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

Cell Rep. 2023 Jan 31;42(1):112012. doi: 10.1016/j.celrep.2023.112012. Epub 2023 Jan 20.


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.

Keywords: CP: Stem cell research; DNA methylation; GREM1; H3K9me3; PI3K-AKT-mTORC1 signaling; chromatin silencing; neural crest cell; self-renewal; transposable elements.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Chromatin
  • Gene Expression
  • Mice
  • Osteogenesis*
  • Proto-Oncogene Proteins c-akt / genetics
  • Signal Transduction
  • Stem Cells
  • TOR Serine-Threonine Kinases / genetics
  • Tripartite Motif-Containing Protein 28* / metabolism


  • Chromatin
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Trim28 protein, mouse
  • Tripartite Motif-Containing Protein 28