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Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 2006 Aug 25;126(4):755-66

Date

08/23/2006

Pubmed ID

16923394

DOI

10.1016/j.cell.2006.06.052

Scopus ID

2-s2.0-33747196725   444 Citations

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.

Author List

Laslo P, Spooner CJ, Warmflash A, Lancki DW, Lee HJ, Sciammas R, Gantner BN, Dinner AR, Singh H

Author

Benjamin N. Gantner PhD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Differentiation
Cell Lineage
DNA, Single-Stranded
DNA-Binding Proteins
Early Growth Response Protein 2
Female
Gene Expression Regulation
Hematopoietic Stem Cells
Macrophages
Male
Mathematics
Mice
Mice, Knockout
Models, Theoretical
Neoplasm Proteins
Neutrophils
Proto-Oncogene Proteins
RNA, Small Interfering
Repressor Proteins
Trans-Activators
Transcription Factors
Transcription, Genetic
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a