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EMBRYONIC STEM CELLS |
aGenome Instability and Chromatin-Remodeling Section and
cDevelopmental Genomics and Aging Section, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA;
bCardiovascular Research Center, Massachusetts General Hospital, Richard B. Simches Research Center, Harvard Medical School, Boston, Massachusetts, USA
Key Words. Chromatin remodeling • Gene targeting • SWI/SNF • Embryonic stem cells • DNA microarray • BAF250B • ARID1B
Correspondence: Weidong Wang, Ph.D., Genome Instability and Chromatin-Remodeling Section, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA. Telephone: 410-558-8334; Fax: 410-558-8331; e-mail: wangw{at}grc.nia.nih.gov or Minoru S. H. Ko, M.D., Ph.D., Developmental Genomics and Aging Section, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA. Telephone: 410-558-8359; Fax: 410-558-8331; e-mail: kom{at}mail.nih.gov
Received October 9, 2007;
accepted for publication February 23, 2008.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS March 6, 2008.
Whether SWI/SNF chromatin remodeling complexes play roles in embryonic stem (ES) cells remains unknown. Here we show that SWI/SNF complexes are present in mouse ES cells, and their composition is dynamically regulated upon induction of ES cell differentiation. For example, the SWI/SNF purified from undifferentiated ES cells contains a high level of BAF155 and a low level of BAF170 (both of which are homologs of yeast SWI3 protein), whereas that from differentiated cells contains nearly equal amounts of both. Moreover, the levels of BAF250A and BAF250B decrease during the differentiation of ES cells, whereas that of BRM increases. The altered expression of SWI/SNF components hinted that these complexes could play roles in ES cell maintenance or differentiation. We therefore generated ES cells with biallelic inactivation of BAF250B and found that these cells display a reduced proliferation rate and an abnormal cell cycle. Importantly, these cells are deficient in the self-renewal capacity of undifferentiated ES cells and exhibit certain phenotypes of differentiated cells, including reduced expression of several pluripotency-related genes and increased expression of some differentiation-related genes. These data suggest that the BAF250B-associated SWI/SNF is essential for mouse ES cells to maintain their normal proliferation and pluripotency. The work presented here underscores the importance of SWI/SNF chromatin remodeling complexes in pluripotent stem cells.
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