Polycomb group (PcG) proteins repress homeotic (Hox) gene expression in specific embryonic regions of mammals but the molecular mechanism of this control is poorly understood. Fujimura and co-workers now report that, in mouse embryos, class 2 PcG components (which bind to DNA regulatory sequences)form complexes of different compositions to control spatial Hoxb8expression (shown in blue). The researchers on p. 2371 reveal that PcG protein binding and histone modifications around Hoxb8 are different in tissues that do and do not express Hoxb8. In particular, they show that the binding near Hoxb8 of a class 2 PcG complex that contains the E3 ubiquitin ligase Rnf2, together with trimethylation of histone H3,which marks inactive chromatin, correlates with transcriptional silencing of Hoxb8. Genetic impairment of Suz12 (a class 1 PcG protein that trimethylates histone tails) and of Rnf2 produces Hox gene derepression. Thus,interactions between class 1 and class 2 PcG proteins maintain repression of Hox genes outside their expression domains in mice, as in Drosophila.