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Macrophage development from hematopoietic stem cells requires PU.1 coordinated microRNA expression

Item Type:Article
Title:Macrophage development from hematopoietic stem cells requires PU.1 coordinated microRNA expression
Creators Name:Ghani, S. and Riemke, P. and Schoenheit, J. and Lenze, D. and Stumm, J. and Hoogenkamp, M. and Lagendijk, A. and Heinz, S. and Bonifer, C. and Bakkers, J. and Abdelilah-Seyfried, S. and Hummel, M. and Rosenbauer, F.
Abstract:The differentiation of hematopoietic stem cells (HSC) into myeloid lineages requires the transcription factor PU.1. While 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 four 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 HSC into functional peritoneal macrophages in mouse transplantation assays. In line with this observation, disruption of Dicer expression or specific antagonization of miR-146a function inhibited the formation of macrophages during early zebrafish development. Collectively, we delineate a PU.1-orchestrated miR program which mediates key functions of PU.1 during myeloid differentiation.
Keywords:PU.1, microRNA, Hematopoiesis, Myeloid Differentiation, Animals, Mice, Zebrafish
Publisher:American Society of Hematology
Page Range:2275-2284
Date:25 August 2011
Official Publication:https://doi.org/10.1182/blood-2011-02-335141
PubMed:View item in PubMed

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