Loss of Asxl1 Alters Mesenchymal Stem Cell Fate through H3K4me3
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Caiying Zhu
PROVIDER: E-GEOD-75788 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood fatality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models,we found that Asxl1 global loss or conditional deletion in osteoblasts and their progenitors in mice leads to significant bone loss and markedly decreased numbers of marrow mesenchymal stem/progenitor cells (MSPCs) compared with wild-type (WT) littermates. Asxl1-/- MSPCs displayed impaired self-renewal and skewed differentiation-away from osteoblasts and favoring adipocytes. RNA-seq analysis reveals the altered expression of genes involved in cell proliferation, skeletal development and morphogenesis. Furthermore, gene set enrichment analysis showed a decreased gene expression of stem cell self-renewal signature,suggesting the role of Asxl1 in regulating the stemness of MSPCs. Importantly, introducing Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1-/- MSPCs. Our study unveils a pivotal role of ASXL1 in maintenance of MSPC functions and skeletal development. Examination of mRNA profiles in wild type and Asxl1-/- MSPCs by deep sequencing
2016-06-30 | E-GEOD-75787 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-07-01 | GSE75788 | GEO
Project description:De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome (BOS), a disease with severe developmental defects and early childhood fatality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss or conditional deletion in osteoblasts and their progenitors in mice leads to significant bone loss and markedly decreased numbers of marrow mesenchymal stem/progenitor cells (MSPCs) compared with wild-type (WT) littermates. Asxl1 null MSPCs display impaired self-renewal and skewed differentiation from osteoblasts towards adipocytes. ChIP-seq data identified that ASXL1 and H3K4me3 co-occupy the promoter regions of genes critical for MSPC self-renewal. Loss of Asxl1 diminished the genome enrichment of H3K4me3. Combined analysis of RNA-seq and ChIP-seq data revealed that Asxl1 loss in MSPCs altered the expression of ASXL1/H3K4me3 target genes controlling self-renewal/lineage commitment. Our study unveil a pivotal role of ASXL1 in H3K4me3-associated bone homeostasis
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Project description:Mesenchymal stem cells (MSC) resemble a multipotent adult stem cell population capable of differentiation into a number of different mesodermal cell types including adipodytes, osteoblasts, chondroblasts. Although still in debate there is some evidence, that these cells can also differentiate into cells of non-mesodermal germal layers including hepatocytes, myocytes, cardiomyocytes or neurons. Analysis of these cells in the course of differentiation makes them an intriguing model for the examination of stemness. More importantly the differentiation capacity of MSC raises high hopes for clinical applications. In this study we have isolated MSC from bone marrow under two different culture conditions, from adipose tissue and from umbilical cord blood. The genome wide gene expression profile of these different human MSC was compared with reference RNA of non-multipotent human fibroblasts HS68. The aim of this study was to elucidate common molecular characteristics of MSC as well as differences in their expression profile. These results might help for a better understanding of MSC and contribute to a reliable quality control that will be necessary for clinical applications.
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Project description:Loss of Asxl1 Alters Mesenchymal Stem Cell Fate through H3K4me3
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