The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primate Research Center and Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
Chinese Institute for Brain Research, Beijing 102206, China.
Cells. 2022 Apr 25;11(9):1450. doi: 10.3390/cells11091450.
ASH2L and DPY30 are important for the assembly and catalytic activity of the complex associated with SET1 (COMPASS), which catalyzes histone methylation and regulates gene expression. However, the regulations among COMPASS components are not fully understood. Here, we leveraged a mouse model and cell lines to observe the outcome of Ash2l depletion and found a significant decrease in DPY30. Analyzing ASH2L ChIP-seq and RNA-seq data excluded transcriptional and translational regulation of ASH2L to DPY30. The decrease in DPY30 was further attributed to the degradation via the ubiquitin-mediated proteasomal pathway. We also verified that three amino acids in the ASH2L Sdc1 DPY30 interaction (SDI) domain are essential for the recognition and binding of DPY30. Lastly, we unexpectedly observed that overexpression of DPY30 in Ash2l-depleted cells rescued the decrease in Ccnd1 and the abnormal cell cycle, which indicates that DPY30 can participate in other complexes to regulate gene expression. Overall, our results, for the first time, reveal that the existence of DPY30 relies on the binding with ASH2L, with degradation of DPY30 via the ubiquitin-proteasome system, and they further indicate that the function of DPY30 can be independent of ASH2L.
ASH2L 和 DPY30 对于与 SET1（COMPASS）相关的复合物的组装和催化活性很重要，该复合物催化组蛋白甲基化并调节基因表达。然而，COMPASS 成分之间的调控机制尚不完全清楚。在这里，我们利用小鼠模型和细胞系观察到 Ash2l 耗竭的结果，并发现 DPY30 显著减少。分析 ASH2L ChIP-seq 和 RNA-seq 数据排除了 ASH2L 对 DPY30 的转录和翻译调控。DPY30 的减少进一步归因于通过泛素介导的蛋白酶体途径进行降解。我们还验证了 ASH2L Sdc1 DPY30 相互作用（SDI）结构域中的三个氨基酸对于 DPY30 的识别和结合是必需的。最后，我们意外地观察到在 Ash2l 耗竭细胞中过表达 DPY30 可以挽救 Ccnd1 的减少和异常的细胞周期，这表明 DPY30 可以参与其他复合物来调节基因表达。总的来说，我们的结果首次揭示了 DPY30 的存在依赖于与 ASH2L 的结合，通过泛素-蛋白酶体系统降解 DPY30，并且进一步表明 DPY30 的功能可以独立于 ASH2L。
