in a context-dependent manner and emphasize the need to define the underlying mechanisms via which altered PRC2 contributes to disease. Accordingly, we compared and contrasted the contribution of PRC1 and PRC2 to Myc-driven lymphomagenesis and show that, in contrast to PRC1, PRC2 behaves as a tumor suppressor by restricting self-renewal of B-cell progenitors.