title: Loss of Asxl1 Alters Self-Renewal and Cell Fate of Bone Marrow Stromal Cell, Leading to Bohring-Opitz-like Syndrome in Mice.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Key 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, China.
authors.forename: Caihong
authors.initials: C
authors.lastname: Xing
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rhodes
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Deng
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Zhaomin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Fuhong
authors.initials: F
authors.lastname: He
authors.affiliation: Key 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, China.
authors.forename: Caiying
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Lihn
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: 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, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: wangqf@big.ac.cn.
authors.forename: Qian-Fei
authors.initials: QF
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA. Electronic address: fxy37@med.miami.edu.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D049109:Cell Proliferation; D003398:Craniosynostoses / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D005816:Genetic Complementation Test; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D061251:Primary Cell Culture; D012097:Repressor Proteins / Q000172:deficiency / Q000235:genetics*; D017423:Sequence Analysis, RNA; D014161:Transduction, Genetic
chemical_list: C510915:Asxl1 protein, mouse; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D012097:Repressor Proteins
keywords: ASXL1 mutation; Bohring-Opitz syndrome; bone marrow stromal cell; self-renewal and differentiation; skeletal development