Antagonism between C/EBPbeta and FOG in eosinophil lineage commitment of multipotent hematopoietic progenitors.
The commitment of multipotent cells to particular developmental pathways requires specific changes in their transcription factor complement to generate the patterns of gene expression characteristic of specialized cell types. We have studied the role of the GATA cofactor Friend of GATA (FOG) in the differentiation of avian multipotent hematopoietic progenitors. We found that multipotent cells express high levels of FOG mRNA, which were rapidly down-regulated upon their C/EBPbeta-mediated commitment to the eosinophil lineage. Expression of FOG in eosinophils led to a loss of eosinophil markers and the acquisition of a multipotent phenotype, and constitutive expression of FOG in multipotent progenitors blocked activation of eosinophil-specific gene expression by C/EBPbeta. Our results show that FOG is a repressor of the eosinophil lineage, and that C/EBP-mediated down-regulation of FOG is a critical step in eosinophil lineage commitment. Furthermore, our results indicate that maintenance of a multipotent state in hematopoiesis is achieved through cooperation between FOG and GATA-1. We present a model in which C/EBPbeta induces eosinophil differentiation by the coordinate direct activation of eosinophil-specific promoters and the removal of FOG, a promoter of multipotency as well as a repressor of eosinophil gene expression.
Querfurth
E
E
Laboratory of Gene Therapy Research, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
Schuster
M
M
Kulessa
H
H
Crispino
J D
JD
Döderlein
G
G
Orkin
S H
SH
Graf
T
T
Nerlov
C
C
D000818:Animals; D030161:Avian Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002642:Chick Embryo; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D004804:Eosinophils / Q000166:cytology* / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D008957:Models, Genetic; D022423:Myeloid Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014157:Transcription Factors
D030161:Avian Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C099044:EOS47 protein, Gallus gallus; D050981:Erythroid-Specific DNA-Binding Factors; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C498432:ZFPM1 protein, human