@article{945e10da95e64b1d98430d1a5cd60cd1,
title = "Sustained PU.1 Levels Balance Cell-Cycle Regulators to Prevent Exhaustion of Adult Hematopoietic Stem Cells",
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.",
author = "Staber, {Philipp B.} and Pu Zhang and Min Ye and Welner, {Robert S.} and C{\'e}sar Nombela-Arrieta and Christian Bach and Marc Kerenyi and Bartholdy, {Boris A.} and Hong Zhang and Meritxell Alberich-Jord{\`a} and Sanghoon Lee and Henry Yang and Felicia Ng and Junyan Zhang and Mathias Leddin and Silberstein, {Leslie E.} and Gerald Hoefler and Orkin, {Stuart H.} and Berthold G{\"o}ttgens and Frank Rosenbauer and Gang Huang and Tenen, {Daniel G.}",
note = "Funding Information: We thank Christopher Hetherington and Alexander Ebralidze for expert assistance with quantitative 3C analysis, the Dartmouth Transgenic Facility directed by Steven Fiering, and the BIDMC Flow Cytometry Facility. We thank Dr. Wenyi Wei and Dr. Peter Sicinski for providing reagents (the anti-Cdc25a antibody and the Cdk1 expression construct, respectively). We are grateful to the members of the Tenen laboratory for helpful discussions, especially Annalisa Di Ruscio, Elena Levantini, and Deepak Bararia. This work was supported by NIH grant R01HL112719 to D.G.T. and by fellowships from the Austrian Research Foundation (Erwin Schr{\"o}dinger Stipendium: J2876-B12) and the Austrian Academy of Science (APART Stipendium: 11379) to P.B.S. Starting in January, 2012, P.B.S. has received a Marie Curie International Outgoing Fellowship from the European Union (PIOF-254486). C.B. was supported by the German Research Foundation (DFG fellowship BA 4186/1-1). F.N. is the recipient of a Yousef Jameel scholarship administered by the Cambridge Commonwealth and Overseas Trust. ",
year = "2013",
month = mar,
day = "7",
doi = "10.1016/j.molcel.2013.01.007",
language = "English (US)",
volume = "49",
pages = "934--946",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}