ZFIN ID: ZDB-PUB-110713-30
Macrophage development from hematopoietic stem cells requires PU.1 coordinated microRNA expression
Ghani, S., Riemke, P., Schönheit, J., Lenze, D., Stumm, J., Hoogenkamp, M., Lagendijk, A., Heinz, S., Bonifer, C., Bakkers, J., Abdelilah-Seyfried, S., Hummel, M., and Rosenbauer, F.
Date: 2011
Source: Blood   118(8): 2275-84 (Journal)
Registered Authors: Abdelilah-Seyfried, Salim, Bakkers, Jeroen
Keywords: none
MeSH Terms:
  • 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
PubMed: 21730352 Full text @ Blood
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.