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

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Item Type:Article
Title:PU.1 level-directed chromatin structure remodeling at the Irf8 gene drives dendritic cell commitment
Creators Name:Schönheit, J. and Kuhl, C. and Gebhardt, M.L. and Klett, F.F. and Riemke, P. and Scheller, M. and Huang, G. and Naumann, R. and Leutz, A. and Stocking, C. and Priller, J. and Andrade-Navarro, M.A. and Rosenbauer, F.
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.
Keywords:Base Sequence, Bone Marrow Cells, Cell Differentiation, Cell Lineage, Chromatin, Chromatin Assembly and Disassembly, Cultured Cells, Dendritic Cells, Genetic Promoter Regions, Interferon Regulatory Factors, Myeloid Cells, Proto-Oncogene Proteins, Trans-Activators, Animals, Mice
Source:Cell Reports
Publisher:Cell Press / Elsevier
Page Range:1617-1628
Date:30 May 2013
Official Publication:https://doi.org/10.1016/j.celrep.2013.04.007
PubMed:View item in PubMed

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