Model for the different oncogenic roles of EZH2 and BMI1. (a) In normal development, genes such as the INK4a/ARF locus are bound by EZH2, marked by H3K27me3 and bound by BMI1. (b) On oncogene activation (indicated by lightning symbol) such as constitutive Ras or Myc expression, the INK4a/ARF locus becomes expressed as part of a tumour suppressive response. (c) Increased BMI1 expression results in more BMI1 protein binding to known Polycomb group (PcG)-target genes. This prevents activation of these genes even when signals are present that would normally activate these genes. (d) Increased EZH2 expression does not prevent INK4a/ARF activation (although this locus may still be inactivated by other mechanisms). In contrast, the role of EZH2 in tumourigenesis may be due to silencing of genes not normally targeted by PcG or due to methylation of non-histone proteins (indicated by diamond on protein 'X').