Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation
Copyright policy )Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation
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.
- University of Groningen Netherlands
- University of Copenhagen Denmark
- University of Copenhagen Denmark
- University Medical Center Groningen Netherlands
EXPRESSION, GROUP PROTEINS, Chromatin Immunoprecipitation, Ubiquitin-Protein Ligases, Messenger, Blotting, Western, CLONAL ANALYSIS, Polycomb-Group Proteins, Apoptosis, Inbred C57BL, Small Interfering, MOUSE, Real-Time Polymerase Chain Reaction, Mitochondrial Membrane Transport Proteins, Ligases, Experimental, Mice, GROUP GENES, Inbred DBA, Animals, RNA, Messenger, INK4A-ARF LOCUS, RNA, Small Interfering, LIFE-SPAN, Cell Proliferation, Polycomb Repressive Complex 1, Leukemia, Leukemia, Experimental, Blotting, Reverse Transcriptase Polymerase Chain Reaction, PROLIFERATION, CHIP-SEQ, Cell Differentiation, Flow Cytometry, Hematopoietic Stem Cells, Survival Rate, Mice, Inbred C57BL, SENESCENCE, Mice, Inbred DBA, RNA, Western
EXPRESSION, GROUP PROTEINS, Chromatin Immunoprecipitation, Ubiquitin-Protein Ligases, Messenger, Blotting, Western, CLONAL ANALYSIS, Polycomb-Group Proteins, Apoptosis, Inbred C57BL, Small Interfering, MOUSE, Real-Time Polymerase Chain Reaction, Mitochondrial Membrane Transport Proteins, Ligases, Experimental, Mice, GROUP GENES, Inbred DBA, Animals, RNA, Messenger, INK4A-ARF LOCUS, RNA, Small Interfering, LIFE-SPAN, Cell Proliferation, Polycomb Repressive Complex 1, Leukemia, Leukemia, Experimental, Blotting, Reverse Transcriptase Polymerase Chain Reaction, PROLIFERATION, CHIP-SEQ, Cell Differentiation, Flow Cytometry, Hematopoietic Stem Cells, Survival Rate, Mice, Inbred C57BL, SENESCENCE, Mice, Inbred DBA, RNA, Western
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