VGLL4 promotes osteoblast differentiation by antagonizing TEADs-inhibited Runx2 transcription.
VGLL4 promotes osteoblast differentiation by antagonizing TEADs-inhibited Runx2 transcription.
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VGLL4通过拮抗TEADs抑制的Runx2转录促进成骨细胞分化
DOI：
10.1126/sciadv.aba4147
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发表时间：
2020-10
期刊：
影响因子：
13.6
通讯作者：
Zou W
中科院分区：
文献类型：
--
作者：
Suo J;Feng X;Li J;Wang J;Wang Z;Zhang L;Zou W
VGLL4 通过损害 TEADs-RUNX2 相互作用来缓解 TEADs 介导的 RUNX2 转录抑制。 VGLL4 已被鉴定为 YAP 抑制剂。然而，VGLL4 在骨发育和骨稳态中的确切功能仍不清楚。在这项研究中，我们证明VGLL4打破了TEADs介导的RUNX2转录抑制，从而促进成骨细胞分化和骨发育。我们发现间充质干细胞和前成骨细胞中 VGLL4 的敲除显示出骨质疏松症和由于成骨细胞分化障碍导致的锁骨颅骨发育不良样表型。从机制上讲，我们发现 TEAD 转录因子以不依赖 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 转录活性。此外，VGLL4 通过其两个 TDU 结构域直接与 RUNX2 竞争结合 TEAD，从而减轻了 TEAD 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发育中发挥重要作用，而 TEAD 调节 RUNX2 的转录活性，这可能为锁骨颅骨发育不良和骨质疏松症的治疗提供线索。
VGLL4 relieves TEADs-mediated RUNX2 transcriptional inhibition by impairing TEADs-RUNX2 interaction. 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.
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