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

doi:10.1016/j.cell.2006.06.052

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

Academic Institute

Research output: Contribution to journal › Article › peer-review

496 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 language	English (US)
Pages (from-to)	755-766
Number of pages	12
Journal	Cell
Volume	126
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2006.06.052
State	Published - Aug 25 2006

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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title = "Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates",

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

note = "Funding Information: We are grateful to J. Svaren (University of Wisconsin) for providing the Egr-1,2 plasmid constructs. We thank T. Gridley (Jackson Laboratories) for Egr-2 +/− mice and J. Millbrandt (Washington University) for Egr-1 +/− mice. A.W. is supported by an NSF graduate research fellowship. B.N.G. is supported by a NIH training grant (T32 AI07090). ",

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doi = "10.1016/j.cell.2006.06.052",

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AU - Laslo, Peter

AU - Spooner, Chauncey J.

AU - Warmflash, Aryeh

AU - Lancki, David W.

AU - Lee, Hyun Jun

AU - Sciammas, Roger

AU - Gantner, Benjamin N.

AU - Dinner, Aaron R.

AU - Singh, Harinder

N1 - Funding Information: We are grateful to J. Svaren (University of Wisconsin) for providing the Egr-1,2 plasmid constructs. We thank T. Gridley (Jackson Laboratories) for Egr-2 +/− mice and J. Millbrandt (Washington University) for Egr-1 +/− mice. A.W. is supported by an NSF graduate research fellowship. B.N.G. is supported by a NIH training grant (T32 AI07090).

PY - 2006/8/25

Y1 - 2006/8/25

N2 - 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.

AB - 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.

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Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates

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