Macrophage development from HSCs requires PU.1-coordinated microRNA expression

The differentiation of HSCs into myeloid lineages requires the transcription factor PU.1. Whereas PU.1-dependent induction of myeloid-specific target genes has been intensively studied, negative regulation of stem cell or alternate lineage programs remains incompletely characterized. To test for suc...

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Published in:Blood Vol. 118; no. 8; p. 2275
Main Authors: Ghani, Saeed, Riemke, Pia, Schönheit, Jörg, Lenze, Dido, Stumm, Jürgen, Hoogenkamp, Maarten, Lagendijk, Anne, Heinz, Sven, Bonifer, Constanze, Bakkers, Jeroen, Abdelilah-Seyfried, Salim, Hummel, Michael, Rosenbauer, Frank
Format: Journal Article
Language:English
Published: United States 25.08.2011
Subjects:
Animals
Cell Differentiation - genetics
Cell Line
Cell Lineage - genetics
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
In Vitro Techniques
Macrophages, Peritoneal - cytology
Macrophages, Peritoneal - metabolism
Mice
Mice, Inbred C57BL
MicroRNAs - genetics
Myelopoiesis - genetics
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - genetics
RNA, Small Interfering - genetics
Trans-Activators - antagonists & inhibitors
Trans-Activators - genetics
Zebrafish - embryology
Zebrafish - genetics
ISSN:1528-0020, 1528-0020
Online Access:Get more information
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Summary:The differentiation of HSCs into myeloid lineages requires the transcription factor PU.1. Whereas PU.1-dependent induction of myeloid-specific target genes has been intensively studied, negative regulation of stem cell or alternate lineage programs remains incompletely characterized. To test for such negative regulatory events, we searched for PU.1-controlled microRNAs (miRs) by expression profiling using a PU.1-inducible myeloid progenitor cell line model. We provide evidence that PU.1 directly controls expression of at least 4 of these miRs (miR-146a, miR-342, miR-338, and miR-155) through temporally dynamic occupation of binding sites within regulatory chromatin regions adjacent to their genomic coding loci. Ectopic expression of the most robustly induced PU.1 target miR, miR-146a, directed the selective differentiation of HSCs into functional peritoneal macrophages in mouse transplantation assays. In agreement with this observation, disruption of Dicer expression or specific antagonization of miR-146a function inhibited the formation of macrophages during early zebrafish (Danio rerio) development. In the present study, we describe a PU.1-orchestrated miR program that mediates key functions of PU.1 during myeloid differentiation.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2011-02-335141