Loss of Asxl1 alters self-renewal and cell fate of bone marrow stromal cell, leading to bohring-opitz-like syndrome in mice Academic Article uri icon

Overview

MeSH Major

  • DNA Methylation
  • DNA-Binding Proteins
  • Isocitrate Dehydrogenase
  • Leukemia, Myeloid, Acute
  • Mutation
  • Myeloid Cells
  • Proto-Oncogene Proteins

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.

publication date

  • June 14, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4911496

Digital Object Identifier (DOI)

  • 10.1016/j.stemcr.2016.04.013

PubMed ID

  • 27237378

Additional Document Info

start page

  • 914

end page

  • 25

volume

  • 6

number

  • 6