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

Ghani, S. and Riemke, P. and Schonheit, J. and Lenze, D. and Stumm, J. and Hoogenkamp, M. and Lagendijk, A.K. and Heinz, S.K. and Bonifer, C. and Bakkers, J. and Abdelilah-Seyfried, S. and Hummel, M. and Rosenbauer, F. (2011) Macrophage development from HSCs requires PU.1-coordinated microRNA expression. Blood, 118, 2275-84. ISSN 0006-4971.

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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. [KEYWORDS: Animals, Cell Differentiation/genetics, Cell Line, Cell Lineage/genetics, Hematopoietic Stem Cells/ cytology/ metabolism, Macrophages, Peritoneal/ cytology/ metabolism, Mice, Mice, Inbred C57BL, MicroRNAs/ genetics, Myelopoiesis/genetics, Proto-Oncogene Proteins/antagonists & inhibitors/ genetics, RNA, Small Interfering/genetics, Trans-Activators/antagonists & inhibitors/ genetics, Zebrafish/embryology/genetics]

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:12829
Deposited On:03 Dec 2012 15:03
Last Modified:08 Jan 2013 09:50

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