2. Academic Validation
  3. VGLL4 promotes osteoblast differentiation by antagonizing TEADs-inhibited Runx2 transcription

VGLL4 promotes osteoblast differentiation by antagonizing TEADs-inhibited Runx2 transcription

  • Sci Adv. 2020 Oct 23;6(43):eaba4147. doi: 10.1126/sciadv.aba4147.
Jinlong Suo 1,  Xue Feng 1,  Jiayi Li 2,  Jinghui Wang 1,  Zuoyun Wang 3,  Lei Zhang 3 4 5,  Weiguo Zou 3 4 5
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Laboratory Medicine, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, China.
  • 3 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. [email protected] [email protected] [email protected].
  • 4 School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.
  • 5 Bio-Research Innovation Center, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Suzhou 215121, China.
PMID: 33097532 DOI: 10.1126/sciadv.aba4147
Abstract

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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