Antagonism of FOG-1 and GATA factors in fate choice for the mast cell lineage.
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.
Cantor
Alan B
AB
Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Boston, MA 02115, USA. alan.cantor@childrens.harvard.edu
Iwasaki
Hiromi
H
Arinobu
Yojiro
Y
Moran
Tyler B
TB
Shigematsu
Hirokazu
H
Sullivan
Matthew R
MR
Akashi
Koichi
K
Orkin
Stuart H
SH
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015017:Yolk Sac / Q000166:cytology / Q000378:metabolism
D050982:GATA1 Transcription Factor; D050989:GATA2 Transcription Factor; C494689:Gata1 protein, mouse; C494712:Gata2 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse