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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2170-2179. Prepublished online as a Blood First Edition Paper on November 17, 2005; DOI 10.1182/blood-2005-09-3585. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: 2005-09-3585v1 107/5/2170    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kamminga, L. M. Articles by de Haan, G. Search for Related Content PubMed PubMed Citation Articles by Kamminga, L. M. Articles by de Haan, G. Related Collections Hematopoiesis and Stem Cells Stem Cells in Hematology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  STEM CELLS IN HEMATOLOGY The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion Leonie M. Kamminga, Leonid V. Bystrykh, Aletta de Boer, Sita Houwer, José Douma, Ellen Weersing, Bert Dontje, and Gerald de Haan From the Department of Cell Biology, Section Stem Cell Biology, University Medical Center Groningen, University of Groningen, The Netherlands. The molecular mechanism responsible for a decline of stem cell functioning after replicative stress remains unknown. We used mouse embryonic fibroblasts (MEFs) and hematopoietic stem cells (HSCs) to identify genes involved in the process of cellular aging. In proliferating and senescent MEFs one of the most differentially expressed transcripts was Enhancer of zeste homolog 2 (Ezh2), a Polycomb group protein (PcG) involved in histone methylation and deacetylation. Retroviral overexpression of Ezh2 in MEFs resulted in bypassing of the senescence program. More importantly, whereas normal HSCs were rapidly exhausted after serial transplantations, overexpression of Ezh2 completely conserved long-term repopulating potential. Animals that were reconstituted with 3 times serially transplanted control bone marrow cells all died due to hematopoietic failure. In contrast, similarly transplanted Ezh2-overexpressing stem cells restored stem cell quality to normal levels. In a "genetic genomics" screen, we identified novel putative Ezh2 target or partner stem cell genes that are associated with chromatin modification. Our data suggest that stabilization of the chromatin structure preserves HSC potential after replicative stress. 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