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Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation

Nature Cell Biology volume 15, pages 353–362 (2013)Cite this article

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Abstract

The balance between self-renewal and differentiation of adult stem cells is essential for tissue homeostasis. Here we show that in the haematopoietic system this process is governed by polycomb chromobox (Cbx) proteins. Cbx7 is specifically expressed in haematopoietic stem cells (HSCs), and its overexpression enhances self-renewal and induces leukaemia. This effect is dependent on integration into polycomb repressive complex-1 (PRC1) and requires H3K27me3 binding. In contrast, overexpression of Cbx2, Cbx4 or Cbx8 results in differentiation and exhaustion of HSCs. ChIP-sequencing analysis shows that Cbx7 and Cbx8 share most of their targets; we identified approximately 200 differential targets. Whereas genes targeted by Cbx8 are highly expressed in HSCs and become repressed in progenitors, Cbx7 targets show the opposite expression pattern. Thus, Cbx7 preserves HSC self-renewal by repressing progenitor-specific genes. Taken together, the presence of distinct Cbx proteins confers target selectivity to PRC1 and provides a molecular balance between self-renewal and differentiation of HSCs.

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Figure 1: Enforced expression of Cbx genes reveals distinct effects on in vitro progenitor and HSC potential.
Figure 2: Cbx7 induces distinct types of leukaemia, whereas Cbx2, Cbx4 and Cbx8 induce a competitive disadvantage in vivo.
Figure 3: Cbx7 increases the proliferative capacity of purified multipotent haematopoietic subsets.
Figure 4: Cbx7 induces self-renewal of LT-HSCs, ST-HSCs and MPPs, but not of lineage restricted progenitors.
Figure 5: Cbx7 is required for HSPC self-renewal.
Figure 6: Cbx7-induced self-renewal requires PRC1 integration and H3K27me3 binding.
Figure 7: Cbx7 and Cbx8 targets are coordinately regulated during HSC differentiation and show reciprocal expression patterns.

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Acknowledgements

We thank H. Moes, G. Mesander, H. de Bruin and R. J. van der Lei for expert flow cytometry assistance, the entire staff of the Central Animal Facility at the UMCG, K. Magnussen from the National High-throughput Sequencing Centre of the University of Copenhagen, B. Dethmers-Ausema, R. Bron, F. Feringa, K. van der Laan, V. Stojanovska and K. Wakker for laboratory assistance, J. Engelbert for bioinformatical assistance, and B. Dykstra, M. Niemantsverdriet, R. van Os and H. Schepers for valuable scientific discussions. We also acknowledge financial support from the Netherlands Organization for Scientific Research (VICI 918-76-601 and ALW to G.d.H), the Netherlands Institute for Regenerative Medicine, the Dutch Cancer Society (grant 2007-3729, and UMCG-2011-5277 to S.B.) and the European Community (EuroSystem, 200720). The work in the Helin laboratory was supported by the Danish National Research Foundation, the Novo Nordisk Foundation and the Danish Cancer Society.

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  1. European Institute for the Biology of Ageing (ERIBA), Section Ageing Biology and Stem Cells, University Medical Centre Groningen, University of Groningen, Groningen 9700 AD, The Netherlands

    Karin Klauke, Višnja Radulović, Mathilde Broekhuis, Ellen Weersing, Erik Zwart, Sandra Olthof, Martha Ritsema, Sophia Bruggeman, Leonid Bystrykh & Gerald de Haan

  2. Biotech Research and Innovation Centre (BRIC), Centre for Epigenetics and DanStem, University of Copenhagen, Copenhagen 2200, Denmark

    Xudong Wu & Kristian Helin

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Contributions

K.K., L.B., K.H. and G.d.H. initiated research and developed the concept of the paper. K.K., L.B., and G.d.H. designed research; K.K. and V.R. performed experiments with contributions from M.B., E.W., S.O., M.R., S.B. and X.W; E.Z. performed bioinformatics analyses with contributions from L.B. and K.K.; K.K. and L.B. analysed and interpreted data; and K.K. wrote the manuscript with contributions from L.B., K.H. and G.d.H.

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Correspondence to Gerald de Haan.

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Klauke, K., Radulović, V., Broekhuis, M. et al. Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation. Nat Cell Biol 15, 353–362 (2013). https://doi.org/10.1038/ncb2701

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