PU.1 level-directed chromatin structure remodeling at the Irf8 gene drives dendritic cell commitment

Cell Rep. 2013 May 30;3(5):1617-28. doi: 10.1016/j.celrep.2013.04.007. Epub 2013 Apr 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bone Marrow Cells / cytology
  • Cell Differentiation
  • Cell Lineage
  • Cells, Cultured
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly*
  • Dendritic Cells / cytology*
  • Dendritic Cells / metabolism
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Interferon Regulatory Factors / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Cells / cytology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism*

Substances

  • Chromatin
  • Interferon Regulatory Factors
  • Proto-Oncogene Proteins
  • Trans-Activators
  • interferon regulatory factor-8
  • proto-oncogene protein Spi-1

Associated data

  • GEO/GSE45467