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

Karin Klauke; Višnja Radulović; Mathilde Broekhuis; Ellen Weersing; Erik Zwart; Sandra Olthof; Martha Ritsema; Sophia Bruggeman; Xudong Wu; Kristian Helin; Leonid Bystrykh; Gerald de Haan

doi:10.1038/ncb2701

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

Nat Cell Biol. 2013 Apr;15(4):353-62. doi: 10.1038/ncb2701. Epub 2013 Mar 17.

Authors

Karin Klauke¹, Višnja Radulović, Mathilde Broekhuis, Ellen Weersing, Erik Zwart, Sandra Olthof, Martha Ritsema, Sophia Bruggeman, Xudong Wu, Kristian Helin, Leonid Bystrykh, Gerald de Haan

Affiliation

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.

PMID: 23502315
DOI: 10.1038/ncb2701

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Blotting, Western
Cell Differentiation*
Cell Proliferation*
Chromatin Immunoprecipitation
Flow Cytometry
Hematopoietic Stem Cells / cytology*
Hematopoietic Stem Cells / metabolism
Leukemia, Experimental / etiology
Leukemia, Experimental / mortality
Leukemia, Experimental / pathology*
Ligases
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mitochondrial Membrane Transport Proteins
Polycomb Repressive Complex 1 / antagonists & inhibitors
Polycomb Repressive Complex 1 / genetics
Polycomb Repressive Complex 1 / metabolism*
Polycomb-Group Proteins / genetics
Polycomb-Group Proteins / metabolism*
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Survival Rate
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism

Substances

Cbx2 protein, mouse
Cbx7 protein, mouse
Mitochondrial Membrane Transport Proteins
Polycomb-Group Proteins
RNA, Messenger
RNA, Small Interfering
Cbx8 protein, mouse
Polycomb Repressive Complex 1
Ubiquitin-Protein Ligases
Ligases
Cbx4 protein, mouse