Sustained PU.1 Levels Balance Cell-Cycle Regulators to Prevent Exhaustion of Adult Hematopoietic Stem Cells

被引：109

作者：

Staber, Philipp B. ^{[1
,5
,7
]}

Zhang, Pu ^{[1
]}

Ye, Min ^{[1
]}

Welner, Robert S. ^{[1
]}

Nombela-Arrieta, Cesar ^{[2
]}

Bach, Christian ^{[1
]}

Kerenyi, Marc ^{[1
,3
,4
]}

Bartholdy, Boris A. ^{[1
]}

Zhang, Hong ^{[1
]}

Alberich-Jorda, Meritxell ^{[1
]}

Lee, Sanghoon ^{[8
]}

Yang, Henry ^{[8
]}

Ng, Felicia ^{[9
,10
,11
]}

Zhang, Junyan ^{[1
]}

Leddin, Mathias ^{[12
]}

Silberstein, Leslie E. ^{[1
,2
]}

Hoefler, Gerald ^{[6
]}

Orkin, Stuart H. ^{[1
,3
,4
,13
]}

Goettgens, Berthold ^{[9
,10
,11
]}

Rosenbauer, Frank ^{[12
,14
]}

Huang, Gang ^{[15
]}

Tenen, Daniel G. ^{[1
,8
]}

机构：

[1] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Boston Childrens Hosp, Joint Program Transfus Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA

[5] Med Univ Graz, Div Hematol, A-8036 Graz, Austria

[6] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[7] Med Univ Vienna, Comprehens Canc Ctr Vienna, Div Hematol & Hemostaseol, A-1090 Vienna, Austria

[8] Natl Univ Singapore, Canc Sci Inst, Singapore 119615, Singapore

[9] Cambridge Inst Med Res, Cambridge CB2 0XY, England

[10] Wellcome Trust Res Labs, Cambridge CB2 0XY, England

[11] MRC Stem Cell Inst, Cambridge CB2 0XY, England

[12] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany

[13] Howard Hughes Med Inst, Boston, MA 02115 USA

[14] Univ Munster, Inst Mol Tumor Biol, D-48149 Munster, Germany

[15] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

来源：

MOLECULAR CELL | 2013年 / 49卷 / 05期

基金：

英国生物技术与生命科学研究理事会;

关键词：

TRANSCRIPTION FACTOR PU.1; SELF-RENEWAL; PROGENITOR CELLS; GENE; ELEMENTS; DIFFERENTIATION; PROLIFERATION; MAINTENANCE; ACTIVATION; MACROPHAGE;

D O I：

10.1016/j.molcel.2013.01.007

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：

To provide a lifelong supply of blood cells, hematopoietic stem cells (HSCs) need to carefully balance both self-renewing cell divisions and quiescence. Although several regulators that control this mechanism have been identified, we demonstrate that the transcription factor PU.1 acts upstream of these regulators. So far, attempts to uncover PU.1's role in HSC biology have failed because of the technical limitations of complete loss-of-function models. With the use of hypomorphic mice with decreased PU.1 levels specifically in phenotypic HSCs, we found reduced HSC long-term repopulation potential that could be rescued completely by restoring PU.1 levels. PU.1 prevented excessive HSC division and exhaustion by controlling the transcription of multiple cell-cycle regulators. Levels of PU.1 were sustained through autoregulatory PU.1 binding to an upstream enhancer that formed an active looped chromosome architecture in HSCs. These results establish that PU.1 mediates chromosome looping and functions as a master regulator of HSC proliferation.

引用

页码：934 / 946

页数：13

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