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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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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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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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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DOI: https://doi.org/10.1038/ncb2701
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