title: Epigenomic Profiling of Human CD4+T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development.
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.
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Durek
authors.affiliation: Department of Genetics, University of Saarland, 66123 Saarbrücken, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Nordström
authors.affiliation: Department of Genetics, University of Saarland, 66123 Saarbrücken, Germany.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasparoni
authors.affiliation: Department of Genetics, University of Saarland, 66123 Saarbrücken, Germany.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Salhab
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kressler
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: de Almeida
authors.affiliation: Life and Medical Sciences Institute, Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bassler
authors.affiliation: Life and Medical Sciences Institute, Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulas
authors.affiliation: 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Jieyi
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Petar
authors.initials: P
authors.lastname: Glažar
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Filippos
authors.initials: F
authors.lastname: Klironomos
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Anupam
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Otto Warburg Laboratories: Epigenomics at Max Plank Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kinkley
authors.affiliation: Otto Warburg Laboratories: Epigenomics at Max Plank Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 78108 Freiburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Arrigoni
authors.affiliation: 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.
authors.forename: Azim Dehghani
authors.initials: AD
authors.lastname: Amirabad
authors.affiliation: 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.
authors.forename: Fatemeh Behjati
authors.initials: FB
authors.lastname: Ardakani
authors.affiliation: Applied Bioinformatics, Deutsches Krebsforschungszentrum, 59120 Heidelberg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Feuerbach
authors.affiliation: Institute for Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University 81675 Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gorka
authors.affiliation: Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ebert
authors.affiliation: Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Müller
authors.affiliation: Otto Warburg Laboratories: Epigenomics at Max Plank Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Frischbutter
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, 13353 Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schlickeiser
authors.affiliation: Cell Biology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Carla
authors.initials: C
authors.lastname: Cendon
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fröhler
authors.affiliation: Data Management and Genomics IT, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Felder
authors.affiliation: Department of Genetics, University of Saarland, 66123 Saarbrücken, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Gasparoni
authors.affiliation: Applied Bioinformatics, Deutsches Krebsforschungszentrum, 59120 Heidelberg, Germany.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Imbusch
authors.affiliation: Applied Bioinformatics, Deutsches Krebsforschungszentrum, 59120 Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.affiliation: Data Management and Genomics IT, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany.
authors.forename: Gideon
authors.initials: G
authors.lastname: Zipprich
authors.affiliation: Institut für Transfusionsmedizin, Charité University Medicine, 12203 Berlin, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Tauchmann
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, 13353 Berlin, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Reinke
authors.affiliation: Center for Musculoskeletal Surgery, Charité University Medicine, 10117 Berlin, Germany.
authors.forename: Georgi
authors.initials: G
authors.lastname: Wassilew
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 78108 Freiburg, Germany.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Richter
authors.affiliation: Applied Bioinformatics, Deutsches Krebsforschungszentrum, 59120 Heidelberg, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Sieverling
authors.affiliation: http://www.deutsches-epigenom-programm.de/.
authors.affiliation: Cell Biology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Chang
authors.affiliation: Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Charité University Medicine, 12000 Berlin, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Syrbe
authors.affiliation: Institut für Transfusionsmedizin, Charité University Medicine, 12203 Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalus
authors.affiliation: Data Management and Genomics IT, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Eils
authors.affiliation: Applied Bioinformatics, Deutsches Krebsforschungszentrum, 59120 Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 78108 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Manke
authors.affiliation: 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.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Department of Computational Biology and Applied Algorithmics, Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
authors.affiliation: Systems Biology of Gene Regulatory Elements, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rajewsky
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Cell Biology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Jun
authors.initials: J
authors.lastname: Dong
authors.affiliation: Institute of Medical Immunology, Charité University Medicine, 13353 Berlin, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.affiliation: Otto Warburg Laboratories: Epigenomics at Max Plank Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Ho-Ryun
authors.initials: HR
authors.lastname: Chung
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: 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.
authors.forename: Marcel H
authors.initials: MH
authors.lastname: Schulz
authors.affiliation: Life and Medical Sciences Institute, Genomics and Immunoregulation, University of Bonn, 53115 Bonn, Germany.
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.affiliation: Cell Biology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: Department of Genetics, University of Saarland, 66123 Saarbrücken, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Walter
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.affiliation: Experimental Rheumatology, German Rheumatism Research Centre, 10117 Berlin, Germany. Electronic address: julia.polansky@drfz.de.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Polansky
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D044127:Epigenesis, Genetic / Q000276:immunology*; D057890:Epigenomics / Q000379:methods*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D000069550:Machine Learning; D016133:Polymerase Chain Reaction; D059467:Transcriptome