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
Affiliations
Huadie Liu
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Ye Liu
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Seung-Gi Jin
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
Jennifer Johnson
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
Hongwen Xuan
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
Di Lu
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Jianshuang Li
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Lukai Zhai
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Xianfeng Li
Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Yaguang Zhao
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA; Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Minmin Liu
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
Sonya E.L. Craig
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Joseph S. Floramo
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Vladimir Molchanov
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Jie Li
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA
Jia-Da Li
Hunan International Scientific and Technological Cooperation Base of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, Hunan 410078, China
Connie Krawczyk
Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI 49503, USA
Xiaobing Shi
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
Gerd P. Pfeifer
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA
Tao Yang
Department of Cell Biology, Van Andel Institute, Grand Rapids, MI 49503, USA; Corresponding author
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.
