Abstract
Hematopoietic stem cells and their progenitors exhibit multilineage patterns of gene expression. Molecular mechanisms underlying the generation and refinement of these patterns during cell fate determination remain unexplored because of the absence of suitable experimental systems. Using PU.1(-/-) progenitors, we demonstrate that at subthreshold levels, this Ets transcription factor regulates a mixed pattern (macrophage/neutrophil) of gene expression within individual myeloid progenitors. Increased PU.1 levels refine the pattern and promote macrophage differentiation by modulating a novel regulatory circuit comprised of counter antagonistic repressors, Egr-1,2/Nab-2 and Gfi-1. Egr-1 and Egr-2 function redundantly to activate macrophage genes and to repress the neutrophil program. These results are used to assemble and mathematically model a gene regulatory network that exhibits both graded and bistable behaviors and accounts for the onset and resolution of mixed lineage patterns during cell fate determination.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Differentiation / physiology*
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Cell Lineage*
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DNA, Single-Stranded / genetics
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DNA, Single-Stranded / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Early Growth Response Protein 2 / genetics
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Early Growth Response Protein 2 / metabolism
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Female
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Gene Expression Regulation*
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / physiology*
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Macrophages / cytology
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Macrophages / physiology
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Male
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Mathematics
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Mice
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Mice, Knockout
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Models, Theoretical
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neutrophils / cytology
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Neutrophils / physiology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Transcription, Genetic*
Substances
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DNA enzyme ED5
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DNA, Single-Stranded
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DNA-Binding Proteins
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Early Growth Response Protein 2
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Egr2 protein, mouse
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Gfi1 protein, mouse
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Nab2 protein, mouse
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Neoplasm Proteins
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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proto-oncogene protein Spi-1