Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice

Peng Zhang, Caihong Xing, Steven D. Rhodes, Yongzheng He, Kai Deng, Zhaomin Li, Fuhong He, Caiying Zhu, Lihn Nguyen, Yuan Zhou, Shi Chen, Khalid S. Mohammad, Theresa A. Guise, Omar Abdel-Wahab, Mingjiang Xu, Qian Fei Wang, Feng-Chun Yang

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood mortality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss as well as conditional deletion in osteoblasts and their progenitors led to significant bone loss and a markedly decreased number of bone marrow stromal cells (BMSCs) compared with wild-type littermates. Asxl1 -/- BMSCs displayed impaired self-renewal and skewed differentiation, away from osteoblasts and favoring adipocytes. RNA-sequencing analysis revealed altered expression of genes involved in cell proliferation, skeletal development, and morphogenesis. Furthermore, gene set enrichment analysis showed decreased expression of stem cell self-renewal gene signature, suggesting a role of Asxl1 in regulating the stemness of BMSCs. Importantly, re-introduction of Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1 -/- BMSCs. Our study unveils a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development. In this article, Yang, Wang, and colleagues show that loss of Asxl1 led to multiple skeletal developmental defects, closely reminiscent of Bohring-Opitz syndrome. They identified that the skeletal defects were associated with an impaired self-renewal and skewed lineage commitment of bone marrow stromal cells (BMSCs). These findings indicate a pivotal role of ASXL1 in the maintenance of BMSC functions and skeletal development.

Original languageEnglish (US)
JournalStem Cell Reports
DOIs
StateAccepted/In press - Jan 26 2016

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Keywords

  • ASXL1 mutation
  • Bohring-Opitz syndrome
  • Bone marrow stromal cell
  • Self-renewal and differentiation
  • Skeletal development

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Developmental Biology
  • Genetics

Cite this

Zhang, P., Xing, C., Rhodes, S. D., He, Y., Deng, K., Li, Z., He, F., Zhu, C., Nguyen, L., Zhou, Y., Chen, S., Mohammad, K. S., Guise, T. A., Abdel-Wahab, O., Xu, M., Wang, Q. F., & Yang, F-C. (Accepted/In press). Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice. Stem Cell Reports. https://doi.org/10.1016/j.stemcr.2016.04.013