Bmi1 confers resistance to oxidative stress on hematopoietic stem cells
Shunsuke Nakamura, Motohiko Oshima, Jin Yuan, Atsunori Saraya, Satoru Miyagi, Takaaki Konuma, Satoshi Yamazaki, Mitsujiro Osawa, Hiromitsu Nakauchi, Haruhiko Koseki, Atsushi Iwama, Shunsuke Nakamura, Motohiko Oshima, Jin Yuan, Atsunori Saraya, Satoru Miyagi, Takaaki Konuma, Satoshi Yamazaki, Mitsujiro Osawa, Hiromitsu Nakauchi, Haruhiko Koseki, Atsushi Iwama
Abstract
Background: The polycomb-group (PcG) proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC) 1, maintained self-renewing hematopoietic stem cells (HSCs) during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed.
Methodology/principal findings: In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26Stop(FL)Bmi1). Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26Stop(FL)Bmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS).
Conclusions/significance: Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Simon JA, Kingston RE. Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol. 2009;10:697–708.
- Iwama A, Oguro H, Negishi M, Kato Y, Nakauchi H. Epigenetic regulation of hematopoietic stem cell self-renewal by polycomb group genes. Int J Hematol. 2005;81:294–300.
- Konuma T, Oguro H, Iwama A. Role of the polycomb group proteins in hematopoietic stem cells. Dev Growth Differ. 2010;52:505–516.
- Sauvageau M, Sauvageau G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell. 2010;7:299–313.
- Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature. 2003;423:255–260.
- Park IK, Qian D, Kiel M, Becker MW, Pihalja M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003;423:302–305.
- Iwama A, Oguro H, Negishi M, Kato Y, Morita Y, et al. Enhanced self-renewal of hematopoietic stem cells mediated by the polycomb gene product Bmi-1. Immunity. 2004;21:843–851.
- Oguro H, Iwama A, Morita Y, Kamijo T, van Lohuizen M, et al. Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice. J Exp Med. 2006;203:2247–2253.
- Oguro H, Yuan J, Ichikawa H, Ikawa T, Yamazaki S, et al. Poised lineage specification in multipotent hematopoietic stem and progenitor cells by the polycomb protein Bmi1. Cell Stem Cell. 2010;6:279–286.
- Mihara K, Chowdhury M, Nakaju N, Hidani S, Ihara A, et al. Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis. Blood. 2006;107:305–308.
- Rizo A, Horton SJ, Olthof S, Dontje B, Ausema A, et al. BMI1 collaborates with BCR-ABL in leukemic transformation of human CD34+ cells. Blood. 2010;116:4621–4630.
- Kisanuki YY, Hammer RE, Miyazaki J, Williams SC, Richardson JA, et al. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev Biol. 2001;230:230–242.
- Takano H, Ema H, Sudo K, Nakauchi H. Asymmetric division and lineage commitment at the level of hematopoietic stem cells: inference from differentiation in daughter cell and granddaughter cell pairs. J Exp Med. 2004;199:295–302.
- Ema H, Takano H, Sudo K, Nakauchi H. In vitro self-renewal division of hematopoietic stem cells. J Exp Med. 2000;192:1281–1288.
- Shima H, Takubo K, Iwasaki H, Yoshihara H, Gomei Y, et al. Reconstitution activity of hypoxic cultured human cord blood CD34-positive cells in NOG mice. Biochem Biophys Res Commun. 2009;378:467–472.
- Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12:446–451.
- Yahata T, Takanashi T, Muguruma Y, Ibrahim AA, Matsuzawa H, et al. Accumulation of oxidative DNA damage restricts the self-renewal capacity of human hematopoietic stem cells. Blood. 2011;118:2941–2950.
- Rossi DJ, Jamieson CH, Weissman IL. Stems cells and the pathways to aging and cancer. Cell. 2008;132:681–696.
- Chagraoui J, Hébert J, Girard S, Sauvageau G. An anticlastogenic function for the Polycomb Group gene Bmi1. Proc Natl Acad Sci USA. 2011;108:5284–5289.
- Ginjala V, Nacerddine K, Kulkarni A, Oza J, Hill SJ, et al. BMI1 is recruited to DNA breaks and contributes to DNA damage-induced H2A ubiquitination and repair. Mol Cell Biol. 2011;31:1972–1982.
- Facchino S, Abdouh M, Chatoo W, Bernier G. BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery. J Neurosci. 2010;30:10096–10111.
- Shao L, Li H, Pazhanisamy SK, Meng A, Wang Y, et al. Reactive oxygen species and hematopoietic stem cell senescence. Int J Hematol. 2010;94:24–32.
- Jang YY, Sharkis SJ. A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood. 2007;110:3056–3063.
- Liu J, Liu C, Chen J, Song S, Lee IH, et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature. 2009;459:387–392.
- Rizo A, Olthof S, Han L, Vellenga E, de Haan G, et al. Repression of BMI1 in normal and leukemic human CD34+ cells impairs self-renewal and induces apoptosis. Blood. 2009;114:1498–1505.
- Owusu-Ansah E, Banerjee U. Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature. 2009;461:537–541.
- Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, et al. The polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev. 2007;21:525–530.
- Negishi M, Saraya A, Mochizuki S, Helin K, Koseki H, et al. A novel zinc finger protein Zfp277 mediates transcriptional repression of the Ink4a/Arf locus through polycomb repressive complex 1. PLoS One. 2010;5:e12373.
- Kamminga LM, Bystrykh LV, de Boer A, Houwer S, Douma J, et al. The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion. Blood. 2006;107:2170–2179.
- Stapels M, Piper C, Yang T, Li M, Stowell C, et al. Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance. Sci Signal. 2010;3:ra15.
- Bracken AP, Helin K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer. 2009;9:773–784.
- Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458:780–783.
- Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, et al. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood. 2011;118:2830–2839.
- Sasaki Y, Derudder E, Hobeika E, Pelanda R, Reth M, et al. Canonical NF-kappaB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity. 2006;24:729–739.
- Fukamachi H, Fukuda K, Suzuki M, Furumoto T, Ichinose M, et al. Mesenchymal transcription factor Fkh6 is essential for the development and differentiation of parietal cells. Biochem Biophys Res Commun. 2001;280:1069–1076.
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