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

Philipp B. Staber, Pu Zhang, Min Ye, Robert S. Welner, César Nombela-Arrieta, Christian Bach, Marc Kerenyi, Boris A. Bartholdy, Hong Zhang, Meritxell Alberich-Jordà, Sanghoon Lee, Henry Yang, Felicia Ng, Junyan Zhang, Mathias Leddin, Leslie E. Silberstein, Gerald Hoefler, Stuart H. Orkin, Berthold Göttgens, Frank RosenbauerGang Huang, Daniel G. Tenen

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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.

Original languageEnglish (US)
Pages (from-to)934-946
Number of pages13
JournalMolecular Cell
Volume49
Issue number5
DOIs
StatePublished - Mar 7 2013

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Staber, P. B., Zhang, P., Ye, M., Welner, R. S., Nombela-Arrieta, C., Bach, C., Kerenyi, M., Bartholdy, B. A., Zhang, H., Alberich-Jordà, M., Lee, S., Yang, H., Ng, F., Zhang, J., Leddin, M., Silberstein, L. E., Hoefler, G., Orkin, S. H., Göttgens, B., ... Tenen, D. G. (2013). Sustained PU.1 Levels Balance Cell-Cycle Regulators to Prevent Exhaustion of Adult Hematopoietic Stem Cells. Molecular Cell, 49(5), 934-946. https://doi.org/10.1016/j.molcel.2013.01.007