The Polycomb Group Gene Ezh2 Prevents Hematopoietic Stem Cell Exhaustion

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2005 Nov 19

PMID 16293602

Citations 178

Authors

Leonie M Kamminga

Leonid V Bystrykh

Aletta de Boer

Sita Houwer

Jose Douma

Ellen Weersing

Bert Dontje

Gerald de Haan

Affiliations

Soon will be listed here.

Abstract

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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References

Trevisan M, Iscove N . Phenotypic analysis of murine long-term hemopoietic reconstituting cells quantitated competitively in vivo and comparison with more advanced colony-forming progeny. J Exp Med. 1995; 181(1):93-103. PMC: 2191852. DOI: 10.1084/jem.181.1.93. View

de Haan G, Bystrykh L, Weersing E, Dontje B, Geiger H, Ivanova N . A genetic and genomic analysis identifies a cluster of genes associated with hematopoietic cell turnover. Blood. 2002; 100(6):2056-62. DOI: 10.1182/blood-2002-03-0808. View

Pirrotta V . Chromatin complexes regulating gene expression in Drosophila. Curr Opin Genet Dev. 1995; 5(4):466-72. DOI: 10.1016/0959-437x(95)90050-q. View

Morrison S, Uchida N, Weissman I . The biology of hematopoietic stem cells. Annu Rev Cell Dev Biol. 1995; 11:35-71. DOI: 10.1146/annurev.cb.11.110195.000343. View

Morrison S, Wandycz A, Akashi K, Globerson A, Weissman I . The aging of hematopoietic stem cells. Nat Med. 1996; 2(9):1011-6. DOI: 10.1038/nm0996-1011. View

de Haan G, Nijhof W, Van Zant G . Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity. Blood. 1997; 89(5):1543-50. View

Gardner R, Astle C, Harrison D . Hematopoietic precursor cell exhaustion is a cause of proliferative defect in primitive hematopoietic stem cells (PHSC) after chemotherapy. Exp Hematol. 1997; 25(6):495-501. View

de Haan G, Van Zant G . Intrinsic and extrinsic control of hemopoietic stem cell numbers: mapping of a stem cell gene. J Exp Med. 1997; 186(4):529-36. PMC: 2199035. DOI: 10.1084/jem.186.4.529. View

Villeponteau B . The heterochromatin loss model of aging. Exp Gerontol. 1997; 32(4-5):383-94. DOI: 10.1016/s0531-5565(96)00155-6. View

10.

Lessard J, Baban S, Sauvageau G . Stage-specific expression of polycomb group genes in human bone marrow cells. Blood. 1998; 91(4):1216-24. View

11.

Sewalt R, van der Vlag J, Gunster M, Hamer K, den Blaauwen J, Satijn D . Characterization of interactions between the mammalian polycomb-group proteins Enx1/EZH2 and EED suggests the existence of different mammalian polycomb-group protein complexes. Mol Cell Biol. 1998; 18(6):3586-95. PMC: 108940. DOI: 10.1128/MCB.18.6.3586. View

12.

Jacobs J, Kieboom K, Marino S, DePinho R, van Lohuizen M . The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 1999; 397(6715):164-8. DOI: 10.1038/16476. View

13.

Todaro G, Green H . Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines. J Cell Biol. 1963; 17:299-313. PMC: 2106200. DOI: 10.1083/jcb.17.2.299. View

14.

Hayflick L . THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS. Exp Cell Res. 1965; 37:614-36. DOI: 10.1016/0014-4827(65)90211-9. View

15.

Strahl B, Allis C . The language of covalent histone modifications. Nature. 2000; 403(6765):41-5. DOI: 10.1038/47412. View

16.

Chen J, Astle C, Harrison D . Genetic regulation of primitive hematopoietic stem cell senescence. Exp Hematol. 2000; 28(4):442-50. DOI: 10.1016/s0301-472x(99)00157-5. View

17.

Fukuyama T, Otsuka T, Shigematsu H, Uchida N, Arima F, Ohno Y . Proliferative involvement of ENX-1, a putative human polycomb group gene, in haematopoietic cells. Br J Haematol. 2000; 108(4):842-7. DOI: 10.1046/j.1365-2141.2000.01914.x. View

18.

Raaphorst F, van Kemenade F, Blokzijl T, Fieret E, Hamer K, Satijn D . Coexpression of BMI-1 and EZH2 polycomb group genes in Reed-Sternberg cells of Hodgkin's disease. Am J Pathol. 2000; 157(3):709-15. PMC: 1885707. DOI: 10.1016/S0002-9440(10)64583-X. View

19.

Kamminga L, Akkerman I, Weersing E, Ausema A, Dontje B, Van Zant G . Autonomous behavior of hematopoietic stem cells. Exp Hematol. 2001; 28(12):1451-9. DOI: 10.1016/s0301-472x(00)00543-9. View

20.

Varambally S, Dhanasekaran S, Zhou M, Barrette T, Kumar-Sinha C, Sanda M . The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002; 419(6907):624-9. DOI: 10.1038/nature01075. View