title: Macrophage development from HSCs requires PU.1-coordinated microRNA expression.
abstract: 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.
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Saeed
authors: S
authors: Ghani
authors: Pia
authors: P
authors: Riemke
authors: Jörg
authors: J
authors: Schönheit
authors: Dido
authors: D
authors: Lenze
authors: Jürgen
authors: J
authors: Stumm
authors: Maarten
authors: M
authors: Hoogenkamp
authors: Anne
authors: A
authors: Lagendijk
authors: Sven
authors: S
authors: Heinz
authors: Constanze
authors: C
authors: Bonifer
authors: Jeroen
authors: J
authors: Bakkers
authors: Salim
authors: S
authors: Abdelilah-Seyfried
authors: Michael
authors: M
authors: Hummel
authors: Frank
authors: F
authors: Rosenbauer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D066298:In Vitro Techniques; D017737:Macrophages, Peritoneal / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D038042:Myelopoiesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C534190:Mirn146 microRNA, mouse