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

Authors:
Pawel Durek, Karl Nordström, Gilles Gasparoni, Abdulrahman Salhab, Christopher Kressler, Melanie de Almeida, Kevin Bassler, Thomas Ulas, Florian Schmidt, Jieyi Xiong, Petar Glažar, Filippos Klironomos, Anupam Sinha, Sarah Kinkley, Xinyi Yang, Laura Arrigoni, Azim Dehghani Amirabad, Fatemeh Behjati Ardakani, Lars Feuerbach, Oliver Gorka, Peter Ebert, Fabian Müller, Na Li, Stefan Frischbutter, Stephan Schlickeiser, Carla Cendon, Sebastian Fröhler, Bärbel Felder, Nina Gasparoni, Charles D Imbusch, Barbara Hutter, Gideon Zipprich, Yvonne Tauchmann, Simon Reinke, Georgi Wassilew, Ute Hoffmann, Andreas S Richter, Lina Sieverling, - -, Hyun-Dong Chang, Uta Syrbe, Ulrich Kalus, Jürgen Eils, Benedikt Brors, Thomas Manke, Jürgen Ruland, Thomas Lengauer, Nikolaus Rajewsky, Wei Chen, Jun Dong, Birgit Sawitzki, Ho-Ryun Chung, Philip Rosenstiel, Marcel H Schulz, Joachim L Schultze, Andreas Radbruch, Jörn Walter, Alf Hamann, Julia K Polansky
Year of publication:
2016
Volume:
45
Issue:
5
Issn:
1074-7613
Journal title abbreviated:
IMMUNITY
Journal title long:
Immunity (Cambridge, Mass.)
Impact factor:
24.082
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.