TY - JOUR
T1 - PU.1 Level-Directed Chromatin Structure Remodeling at the Irf8 Gene Drives Dendritic Cell Commitment
AU - Schönheit, Jörg
AU - Kuhl, Christiane
AU - Gebhardt, Marie Luise
AU - Klett, Francisco Fernández
AU - Riemke, Pia
AU - Scheller, Marina
AU - Huang, Gang
AU - Naumann, Ronald
AU - Leutz, Achim
AU - Stocking, Carol
AU - Priller, Josef
AU - Andrade-Navarro, Miguel A.
AU - Rosenbauer, Frank
N1 - Funding Information:
We thank V. Malchin, N. Endruhn, V. Gröning, M. Käse, and A. Schenk for technical assistance; T. Schröder for plasmids; S. Jung for Cx3cr1 GFP mice; and M. Feuerer for suggestions on the manuscript. This work was supported by grants from the Helmholtz Association of German Research Centers to F.R., the Helmholtz Alliance on Systems Biology to M.A.A.-N., the Deutsche Forschungsgemeinschaft Priority program 1463 to F.R. and M.A.A.-N, the Deutsche Forschungsgemeinschaft Research Unit 1336 to J.P. and F.R., the Deutsche Krebshilfe to C.S. and F.R., and the Deutsche Jose Carreras’s Stiftung to C.S. J.S., C.K., P.R., M.S. and G.H. conducted experiments. M.L.G. and M.A.A.-N. performed computational analyses. F.F.K. and J.P. performed immunohistochemistry. R.N. injected the transgenic constructs into fertilized eggs. A.L. and C.S. provided essential experimental support. F.R. and J.S. wrote the manuscript. F.R. designed and supervised the project. All authors made comments on the manuscript.
PY - 2013/5/30
Y1 - 2013/5/30
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2013.04.007
DO - 10.1016/j.celrep.2013.04.007
M3 - Article
C2 - 23623495
AN - SCOPUS:84878605147
SN - 2211-1247
VL - 3
SP - 1617
EP - 1628
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -