Single-Stranded DNA-Binding Transcriptional Regulator FUBP1 Is Essential for Fetal and Adult Hematopoietic Stem Cell Self-Renewal
Uta Rabenhorst,
Frederic B. Thalheimer,
Katharina Gerlach,
Marek Kijonka,
Stefanie Böhm,
Daniela S. Krause,
Franz Vauti,
Hans-Henning Arnold,
Timm Schroeder,
Frank Schnütgen,
Harald von Melchner,
Michael A. Rieger,
Martin Zörnig
Affiliations
Uta Rabenhorst
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany
Frederic B. Thalheimer
LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
Katharina Gerlach
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany
Marek Kijonka
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany
Stefanie Böhm
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany
Daniela S. Krause
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany
Franz Vauti
Department of Cellular and Molecular Neurobiology, Technical University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany
Hans-Henning Arnold
Department of Cellular and Molecular Neurobiology, Technical University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany
Timm Schroeder
Department of Biosystems Science and Engineering (D-BSSE), ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland
Frank Schnütgen
LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
Harald von Melchner
LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
Michael A. Rieger
LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany
Martin Zörnig
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany
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.
