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

• Published in: Molecular cell Vol. 49; no. 5; pp. 934 - 946
• Main Authors: Staber, Philipp B., Zhang, Pu, Ye, Min, Welner, Robert S., Nombela-Arrieta, César, Bach, Christian, Kerenyi, Marc, Bartholdy, Boris A., Zhang, Hong, Alberich-Jordà, Meritxell, Lee, Sanghoon, Yang, Henry, Ng, Felicia, Zhang, Junyan, Leddin, Mathias, Silberstein, Leslie E., Hoefler, Gerald, Orkin, Stuart H., Göttgens, Berthold, Rosenbauer, Frank, Huang, Gang, Tenen, Daniel G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2013
• Subjects: Adult Stem Cells - metabolism; Adult Stem Cells - pathology; adults; Animals; Blood cells; cell cycle; Cell Cycle - genetics; Cell Differentiation; Cell Proliferation; chromosomes; hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Mice; Mice, Inbred Strains; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; transcription (genetics); transcription factors
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.01.007

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. [Display omitted] ► PU.1 prevents hematopoietic stem cell (HSC) exhaustion ► PU.1 is a master regulator of cell-cycle genes in HSCs ► PU.1 binding mediates chromosome looping in HSCs ► Positive autoregulation via a −14 kb enhancer sustains PU.1 levels in HSCs