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Nucleic Acids Res. 2015 Nov 16;43(20):9680-93. doi: 10.1093/nar/gkv1056. Epub 2015 Oct 17.

Epigenetic program and transcription factor circuitry of dendritic cell development.

Author information

1
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.
2
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.
3
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.
4
IZKF Computational Biology Research Group, RWTH Aachen University Medical School, 52074 Aachen, Germany.
5
Genomics Core Facilities GeneCore, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
6
Ludwig Boltzmann Institute for Cancer Research, University of Veterinary Medicine, Medical University Vienna, 1090 Vienna, Austria.
7
GIGA-Genomics, University of Liège, 4000 Liège, Belgium.
8
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.
9
Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany.
10
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.

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.

PMID:
26476451
PMCID:
PMC4787753
DOI:
10.1093/nar/gkv1056
[Indexed for MEDLINE]
Free PMC Article

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