The group of Stefan Müller unraveled a novel facet of SUMO-regulated gene expression. They discovered that the SUMO-specific isopeptidase SENP3 is needed for proper activity of histone-modifying MLL1/2 complexes. Removal of SUMO2/3 from the MLL1/2 subunit RbBP5 is required for the activation of a subset of HOX genes, including the regulator of osteogenic differentiation DLX3. The importance of this pathway for cell differentiation was demonstrated in a human stem cell model.  The paper by Nayak et al. was published online in Molecular Cell on June, 12.