Institute of Biochemistry II, Goethe University, Faculty of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Department of Oral and Maxillofacial Surgery, University of Regensburg, 93042 Regensburg, Germany.
Mol Cell. 2014 Jul 3;55(1):47-58. doi: 10.1016/j.molcel.2014.05.011. Epub 2014 Jun 12.
The 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.
类泛素 SUMO 系统调节基因表达，但该过程的分子机制尚不完全清楚。我们发现，SUMO 特异性蛋白酶 SENP3 通过调节组蛋白修饰 SET1/MLL 复合物来控制 H3K4 甲基化。SET1/MLL 复合物由组蛋白甲基转移酶和调节组件 WDR5、RbBP5、Ash2L 和 DPY-30 组成。MLL1/MLL2 复合物包含 menin 作为额外的组分，对于 HOX 基因的激活尤为重要。我们证明 SENP3 与 MLL1/MLL2 复合物相关，并催化 RbBP5 的去 SUMO 化。这对于一组 HOX 基因的激活是必需的，包括发育调节因子 DLX3。在 SENP3 缺失的情况下，menin 和 Ash2L 与 DLX3 基因的结合受损，导致 H3K4 甲基化减少和活性 RNA 聚合酶 II 的募集减少。重要的是，SENP3-DLX3 通路决定了人类干细胞的成骨分化，从而阐明了平衡 SUMO 化对于基因表达程序的表观遗传控制的重要性。
