Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates

Peter Laslo, Chauncey J. Spooner, Aryeh Warmflash, David W. Lancki, Hyun Jun Lee, Roger Sciammas, Benjamin N. Gantner, Aaron R. Dinner, Harinder Singh

Research output: Contribution to journalArticle

439 Scopus 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.

Original languageEnglish (US)
Pages (from-to)755-766
Number of pages12
JournalCell
Volume126
Issue number4
DOIs
StatePublished - Aug 25 2006
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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    Laslo, P., Spooner, C. J., Warmflash, A., Lancki, D. W., Lee, H. J., Sciammas, R., Gantner, B. N., Dinner, A. R., & Singh, H. (2006). Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates. Cell, 126(4), 755-766. https://doi.org/10.1016/j.cell.2006.06.052