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

Research output: Contribution to journalArticle

Authors

  • S Ghani
  • P Riemke
  • J Schonheit
  • D Lenze
  • J Stumm
  • A Lagendijk
  • S Heinz
  • J Bakkers
  • S Abdelilah-Seyfried
  • Michael Hummel
  • F Rosenbauer

Colleges, School and Institutes

External organisations

  • German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Institute of Pathology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany;

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.

Details

Original languageEnglish
Pages (from-to)2275-2284
Number of pages10
JournalBlood
Volume118
Issue number8
Publication statusPublished - 25 Aug 2011

Keywords

  • machrophage development, Hematopoietic Stem Cells