title: Single-Stranded DNA-Binding Transcriptional Regulator FUBP1 Is Essential for Fetal and Adult Hematopoietic Stem Cell Self-Renewal.
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.
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Rabenhorst
authors.affiliation: LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Frederic B
authors.initials: FB
authors.lastname: Thalheimer
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Gerlach
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Kijonka
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Böhm
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Krause
authors.affiliation: Department of Cellular and Molecular Neurobiology, Technical University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Vauti
authors.affiliation: Department of Cellular and Molecular Neurobiology, Technical University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany.
authors.forename: Hans-Henning
authors.initials: HH
authors.lastname: Arnold
authors.affiliation: Department of Biosystems Science and Engineering (D-BSSE), ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schnütgen
authors.affiliation: LOEWE Center for Cell and Gene Therapy Frankfurt and Department for Hematology/Oncology, Goethe University Hospital Frankfurt, 60590 Frankfurt am Main, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: von Melchner
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
authors.affiliation: Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany. Electronic address: zoernig@gsh.uni-frankfurt.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Zörnig
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics*; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D053686:Fetal Stem Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000235:genetics
chemical_list: D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; C118921:Fubp protein, mouse