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.
authors: Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA. pstaber@bidmc.harvard.edu
authors: Philipp B
authors: PB
authors: Staber
authors: Pu
authors: P
authors: Zhang
authors: Min
authors: M
authors: Ye
authors: Robert S
authors: RS
authors: Welner
authors: César
authors: C
authors: Nombela-Arrieta
authors: Christian
authors: C
authors: Bach
authors: Marc
authors: M
authors: Kerenyi
authors: Boris A
authors: BA
authors: Bartholdy
authors: Hong
authors: H
authors: Zhang
authors: Meritxell
authors: M
authors: Alberich-Jordà
authors: Sanghoon
authors: S
authors: Lee
authors: Henry
authors: H
authors: Yang
authors: Felicia
authors: F
authors: Ng
authors: Junyan
authors: J
authors: Zhang
authors: Mathias
authors: M
authors: Leddin
authors: Leslie E
authors: LE
authors: Silberstein
authors: Gerald
authors: G
authors: Hoefler
authors: Stuart H
authors: SH
authors: Orkin
authors: Berthold
authors: B
authors: Göttgens
authors: Frank
authors: F
authors: Rosenbauer
authors: Gang
authors: G
authors: Huang
authors: Daniel G
authors: DG
authors: Tenen
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D002454:Cell Differentiation; D049109:Cell Proliferation; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1
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