Cell Reports (Jan 2023)

TRIM28 secures skeletal stem cell fate during skeletogenesis by silencing neural gene expression and repressing GREM1/AKT/mTOR signaling axis

  • Huadie Liu,
  • Ye Liu,
  • Seung-Gi Jin,
  • Jennifer Johnson,
  • Hongwen Xuan,
  • Di Lu,
  • Jianshuang Li,
  • Lukai Zhai,
  • Xianfeng Li,
  • Yaguang Zhao,
  • Minmin Liu,
  • Sonya E.L. Craig,
  • Joseph S. Floramo,
  • Vladimir Molchanov,
  • Jie Li,
  • Jia-Da Li,
  • Connie Krawczyk,
  • Xiaobing Shi,
  • Gerd P. Pfeifer,
  • Tao Yang

Journal volume & issue
Vol. 42, no. 1
p. 112012

Abstract

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Summary: Long bones are generated by mesoderm-derived skeletal progenitor/stem cells (SSCs) through endochondral ossification, a process of sequential chondrogenic and osteogenic differentiation tightly controlled by the synergy between intrinsic and microenvironment cues. Here, we report that loss of TRIM28, a transcriptional corepressor, in mesoderm-derived cells expands the SSC pool, weakens SSC osteochondrogenic potential, and endows SSCs with properties of ectoderm-derived neural crest cells (NCCs), leading to severe defects of skeletogenesis. TRIM28 preferentially enhances H3K9 trimethylation and DNA methylation on chromatin regions more accessible in NCCs; loss of this silencing upregulates neural gene expression and enhances neurogenic potential. Moreover, TRIM28 loss causes hyperexpression of GREM1, which is an extracellular signaling factor promoting SSC self-renewal and SSC neurogenic potential by activating AKT/mTORC1 signaling. Our results suggest that TRIM28-mediated chromatin silencing establishes a barrier for maintaining the SSC lineage trajectory and preventing a transition to ectodermal fate by regulating both intrinsic and microenvironment cues.

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