| ES cell cycle progression and differentiation require the action of the histone methyltransferase Dot1L. | |
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MedLine Citation:
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PMID: 19544450 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mouse embryonic stem cells (ESCs) proliferate with rapid cell cycle kinetics but without loss of pluripotency. The histone methyltransferase Dot1L is responsible for methylation of histone H3 at lysine 79 (H3K79me). We investigated whether ESCs require Dot1L for proper stem cell behavior. ESCs deficient in Dot1L tolerate a nearly complete loss of H3K79 methylation without a substantial impact on proliferation or morphology. However, shortly after differentiation is induced, Dot1L-deficient cells cease proliferating and arrest in G2/M-phase of the cell cycle, with increased levels of aneuploidy. In addition, many aberrant mitotic spindles occur in Dot1L-deficient cells. Surprisingly, these mitotic and cell cycle defects fail to trigger apoptosis, indicating that mouse ESCs lack stringent cell cycle checkpoint control during initial stages of differentiation. Transcriptome analysis indicates that Dot1L deficiency causes the misregulation of a select set of genes, including many with known roles in cell cycle control and cellular proliferation as well as markers of endoderm differentiation. The data indicate a requirement for Dot1L function for early stages of ESC differentiation where Dot1L is necessary for faithful execution of mitosis and proper transcription of many genes throughout the genome. |
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Authors:
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Evan R Barry; Winfried Krueger; Caroline M Jakuba; Eric Veilleux; Dominic J Ambrosi; Craig E Nelson; Theodore P Rasmussen |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Stem cells (Dayton, Ohio) Volume: 27 ISSN: 1549-4918 ISO Abbreviation: Stem Cells Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-08-03 Completed Date: 2009-10-30 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9304532 Medline TA: Stem Cells Country: United States |
Other Details:
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Languages: eng Pagination: 1538-47 Citation Subset: IM |
Affiliation:
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Center for Regenerative Biology, University of Connecticut, Storrs, Connecticut 06269-4243, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / genetics, physiology* Cell Cycle / genetics, physiology* Cell Differentiation / genetics, physiology* Cell Proliferation Chromatin Immunoprecipitation Embryonic Stem Cells / cytology*, metabolism* Karyotyping Methyltransferases / genetics, physiology* Mice Polymerase Chain Reaction RNA Interference |
| Grant Support | |
ID/Acronym/Agency:
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R01AG23687/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
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EC 2.1.1.-/Dot1l protein, mouse; EC 2.1.1.-/Methyltransferases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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