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

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. [Display omitted] •FUBP1 is required for the expansion of LT-HSCs in the fetal liver•FUBP1 is essential for fetal and adult LT-HSC self-renewal•Loss of FUBP1 results in increased LT-HSC cell death and prolonged cell cycle•Loss of FUBP1 does not prevent the differentiation into all hematopoietic lineages Self-renewal of hematopoietic stem cells (HSCs) is required for definitive fetal and adult hematopoiesis. Rabenhorst et al. demonstrate an essential function of the single-stranded DNA-binding transcriptional regulator FUSE-binding protein 1 (FUBP1) for the expansion and maintenance of HSCs by modulating HSC proliferation and survival.