Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity

被引：89

作者：

Majewski, Ian J. ^{[1
,2
]}

Blewitt, Marnie E. ^{[1
]}

de Graaf, Carolyn A. ^{[1
,2
]}

McManus, Edward J. ^{[1
]}

Bahlo, Melanie ^{[1
]}

Hilton, Adrienne A. ^{[1
]}

Hyland, Craig D. ^{[1
]}

Smyth, Gordon K. ^{[1
]}

Corbin, Jason E. ^{[1
]}

Metcalf, Donald ^{[1
]}

Alexander, Warren S. ^{[1
,2
]}

Hilton, Douglas J. ^{[1
,2
]}

机构：

[1] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia

[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia

来源：

PLOS BIOLOGY | 2008年 / 6卷 / 04期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1371/journal.pbio.0060093

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Polycomb group proteins are transcriptional repressors that play a central role in the establishment and maintenance of gene expression patterns during development. Using mice with an N-ethyl-N-nitrosourea ( ENU)-induced mutation in Suppressor of Zeste 12 ( Suz12), a core component of Polycomb Repressive Complex 2 ( PRC2), we show here that loss of Suz12 function enhances hematopoietic stem cell ( HSC) activity. In addition to these effects on a wild-type genetic background, mutations in Suz12 are sufficient to ameliorate the stem cell defect and thrombocytopenia present in mice that lack the thrombopoietin receptor ( c-Mpl). To investigate the molecular targets of the PRC2 complex in the HSC compartment, we examined changes in global patterns of gene expression in cells deficient in Suz12. We identified a distinct set of genes that are regulated by Suz12 in hematopoietic cells, including eight genes that appear to be highly responsive to PRC2 function within this compartment. These data suggest that PRC2 is required to maintain a specific gene expression pattern in hematopoiesis that is indispensable to normal stem cell function.

引用

页码：796 / 809

页数：14

共 68 条

[31] Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin [J].

Kimura, S ;

Roberts, AW ;

Metcalf, D ;

Alexander, WS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (03) :1195-1200

[32] Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27 [J].

Kirmizis, A ;

Bartley, SM ;

Kuzmichev, A ;

Margueron, R ;

Reinberg, D ;

Green, R ;

Farnham, PJ .

GENES & DEVELOPMENT, 2004, 18 (13) :1592-1605

[33]

Kirmizis A, 2003, MOL CANCER THER, V2, P113

[34] Composition and histone substrates of polycomb repressive group complexes change during cellular differentiation [J].

Kuzmichev, A ;

Margueron, R ;

Vaquero, A ;

Preissner, TS ;

Scher, M ;

Kirmizis, A ;

Ougang, XS ;

Brockdorff, N ;

Abate-Shen, C ;

Farnham, P ;

Reinberg, D .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (06) :1859-1864

[35] Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein [J].

Kuzmichev, A ;

Nishioka, K ;

Erdjument-Bromage, H ;

Tempst, P ;

Reinberg, D .

GENES & DEVELOPMENT, 2002, 16 (22) :2893-2905

[36] Control of developmental regulator's by polycomb in human embryonic stem cells [J].

Lee, TI ;

Jenner, RG ;

Boyer, LA ;

Guenther, MG ;

Levine, SS ;

Kumar, RM ;

Chevalier, B ;

Johnstone, SE ;

Cole, MF ;

Isono, K ;

Koseki, H ;

Fuchikami, T ;

Abe, K ;

Murray, HL ;

Zucker, JP ;

Yuan, BB ;

Bell, GW ;

Herbolsheimer, E ;

Hannett, NM ;

Sun, KM ;

Odom, DT ;

Otte, AP ;

Volkert, TL ;

Bartel, DP ;

Melton, DA ;

Gifford, DK ;

Jaenisch, R ;

Young, RA .

CELL, 2006, 125 (02) :301-313

[37] Functional antagonism of the Polycomb-Group genes eed and Bmi1 in hemopoietic cell proliferation [J].

Lessard, J ;

Schumacher, A ;

Thorsteinsdottir, U ;

van Lohuizen, M ;

Magnuson, T ;

Sauvageau, G .

GENES & DEVELOPMENT, 1999, 13 (20) :2691-2703

[38] Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells [J].

Lessard, J ;

Sauvageau, G .

NATURE, 2003, 423 (6937) :255-260

[39] Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method [J].

Livak, KJ ;

Schmittgen, TD .

METHODS, 2001, 25 (04) :402-408

[40] CLONING AND EXPRESSION OF MURINE THROMBOPOIETIN CDNA AND STIMULATION OF PLATELET PRODUCTION IN-VIVO [J].

LOK, S ;

KAUSHANSKY, K ;

HOLLY, RD ;

KUIJPER, JL ;

LOFTONDAY, CE ;

OORT, PJ ;

GRANT, FJ ;

HEIPEL, MD ;

BURKHEAD, SK ;

KRAMER, JM ;

BELL, LA ;

SPRECHER, CA ;

BLUMBERG, H ;

JOHNSON, R ;

PRUNKARD, D ;

CHING, AFT ;

MATHEWES, SL ;

BAILEY, MC ;

FORSTROM, JW ;

BUDDLE, MM ;

OSBORN, SG ;

EVANS, SJ ;

SHEPPARD, PO ;

PRESNELL, SR ;

OHARA, PJ ;

HAGEN, FS ;

ROTH, GJ ;

FOSTER, DC .

NATURE, 1994, 369 (6481) :565-568

← 1 2 3 4 5 6 7 →