The SUMO-Specific Isopeptidase SENP3 Regulates MLL1/MLL2 Methyltransferase Complexes and Controls Osteogenic Differentiation

• The SUMO-specific isopeptidase SENP3 is associated with SET1/MLL complexes
• SENP3 regulates the recruitment of Ash2L and menin to distinct HOX genes
• This controls expression of selected HOX genes, like the osteogenic factor DLX3
• The SENP3-SET1/MLL axis is required for osteogenic differentiation

SummaryThe ubiquitin-like SUMO system regulates gene expression, but the molecular insights into this process are incomplete. We show that the SUMO-specific isopeptidase SENP3 controls H3K4 methylation by regulating histone-modifying SET1/MLL complexes. SET1/MLL complexes are composed of a histone methyltransferase and the regulatory components WDR5, RbBP5, Ash2L, and DPY-30. MLL1/MLL2 complexes contain menin as additional component and are particularly important for the activation of HOX genes. We demonstrate that SENP3 is associated with MLL1/MLL2 complexes and catalyzes deSUMOylation of RbBP5. This is required for activation of a subset of HOX genes, including the developmental regulator DLX3. In the absence of SENP3, the association of menin and Ash2L with the DLX3 gene is impaired, leading to decreased H3K4 methylation and reduced recruitment of active RNA polymerase II. Importantly, the SENP3-DLX3 pathway dictates osteogenic differentiation of human stem cells, thus delineating the importance of balanced SUMOylation for epigenetic control of gene expression programs.

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