Research

Sustained PU.1 Levels Balance Cell-Cycle Regulators to Prevent Exhaustion of Adult Hematopoietic Stem Cells (Mol Cell, Feb 2013)

To guarantee blood supply throughout adult life hematopoietic stem cells (HSCs) need to carefully balance between self-renewing cell divisions and quiescence. Identification of genes controlling HSC self-renewal is of utmost importance given that HSCs are the only stem cells with broad clinical applications. While several regulators have been identified which control this mechanism, we here demonstrate that one transcription factor, PU.1, acts as the master regulator of HSC proliferation. PU.1 has been known for its importance in blood cell maturation, however, attempts to uncover PU.1’s role in HSC biology have failed so far due to technical limitations of complete loss of function models. Using hypomorphic mice with decreased PU.1 levels specifically in phenotypic HSCs we observed a loss of all major HSC functions that could be rescued completely by restoring PU.1 levels. PU.1 prevented excessive HSC cell divisions and exhaustion by controlling transcription of multiple cell cycle regulators. Interestingly, levels of PU.1 itself were sustained through autoregulatory PU.1 binding to an upstream enhancer which formed an active looped chromosome architecture in HSCs.

These results establish PU.1 as master regulator controlling the switch between cell division and quiescence in order to prevent exhaustion of HSCs. Given that even moderate level changes greatly impact stem cell function, these results suggest important therapeutic implications for leukemic patients with reduced PU.1 levels. Moreover, these data provide first proof, that autoregulation of a transcription factor, PU.1, has a crucial function in vivo. We anticipate that our concept of how autoregulation facilitates an active chromosomal conformation will impact future research on transcription factor networks regulating stem cell fate.

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Authors:

Philipp B. Staber1,4,6,*, Pu Zhang1, Min Ye1,Robert S. Welner1,Cesar Nombela-Arrieta2, Christian Bach1, Marc Kerenyi1,3, Boris A. Bartholdy1,Hong Zhang1, Meritxell Alberich-Jorda1, Sanghoon Lee7, Henry Yang7, Felicia Ng8, Junyan Zhang1, Mathias Leddin9, Leslie E. Silberstein1,2, Gerald Hoefler5, Stuart H. Orkin1,3,10, Berthold Gottgens8, Frank Rosenbauer9,11, Gang Huang12,13, and Daniel G. Tenen1,7,13,*

1Harvard Stem Cell Institute
2Boston Children’s Hospital, Joint Program in Transfusion Medicine
3Division of Hematology/Oncology, Children’s Hospital and Dana Farber Cancer Institute
Harvard Medical School, Boston
4Division of Hematology
5Institute of Pathology, Medical University of Graz, 8036 Graz, Austria
6Division of Hematology and Hemostaseology, Comprehensive Cancer Centre Vienna, Medical University of Vienna
7Cancer Science Institute, National University of Singapore
8Cambridge Institute for Medical Research and Wellcome Trust and MRC Stem Cell Institute
9Max Delbruck Center for Molecular Medicine, 13092 Berlin, Germany
10Howard Hughes Medical Institute, Boston, MA 02115, USA
11Institute of Molecular Tumor Biology, University of Munster, 48149 Munster, Germany
12Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center
13These authors contributed equally to this work

Link to PubMed