Haematopoietic stem cells (HSCs) sustain blood production throughout life. HSCs are capable of extensive proliferative expansion, as a single HSC may reconstitute lethally irradiated hosts. In steady-state, HSCs remain largely quiescent and self-renew at a constant low rate, forestalling their exhaustion during adult life. Whereas nuclear regulatory factors promoting proliferative programmes of HSCs in vivo and ex vivo have been identified, transcription factors restricting their cycling have remained elusive. Here we report that the zinc-finger repressor Gfi-1 (growth factor independent 1), a cooperating oncogene in lymphoid cells, unexpectedly restricts proliferation of HSCs. After loss of Gfi-1, HSCs display elevated proliferation rates as assessed by 5-bromodeoxyuridine incorporation and cell-cycle analysis. Gfi-1-/- HSCs are functionally compromised in competitive repopulation and serial transplantation assays, and are rapidly out-competed in the bone marrow of mouse chimaeras generated with Gfi-1-/- embryonic stem cells. Thus, Gfi-1 is essential to restrict HSC proliferation and to preserve HSC functional integrity.
"HSC quiescence is controlled by both HSC-intrinsic mechanisms and extrinsic factors from the BM microenvironment . Several transcription factors have been implicated in the regulation of HSC quiescence, including Gfi-1, Pbx1 and MEF/ELF4 –. With regard to HSC-extrinsic niche-derived factors, it has been reported that angiopoietin-1 and thrombopoietin regulate the quiescence of HSCs in the BM through receptors expressed on HSCs –. "
[Show abstract][Hide abstract] ABSTRACT: Hematopoietic stem cells in the bone marrow have the capacity to both self-renew and to generate all cells of the hematopoietic system. The balance of these two activities is controlled by hematopoietic stem cell-intrinsic regulatory mechanisms as well as extrinsic signals from the microenvironment. Here we demonstrate that Meis1, a TALE family homeodomain transcription factor involved in numerous embryonic developmental processes, is selectively expressed in hematopoietic stem/progenitor cells. Conditional Meis1 knockout in adult hematopoietic cells resulted in a significant reduction in the hematopoietic stem/progenitor cells. Suppression of hematopoiesis by Meis1 deletion appears to be caused by impaired self-renewal activity and reduced cellular quiescence of hematopoietic stem/progenitor cells in a cell autonomous manner, resulting in stem cell exhaustion and defective long-term hematopoiesis. Meis1 deficiency down-regulated a subset of Pbx1-dependent hematopoietic stem cell signature genes, suggesting a functional link between them in the maintenance of hematopoietic stem/progenitor cells. These results show the importance of Meis1 in adult hematopoiesis.
PLoS ONE 02/2014; 9(2):e87646. DOI:10.1371/journal.pone.0087646 · 3.23 Impact Factor
"The transcription factor Gfi1 is expressed in multiple tissues, including haematopoietic progenitors and stem cells, lymphoid and myeloid cells (Karsunky et al., 2002; Hock et al., 2004; Yücel et al., 2004; Rosenbauer and Tenen, 2007; Wilson et al., 2010a; Lancrin et al., 2012). We have previously identified an enhancer that is located around 35 kb upstream of Gfi1 (referred to as the Gfi1-35 enhancer) within an intron of the neighbouring gene Evi5 (Wilson et al., 2010a). "
[Show abstract][Hide abstract] ABSTRACT: Comprehensive analysis of cis-regulatory elements is key to understanding the dynamic gene regulatory networks that control embryonic development. While transgenic animals represent the gold standard assay, their generation is costly, entails significant animal usage, and in utero development complicates time-course studies. As an alternative, embryonic stem (ES) cells can readily be differentiated in a process that correlates well with developing embryos. Here, we describe a highly effective platform for enhancer assays using an Hsp68/Venus reporter cassette that targets to the Hprt locus in mouse ES cells. This platform combines the flexibility of Gateway® cloning, live cell trackability of a fluorescent reporter, low background and the advantages of single copy insertion into a defined genomic locus. We demonstrate the successful recapitulation of tissue-specific enhancer activity for two cardiac and two haematopoietic enhancers. In addition, we used this assay to dissect the functionality of the highly conserved Ets/Ets/Gata motif in the Scl+19 enhancer, which revealed that the Gata motif is not required for initiation of enhancer activity. We further confirmed that Gata2 is not required for endothelial activity of the Scl+19 enhancer using Gata2(-/-) Scl+19 transgenic embryos. We have therefore established a valuable toolbox to study gene regulatory networks with broad applicability.
Biology Open 11/2013; 2(11):1229-38. DOI:10.1242/bio.20136296 · 2.42 Impact Factor
"When this gene is deleted, a normal HSC population is generated in the FL; however, BM failure secondary to HSC depletion occurs 1–2 months after birth,92 a time point which directly follows the fetal-to-adult transition in several HSC properties.65, 89 Similarly, Gfi−/− mice develop normally, but when their BM cells are transplanted they have a reduced ability to repopulate irradiated recipients suggesting their adult HSCs are impaired.93 Tel/Etv6 has also been shown to be an essential and selective regulator of adult HSC survival.94 "
[Show abstract][Hide abstract] ABSTRACT: Hematopoietic stem cells (HSCs) comprise a rare population of cells that can regenerate and maintain lifelong blood cell production. This functionality is achieved through their ability to undergo many divisions without activating a poised, but latent, capacity for differentiation into multiple blood cell types. Throughout life, HSCs undergo sequential changes in several key properties. These affect mechanisms that regulate the self-renewal, turnover and differentiation of HSCs as well as the properties of the committed progenitors and terminally differentiated cells derived from them. Recent findings point to the Lin28b-let-7 pathway as a master regulator of many of these changes with important implications for the clinical use of HSCs for marrow rescue and gene therapy, as well as furthering our understanding of the different pathogenesis of childhood and adult-onset leukemia.
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