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

Karin Klauke, Visnja Radulovic, Mathilde Broekhuis, Ellen Weersing, Erik Zwart, Sandra Olthof, Martha Ritsema, Sophia Bruggeman, Xudong Wu, Kristian Helin, Leonid Bystrykh, Gerald de Haan*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

185 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)353-+
Number of pages22
JournalNature Cell Biology
Volume15
Issue number4
DOIs
Publication statusPublished - Apr-2013

Keywords

  • INK4A-ARF LOCUS
  • CLONAL ANALYSIS
  • GROUP PROTEINS
  • GROUP GENES
  • LIFE-SPAN
  • CHIP-SEQ
  • PROLIFERATION
  • MOUSE
  • SENESCENCE
  • EXPRESSION

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