title: Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation.
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.
authors.affiliation: 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.
authors.forename: Karin
authors.initials: K
authors.lastname: Klauke
authors.forename: Višnja
authors.initials: V
authors.lastname: Radulović
authors.forename: Mathilde
authors.initials: M
authors.lastname: Broekhuis
authors.forename: Ellen
authors.initials: E
authors.lastname: Weersing
authors.forename: Erik
authors.initials: E
authors.lastname: Zwart
authors.forename: Sandra
authors.initials: S
authors.lastname: Olthof
authors.forename: Martha
authors.initials: M
authors.lastname: Ritsema
authors.forename: Sophia
authors.initials: S
authors.lastname: Bruggeman
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.forename: Leonid
authors.initials: L
authors.lastname: Bystrykh
authors.forename: Gerald
authors.initials: G
authors.lastname: de Haan
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002454:Cell Differentiation; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D007942:Leukemia, Experimental / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D008025:Ligases; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D033681:Mitochondrial Membrane Transport Proteins; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C570426:Cbx2 protein, mouse; C519505:Cbx7 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C570429:Cbx8 protein, mouse; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C570504:Cbx4 protein, mouse