Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in Mice
Summary: 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 c...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-06-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671116300388 |
| _version_ | 1819181498450837504 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Peng Zhang |
| collection | DOAJ |
| description | Summary: 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. Keywords: Bohring-Opitz syndrome, ASXL1 mutation, bone marrow stromal cell, self-renewal and differentiation, skeletal development |
| first_indexed | 2024-12-22T22:31:11Z |
| format | Article |
| id | doaj.art-a8fd63481cbe4c84b5d14195c86a0d88 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-22T22:31:11Z |
| publishDate | 2016-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-a8fd63481cbe4c84b5d14195c86a0d882022-12-21T18:10:26ZengElsevierStem Cell Reports2213-67112016-06-0166914925Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in MicePeng Zhang0Caihong Xing1Steven D. Rhodes2Yongzheng He3Kai Deng4Zhaomin Li5Fuhong He6Caiying Zhu7Lihn Nguyen8Yuan Zhou9Shi Chen10Khalid S. Mohammad11Theresa A. Guise12Omar Abdel-Wahab13Mingjiang Xu14Qian-Fei Wang15Feng-Chun Yang16Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USAKey Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, ChinaHerman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USAHerman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USAKey Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, ChinaKey Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, ChinaHerman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USAState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, ChinaDepartment of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USADepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USAHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USADepartment of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USAKey Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; Corresponding authorDepartment of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Corresponding authorSummary: 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. Keywords: Bohring-Opitz syndrome, ASXL1 mutation, bone marrow stromal cell, self-renewal and differentiation, skeletal developmenthttp://www.sciencedirect.com/science/article/pii/S2213671116300388 |
| spellingShingle | 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 Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in Mice Stem Cell Reports |
| title | Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in Mice |
| title_full | Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in Mice |
| title_fullStr | Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in Mice |
| title_full_unstemmed | Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in Mice |
| title_short | Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cells, Leading to Bohring-Opitz-like Syndrome in Mice |
| title_sort | loss of asxl1 alters self renewal and cell fate of bone marrow stromal cells leading to bohring opitz like syndrome in mice |
| url | http://www.sciencedirect.com/science/article/pii/S2213671116300388 |
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