Suo Jinlong, Feng Xue, Li Jiayi, Wang Jinghui, Wang Zuoyun, Zhang Lei, Zou Weiguo
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai 200031, China.
Department of Laboratory Medicine, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China.
Sci Adv. 2020 Oct 23;6(43). doi: 10.1126/sciadv.aba4147. Print 2020 Oct.
VGLL4 has been identified as a YAP inhibitor. However, the exact function of VGLL4 in bone development and bone homeostasis remains unclear. In this study, we demonstrated that VGLL4 breaks TEADs-mediated transcriptional inhibition of RUNX2 to promote osteoblast differentiation and bone development. We found that knockout of VGLL4 in mesenchymal stem cells and preosteoblasts showed osteoporosis and a cleidocranial dysplasia-like phenotype due to osteoblast differentiation disorders. Mechanistically, we showed that the TEAD transcriptional factors severely inhibited osteoblast differentiation in a YAP binding-independent manner. TEADs interacted with RUNX2 to repress RUNX2 transcriptional activity. Furthermore, VGLL4 relieved the transcriptional inhibition of TEADs by directly competing with RUNX2 to bind TEADs through its two TDU domains. Collectively, our studies demonstrate that VGLL4 plays an important role in regulating osteoblast differentiation and bone development, and that TEADs regulate the transcriptional activity of RUNX2, which may shed light on treatment of cleidocranial dysplasia and osteoporosis.
VGLL4已被确定为一种YAP抑制剂。然而，VGLL4在骨骼发育和骨稳态中的具体功能仍不清楚。在本研究中，我们证明VGLL4打破了TEADs介导的对RUNX2的转录抑制，从而促进成骨细胞分化和骨骼发育。我们发现，间充质干细胞和成骨前体细胞中VGLL4的敲除由于成骨细胞分化障碍而表现出骨质疏松和锁骨颅骨发育不全样表型。从机制上讲，我们表明TEAD转录因子以一种不依赖YAP结合的方式严重抑制成骨细胞分化。TEADs与RUNX2相互作用以抑制RUNX2的转录活性。此外，VGLL4通过其两个TDU结构域与RUNX2直接竞争结合TEADs，从而解除TEADs的转录抑制。总的来说，我们的研究表明VGLL4在调节成骨细胞分化和骨骼发育中起重要作用，并且TEADs调节RUNX2的转录活性，这可能为锁骨颅骨发育不全和骨质疏松的治疗提供线索。
