The Journal of Experimental Medicine
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Published online February 25, 2008
doi:10.1084/jem.20070544
The Journal of Experimental Medicine, Vol. 205, No. 3, 611-624
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Cantor et al.
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ARTICLE

 Antagonism of FOG-1 and GATA factors in fate choice for the mast cell lineage

Alan B. Cantor1,2, Hiromi Iwasaki4, Yojiro Arinobu3, Tyler B. Moran1, Hirokazu Shigematsu3, Matthew R. Sullivan1, Koichi Akashi3,4, and Stuart H. Orkin1,2,5

1 Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115
2 Department of Pediatrics and 3 Department of Internal Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
4 Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan
5 Howard Hughes Medical Institute, Boston, MA 02115

CORRESPONDENCE Alan B. Cantor: alan.cantor{at}childrens.harvard.edu

The zinc finger transcription factor GATA-1 requires direct physical interaction with the cofactor friend of GATA-1 (FOG-1) for its essential role in erythroid and megakaryocytic development. We show that in the mast cell lineage, GATA-1 functions completely independent of FOG proteins. Moreover, we demonstrate that FOG-1 antagonizes the fate choice of multipotential progenitor cells for the mast cell lineage, and that its down-regulation is a prerequisite for mast cell development. Remarkably, ectopic expression of FOG-1 in committed mast cell progenitors redirects them into the erythroid, megakaryocytic, and granulocytic lineages. These lineage switches correlate with transcriptional down-regulation of GATA-2, an essential mast cell GATA factor, via switching of GATA-1 for GATA-2 at a key enhancer element upstream of the GATA-2 gene. These findings illustrate combinatorial control of cell fate identity by a transcription factor and its cofactor, and highlight the role of transcriptional networks in lineage determination. They also provide evidence for lineage instability during early stages of hematopoietic lineage commitment.

Abbreviations used: BMMC, bone marrow–derived mast cell; ChIP, chromatin immunoprecipitation; CtBP, C-terminal binding protein; eGFP, enhanced GFP; EKLF, erythroid Kruppel-like factor; EPO, erythropoietin; Fc{epsilon}RI, high affinity IgE receptor; FOG, friend of GATA; GMP, granulocyte/macrophage progenitor; GPIb, glycoprotein Ib; MC-CPA, mast cell carboxypeptidase A; MCP, mast cell progenitor; MEL, mouse erythroleukemia; MEP, megakaryocyte/erythroid progenitor; MMCP, mouse mast cell protease; SCF, stem cell factor; Srp, Serpent; TPO, thrombopoietin; Ush, U-shaped; YSMC, yolk sac–derived mast cell.


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