title: PU.1 level-directed chromatin structure remodeling at the Irf8 gene drives dendritic cell commitment.
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.
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schönheit
authors.forename: Christiane
authors.initials: C
authors.lastname: Kuhl
authors.forename: Marie Luise
authors.initials: ML
authors.lastname: Gebhardt
authors.forename: Francisco Fernández
authors.initials: FF
authors.lastname: Klett
authors.forename: Pia
authors.initials: P
authors.lastname: Riemke
authors.forename: Marina
authors.initials: M
authors.lastname: Scheller
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Ronald
authors.initials: R
authors.lastname: Naumann
authors.forename: Achim
authors.initials: A
authors.lastname: Leutz
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.forename: Frank
authors.initials: F
authors.lastname: Rosenbauer
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D002843:Chromatin; D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1