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PMID:18448678

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Citation

Gao, X, Tate, P, Hu, P, Tjian, R, Skarnes, WC and Wang, Z (2008) ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a. Proc. Natl. Acad. Sci. U.S.A. 105:6656-61

Abstract

ATP-dependent chromatin remodeling complexes are a notable group of epigenetic modifiers that use the energy of ATP hydrolysis to change the structure of chromatin, thereby altering its accessibility to nuclear factors. BAF250a (ARID1a) is a unique and defining subunit of the BAF chromatin remodeling complex with the potential to facilitate chromosome alterations critical during development. Our studies show that ablation of BAF250a in early mouse embryos results in developmental arrest (about embryonic day 6.5) and absence of the mesodermal layer, indicating its critical role in early germ-layer formation. Moreover, BAF250a deficiency compromises ES cell pluripotency, severely inhibits self-renewal, and promotes differentiation into primitive endoderm-like cells under normal feeder-free culture conditions. Interestingly, this phenotype can be partially rescued by the presence of embryonic fibroblast cells. DNA microarray, immunostaining, and RNA analyses revealed that BAF250a-mediated chromatin remodeling contributes to the proper expression of numerous genes involved in ES cell self-renewal, including Sox2, Utf1, and Oct4. Furthermore, the pluripotency defects in BAF250a mutant ES cells appear to be cell lineage-specific. For example, embryoid body-based analyses demonstrated that BAF250a-ablated stem cells are defective in differentiating into fully functional mesoderm-derived cardiomyocytes and adipocytes but are capable of differentiating into ectoderm-derived neurons. Our results suggest that BAF250a is a key component of the gene regulatory machinery in ES cells controlling self-renewal, differentiation, and cell lineage decisions.

Links

PubMed PMC2373334 Online version:10.1073/pnas.0801802105

Keywords

Adipocytes/cytology; Animals; Cell Differentiation; Cell Line; Cell Lineage; Cell Proliferation; Chromatin Assembly and Disassembly/genetics; Chromosomal Proteins, Non-Histone/metabolism; DNA-Binding Proteins/metabolism; Embryo, Mammalian/cytology; Embryo, Mammalian/metabolism; Embryonic Development; Embryonic Stem Cells/cytology; Female; Genes, Developmental; Germ Layers/cytology; Germ Layers/embryology; Male; Mice; Mice, Knockout; Muscle, Skeletal/cytology; Myocytes, Cardiac/cytology; Nuclear Proteins/metabolism; Pluripotent Stem Cells/cytology; Transcription Factors/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ARI1A

involved_in

GO:0019827: stem cell population maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3796520

P

Seeded From UniProt

complete

MOUSE:ARI1A

involved_in

GO:0007566: embryo implantation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3796520

P

Seeded From UniProt

complete

MOUSE:ARI1A

involved_in

GO:0006338: chromatin remodeling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3796520

P

Seeded From UniProt

complete

MOUSE:ARI1A

involved_in

GO:0007369: gastrulation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3796520

P

Seeded From UniProt

complete

MOUSE:ARI1A

involved_in

GO:0001704: formation of primary germ layer

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3796520

P

Seeded From UniProt

complete

MOUSE:PO5F1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SOX2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:UTF1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NANOG

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:PO5F1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SOX2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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