title: Epigenetic program and transcription factor circuitry of dendritic cell development.
abstract: Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development.
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, 52074 Aachen, Germany Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, 52074 Aachen, Germany Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany Department of Dermatology, University Hospital Essen, 45147 Essen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Chauvistré
authors.affiliation: IZKF Computational Biology Research Group, RWTH Aachen University Medical School, 52074 Aachen, Germany Aachen Institute for Advanced Study in Computational Engineering Science (AICES), RWTH Aachen University, 52062 Aachen, Germany.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Costa
authors.affiliation: IZKF Computational Biology Research Group, RWTH Aachen University Medical School, 52074 Aachen, Germany.
authors.forename: Eduardo G
authors.initials: EG
authors.lastname: Gusmao
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, 52074 Aachen, Germany Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Mitzka
authors.affiliation: IZKF Computational Biology Research Group, RWTH Aachen University Medical School, 52074 Aachen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hänzelmann
authors.affiliation: Genomics Core Facilities GeneCore, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
authors.forename: Bianka
authors.initials: B
authors.lastname: Baying
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, 52074 Aachen, Germany Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Klisch
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, University of Veterinary Medicine, Medical University Vienna, 1090 Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: GIGA-Genomics, University of Liège, 4000 Liège, Belgium.
authors.forename: Benoit
authors.initials: B
authors.lastname: Hennuy
authors.affiliation: Department of Genetics and Cell Biology, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands Research Schools CARIM and GROW, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands.
authors.forename: Hubert
authors.initials: H
authors.lastname: Smeets
authors.affiliation: Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Kurt
authors.initials: K
authors.lastname: Hoffmann
authors.affiliation: Genomics Core Facilities GeneCore, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, 52074 Aachen, Germany Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Seré
authors.affiliation: Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, 52074 Aachen, Germany Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, 52074 Aachen, Germany martin.zenke@rwth-aachen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenke
mesh_terms: D000818:Animals; D019070:Cell Lineage; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D006657:Histones; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1