Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis.
In the search for genes expressed in hematopoietic stem cells, we identified that the expression of Gfi-1B (growth factor independence-1B) is highly restricted to hematopoietic stem cells, erythroblasts, and megakaryocytes. Gfi-1 and Gfi-1B are zinc finger proteins that share highly conserved SNAG and 6 zinc finger domains. Gfi-1 has been characterized as an oncogene involved in lymphoid malignancies in mice. In contrast, role of Gfi-1B in hematopoiesis has not been well characterized. In this study, we analyzed its function in human hematopoiesis. Enforced expression of Gfi-1B in human CD34(+) hematopoietic progenitors induced a drastic expansion of erythroblasts in an erythropoietin-independent manner. Expression of Gfi-1B did not promote erythroid commitment, but enhanced proliferation of immature erythroblasts. Erythroblasts expanded by exogenous Gfi-1B, however, failed to differentiate beyond proerythroblast stage and showed massive apoptosis. These biologic effects of Gfi-1B were mediated through its zinc finger domain, but not by the SNAG or non-zinc finger domain. Proliferation of erythroblasts was associated with sustained expression of GATA-2 but not of GATA-1, indicating a potential link between Gfi-1B and GATA family regulators. Importantly, the function of Gfi-1B to modulate transcription was dependent on promoter context. In addition, activation of transcription of an artificial promoter was mediated through its zinc finger domain. These findings establish Gfi-1B as a novel erythroid regulator and reveal its specific involvement in the regulation of erythroid cell growth through modulating erythroid-specific gene expression.
D000818:Animals; D001483:Base Sequence; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D017124:Conserved Sequence; D017931:DNA Primers; D004900:Erythroblasts / Q000502:physiology; D004920:Erythropoiesis / Q000502:physiology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008533:Megakaryocytes / Q000502:physiology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016335:Zinc Fingers
D017931:DNA Primers; C111977:GFI1B protein, human; C486395:Gfi1b protein, mouse; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins