The transcriptional repressor GFI-1 antagonizes PU.1 activity through protein-protein interaction.
Mice lacking the zinc finger transcriptional repressor protein GFI-1 are neutropenic. These mice generate abnormal immature myeloid cells exhibiting characteristics of both macrophages and granulocytes. Furthermore, Gfi-1(-/-) mice are highly susceptible to bacterial infection. Interestingly, Gfi-1(-/-) myeloid cells overexpress target genes of the PU.1 transcription factor such as the macrophage colony-stimulating factor receptor and PU.1 itself. We therefore determined whether GFI-1 modulates the transcriptional activity of PU.1. Our data demonstrate that GFI-1 physically interacts with PU.1, repressing PU.1-dependent transcription. This repression is functionally significant, as GFI-1 blocked PU.1-induced macrophage differentiation of a multipotential hematopoietic progenitor cell line. Retroviral expression of GFI-1 in primary murine hematopoietic progenitors increased granulocyte differentiation at the expense of macrophage differentiation. We interbred Gfi-1(+/-) and PU.1(+/-) mice and observed that heterozygosity at the PU.1 locus partially rescued the Gfi-1(-/-) mixed myeloid lineage phenotype, but failed to restore granulocyte differentiation. Our data demonstrate that GFI-1 represses PU.1 activity and that lack of this repression in Gfi-1(-/-) myeloid cells contributes to the observed mixed lineage phenotype.
Dahl
Richard
R
Department of Internal Medicine, Health Sciences Center, University of New Mexico, Albuquerque, New Mexico 87131, USA. RDahl@salud.unm.edu
Iyer
Sangeeta R
SR
Owens
Kristin S
KS
Cuylear
Dorothy D
DD
Simon
M Celeste
MC
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006098:Granulocytes / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008264:Macrophages / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology; D009154:Mutation; D022423:Myeloid Cells / Q000166:cytology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency; D012097:Repressor Proteins; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000172:deficiency; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D000099232:Proto-Oncogene Protein Spi-1
D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C498275:GFI1 protein, human; C079873:Gfi1 protein, mouse