Multilineage transcriptional priming and determination of alternate hematopoietic cell fates.
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.
Laslo
Peter
P
Howard Hughes Medical Institute and Department of Molecular Genetics and Cell Biology, The University of Chicago, 929 East 57th Street, GCIS W522, IL 60637, USA.
Spooner
Chauncey J
CJ
Warmflash
Aryeh
A
Lancki
David W
DW
Lee
Hyun-Jun
HJ
Sciammas
Roger
R
Gantner
Benjamin N
BN
Dinner
Aaron R
AR
Singh
Harinder
H
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008297:Male; D008433:Mathematics; D051379:Mice; D018345:Mice, Knockout; D008962:Models, Theoretical; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000099232:Proto-Oncogene Protein Spi-1
D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C400152:DNA enzyme ED5; C497327:Egr2 protein, mouse; C079873:Gfi1 protein, mouse; C099945:Nab2 protein, mouse