GATA-2 regulates granulocyte-macrophage progenitor cell function.
The zinc finger transcription factor GATA-2 has been implicated in the regulation of hematopoietic stem cells. Herein, we explored the role of GATA-2 as a candidate regulator of the hematopoietic progenitor cell compartment. We showed that bone marrow from GATA-2 heterozygote (GATA-2(+/-)) mice displayed attenuated granulocyte-macrophage progenitor function in colony-forming cell (CFC) and serial replating CFC assays. This defect was mapped to the Lin(-)CD117(+)Sca-1(-)CD34(+)CD16/32(high) granulocyte-macrophage progenitor (GMP) compartment of GATA-2(+/-) marrow, which was reduced in size and functionally impaired in CFC assays and competitive transplantation. Similar functional impairments were obtained using a RNA interference approach to stably knockdown GATA-2 in wild-type GMP. Although apoptosis and cell-cycle distribution remained unperturbed in GATA-2(+/-) GMP, quiescent cells from GATA-2(+/-) GMP exhibited altered functionality. Gene expression analysis showed attenuated expression of HES-1 mRNA in GATA-2-deficient GMP. Binding of GATA-2 to the HES-1 locus was detected in the myeloid progenitor cell line 32Dcl3, and enforced expression of HES-1 expression in GATA-2(+/-) GMP rectified the functional defect, suggesting that GATA-2 regulates myeloid progenitor function through HES-1. These data collectively point to GATA-2 as a novel, pivotal determinant of GMP cell fate.
Rodrigues
Neil P
NP
Medical Research Council Hematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
Boyd
Ashleigh S
AS
Fugazza
Cristina
C
May
Gillian E
GE
Guo
Yanping
Y
Tipping
Alex J
AJ
Scadden
David T
DT
Vyas
Paresh
P
Enver
Tariq
T
D000818:Animals; D002460:Cell Line; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D005838:Genotype; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D011485:Protein Binding; D034622:RNA Interference
D050989:GATA2 Transcription Factor