Zhang, PengXing, CaihongRhodes, Steven D.He, YongzhengDeng, KaiLi, ZhaominHe, FuhongZhu, CaiyingNguyen, LihnZhou, YuanChen, ShiMohammad, Khalid S.Guise, Theresa A.Abdel-Wahab, OmarXu, MingjiangWang, Qian-FeiYang, Feng-Chun2017-04-122017-04-122016-06-14Zhang, P., Xing, C., Rhodes, S. D., He, Y., Deng, K., Li, Z., … Yang, F.-C. (2016). 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, 6(6), 914–925. http://doi.org/10.1016/j.stemcr.2016.04.0132213-6711https://hdl.handle.net/1805/12250De 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalASXL1 mutationBohring-Opitz syndromebone marrow stromal cellself-renewal and differentiationskeletal developmentArticle