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Immunity. 2016 Nov 15;45(5):1148-1161. doi: 10.1016/j.immuni.2016.10.022.

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development.

Author information

1
Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany.
2
Department of Genetics, University of Saarland, 66123 Saarbrücken, Germany.
3
Life and Medical Sciences Institute, Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany.
4
Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany; Excellence Cluster on Multimodal Computing and Interaction, Saarland University, 66123 Saarbrücken, Germany.
5
Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
6
Systems Biology of Gene Regulatory Elements, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
7
Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.
8
Otto Warburg Laboratories: Epigenomics at Max Plank Institute for Molecular Genetics, 14195 Berlin, Germany.
9
Max Planck Institute of Immunobiology and Epigenetics, 78108 Freiburg, Germany.
10
Applied Bioinformatics, Deutsches Krebsforschungszentrum, 59120 Heidelberg, Germany.
11
Institute for Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University 81675 Munich, Germany.
12
Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
13
Institute of Medical Immunology, Charité University Medicine, 13353 Berlin, Germany.
14
Cell Biology, German Rheumatism Research Centre, 10117 Berlin, Germany.
15
Data Management and Genomics IT, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany.
16
Institut für Transfusionsmedizin, Charité University Medicine, 12203 Berlin, Germany.
17
Berlin-Brandenburg Center for Regenerative Therapies, 13353 Berlin, Germany.
18
Center for Musculoskeletal Surgery, Charité University Medicine, 10117 Berlin, Germany.
19
http://www.deutsches-epigenom-programm.de/.
20
Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité University Medicine, 12000 Berlin, Germany.
21
Institute for Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University 81675 Munich, Germany; German Cancer Consortium (DKTK), 59120 Heidelberg, Germany; German Center for Infection Research (DZIF), partner site 81675 Munich, Germany.
22
Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany. Electronic address: julia.polansky@drfz.de.

Abstract

The impact of epigenetics on the differentiation of memory T (Tmem) cells is poorly defined. We generated deep epigenomes comprising genome-wide profiles of DNA methylation, histone modifications, DNA accessibility, and coding and non-coding RNA expression in naive, central-, effector-, and terminally differentiated CD45RA+ CD4+ Tmem cells from blood and CD69+ Tmem cells from bone marrow (BM-Tmem). We observed a progressive and proliferation-associated global loss of DNA methylation in heterochromatic parts of the genome during Tmem cell differentiation. Furthermore, distinct gradually changing signatures in the epigenome and the transcriptome supported a linear model of memory development in circulating T cells, while tissue-resident BM-Tmem branched off with a unique epigenetic profile. Integrative analyses identified candidate master regulators of Tmem cell differentiation, including the transcription factor FOXP1. This study highlights the importance of epigenomic changes for Tmem cell biology and demonstrates the value of epigenetic data for the identification of lineage regulators.

PMID:
27851915
DOI:
10.1016/j.immuni.2016.10.022
[Indexed for MEDLINE]
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