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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Official URL: http://dx.doi.org/10.1182/blood-2011-02-335141
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]
|Deposited On:||03 Dec 2012 15:03|
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