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Cell Rep. 2015 Jun 30;11(12):1847-55. doi: 10.1016/j.celrep.2015.05.038. Epub 2015 Jun 18.

Single-Stranded DNA-Binding Transcriptional Regulator FUBP1 Is Essential for Fetal and Adult Hematopoietic Stem Cell Self-Renewal.

Author information

1
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
2
LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany.
3
Department of Cellular and Molecular Neurobiology, Technical University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany.
4
Department of Biosystems Science and Engineering (D-BSSE), ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
5
LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: m.rieger@em.uni-frankfurt.de.
6
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany. Electronic address: zoernig@gsh.uni-frankfurt.de.

Abstract

The ability of hematopoietic stem cells (HSCs) to self-renew is a prerequisite for the establishment of definitive hematopoiesis and life-long blood regeneration. Here, we report the single-stranded DNA-binding transcriptional regulator far upstream element (FUSE)-binding protein 1 (FUBP1) as an essential factor of HSC self-renewal. Functional inactivation of FUBP1 in two different mouse models resulted in embryonic lethal anemia at around E15.5 caused by severely diminished HSCs. Fetal and adult HSCs lacking FUBP1 revealed an HSC-intrinsic defect in their maintenance, expansion, and long-term blood reconstitution, but could differentiate into all hematopoietic lineages. FUBP1-deficient adult HSCs exhibit significant transcriptional changes, including upregulation of the cell-cycle inhibitor p21 and the pro-apoptotic Noxa molecule. These changes caused an increase in generation time and death of HSCs as determined by video-microscopy-based tracking. Our data establish FUBP1 and its recognition of single-stranded genomic DNA as an important element in the transcriptional regulation of HSC self-renewal.

PMID:
26095368
DOI:
10.1016/j.celrep.2015.05.038
[Indexed for MEDLINE]
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