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

TY - JOUR

T1 - Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation

AU - Klauke, Karin

AU - Radulović, Višnja

AU - Broekhuis, Mathilde

AU - Weersing, Ellen

AU - Zwart, Erik

AU - Olthof, Sandra

AU - Ritsema, Martha

AU - Bruggeman, Sophia

AU - Wu, Xudong

AU - Helin, Kristian

AU - Bystrykh, Leonid

AU - de Haan, Gerald

PY - 2013/4

Y1 - 2013/4

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Blotting, Western

KW - Cell Differentiation

KW - Cell Proliferation

KW - Chromatin Immunoprecipitation

KW - Flow Cytometry

KW - Hematopoietic Stem Cells

KW - Leukemia, Experimental

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred DBA

KW - Polycomb Repressive Complex 1

KW - Polycomb-Group Proteins

KW - RNA, Messenger

KW - RNA, Small Interfering

KW - Real-Time Polymerase Chain Reaction

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Survival Rate

KW - Ubiquitin-Protein Ligases

U2 - 10.1038/ncb2701

DO - 10.1038/ncb2701

M3 - Journal article

C2 - 23502315

SN - 1465-7392

VL - 15

SP - 353

EP - 362

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 4

ER -