PU.1 Level-Directed Chromatin Structure Remodeling at the Irf8 Gene Drives Dendritic Cell Commitment

Jörg Schönheit, Christiane Kuhl, Marie Luise Gebhardt, Francisco Fernández Klett, Pia Riemke, Marina Scheller, Gang Huang, Ronald Naumann, Achim Leutz, Carol Stocking, Josef Priller, Miguel A. Andrade-Navarro, Frank Rosenbauer

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

Dendritic cells (DCs) are essential regulators of immune responses; however, transcriptional mechanisms that establish DC lineage commitment are poorly defined. Here, we report that the PU.1 transcription factor induces specific remodeling of the higher-order chromatin structure at the interferon regulatory factor 8 (Irf8) gene to initiate DC fate choice. An Irf8 reporter mouse enabled us to pinpoint an initial progenitor stage at which DCs separate from other myeloid lineages in the bone marrow. In the absence of Irf8, this progenitor undergoes DC-to-neutrophil reprogramming, indicating that DC commitment requires an active, Irf8-dependent escape from alternative myeloid lineage potential. Mechanistically, myeloid Irf8 expression depends on high PU.1 levels, resulting in local chromosomal looping and activation of a lineage- and developmental-stage-specific cis-enhancer. These data delineate PU.1 as a concentration-dependent rheostat of myeloid lineage selection by controlling long-distance contacts between regulatory elements and suggest that specific higher-order chromatin remodeling at the Irf8 gene determines DC differentiation.

Original languageEnglish (US)
Pages (from-to)1617-1628
Number of pages12
JournalCell Reports
Volume3
Issue number5
DOIs
StatePublished - May 30 2013
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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