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Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells

Item Type:Article
Title:Sustained PU.1 levels balance cell-cycle regulators to prevent exhaustion of adult hematopoietic stem cells
Creators Name:Staber, P.B. and Zhang, P. and Ye, M. and Welner, R.S. and Nombela-Arrieta, C. and Bach, C. and Kerenyi, M. and Bartholdy, B.A. and Zhang, H. and Alberich-Jorda, M. and Lee, S. and Yang, H. and Ng, F. and Zhang, J. and Leddin, M. and Silberstein, L.E. and Hoefler, G. and Orkin, S.H. and Goettgens, B. and Rosenbauer, F. and Huang, G. and Tenen, D.G.
Abstract: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.
Keywords:Adult Stem Cells, Cell Cycle, Cell Differentiation, Cell Proliferation, Hematopoietic Stem Cells, Inbred Strains Mice, Proto-Oncogene Proteins, Trans-Activators, Animals, Mice
Source:Molecular Cell
ISSN:1097-2765
Publisher:Cell Press (U.S.A.)
Volume:49
Number:5
Page Range:934-946
Date:7 March 2013
Official Publication:https://doi.org/10.1016/j.molcel.2013.01.007
PubMed:View item in PubMed

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