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

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.

Ho-Ryun Chung | Thomas Lengauer | Florian Schmidt | Marcel H Schulz | Marcel H. Schulz | Thomas Manke | Jörn Walter | Philip Rosenstiel | Barbara Hutter | Benedikt Brors | Thomas Ulas | Laura Arrigoni | Ute Hoffmann | Nikolaus Rajewsky | Lars Feuerbach | Na Li | Peter Ebert | Azim Dehghani Amirabad | Jürgen Eils | Gilles Gasparoni | Anupam Sinha | Karl Nordström | Andreas S. Richter | Jürgen Ruland | Lina Sieverling | Hyun-Dong Chang | Petar Glažar | Joachim L Schultze | Kevin Bassler | Georgi Wassilew | Fabian Müller | Alf Hamann | Sebastian Fröhler | Gideon Zipprich | Pawel Durek | Fatemeh Behjati Ardakani | Thomas Lengauer | Petar Glažar | N. Rajewsky | Na Li | B. Hutter | P. Rosenstiel | B. Brors | J. Walter | Ho-Ryun Chung | Hyun-Dong Chang | G. Wassilew | Jun Dong | K. Nordström | J. Ruland | P. Durek | F. Klironomos | A. Radbruch | F. Müller | T. Ulas | J. Schultze | Florian Schmidt | Nina Gasparoni | G. Gasparoni | J. Polansky | Peter Ebert | A. Sinha | Jieyi Xiong | Gideon Zipprich | B. Felder | J. Eils | Wei Chen | A. Hamann | U. Syrbe | S. Kinkley | K. Baßler | L. Arrigoni | T. Manke | S. Frischbutter | B. Sawitzki | L. Feuerbach | L. Sieverling | Charles D Imbusch | C. Kressler | Abdulrahman Salhab | Xinyi Yang | S. Schlickeiser | Filippos Klironomos | Andreas Radbruch | Sarah Kinkley | Wei Chen | Uta Syrbe | Abdulrahman Salhab | Christopher Kressler | Melanie de Almeida | Jieyi Xiong | Xinyi Yang | Oliver Gorka | Stefan Frischbutter | Stephan Schlickeiser | Carla Cendon | Bärbel Felder | Nina Gasparoni | Yvonne Tauchmann | Simon Reinke | Andreas S Richter | Ulrich Kalus | Jun Dong | Birgit Sawitzki | Julia K Polansky | U. Hoffmann | Charles D. Imbusch | U. Kalus | Carla Cendón | Sebastian Fröhler | O. Gorka | Melanie de Almeida | C. Imbusch | Yvonne Tauchmann | S. Reinke | A. Amirabad | K. Bassler | Laura Arrigoni

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