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The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells

View ORCID ProfileEliza Mari Kwesi-Maliepaard, View ORCID ProfileMuhammad Assad Aslam, View ORCID ProfileMir Farshid Alemdehy, View ORCID ProfileTeun van den Brand, View ORCID ProfileChelsea McLean, View ORCID ProfileHanneke Vlaming, Tibor van Welsem, View ORCID ProfileTessy Korthout, Cesare Lancini, Sjoerd Hendriks, View ORCID ProfileTomasz Ahrends, View ORCID ProfileDieke van Dinther, View ORCID ProfileJoke M.M. den Haan, View ORCID ProfileJannie Borst, View ORCID ProfileElzo de Wit, View ORCID ProfileFred van Leeuwen, View ORCID ProfileHeinz Jacobs
doi: https://doi.org/10.1101/826255
Eliza Mari Kwesi-Maliepaard
1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Muhammad Assad Aslam
2Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
3Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, 60800 Multan, Pakistan
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Mir Farshid Alemdehy
2Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Teun van den Brand
4Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, and Oncode Institute, The Netherlands
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Chelsea McLean
1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Hanneke Vlaming
1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Tibor van Welsem
1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Tessy Korthout
1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Cesare Lancini
1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Sjoerd Hendriks
1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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Tomasz Ahrends
5Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, and Oncode Institute, The Netherlands
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Dieke van Dinther
6Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, 1081HV Amsterdam, The Netherlands
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Joke M.M. den Haan
6Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Location VUmc, 1081HV Amsterdam, The Netherlands
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Jannie Borst
5Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, and Oncode Institute, The Netherlands
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Elzo de Wit
4Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, and Oncode Institute, The Netherlands
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Fred van Leeuwen
1Division of Gene Regulation, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
7Department of Medical Biology, Amsterdam UMC, location AMC, UvA, 1105 AZ Amsterdam, The Netherlands
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  • For correspondence: fred.v.leeuwen@nki.nl h.jacobs@nki.nl
Heinz Jacobs
2Division of Tumor Biology & Immunology, Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands
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  • ORCID record for Heinz Jacobs
  • For correspondence: fred.v.leeuwen@nki.nl h.jacobs@nki.nl
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Abstract

Cytotoxic T-cell differentiation is guided by epigenome adaptations but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+ T cells. T-cell specific ablation of Dot1L resulted in loss of naïve CD8+ T cells and premature differentiation towards a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Without DOT1L, the memory-like CD8+ cells fail to acquire full effector functions in vitro and in vivo. Mechanistically, DOT1L controlled T-cell differentiation and function by ensuring normal T-cell receptor density and signaling, and by maintaining epigenetic identity, in part by indirectly supporting the repression of developmentally-regulated genes. Through our study DOT1L is emerging as a central player in physiology of CD8+ T cells, acting as a barrier to prevent premature differentiation and supporting the licensing of the full effector potential of cytotoxic T cells.

Footnotes

  • Lead contact: Fred van Leeuwen

  • Fixed small text issues.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 18, 2019.
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The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells
Eliza Mari Kwesi-Maliepaard, Muhammad Assad Aslam, Mir Farshid Alemdehy, Teun van den Brand, Chelsea McLean, Hanneke Vlaming, Tibor van Welsem, Tessy Korthout, Cesare Lancini, Sjoerd Hendriks, Tomasz Ahrends, Dieke van Dinther, Joke M.M. den Haan, Jannie Borst, Elzo de Wit, Fred van Leeuwen, Heinz Jacobs
bioRxiv 826255; doi: https://doi.org/10.1101/826255
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The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells
Eliza Mari Kwesi-Maliepaard, Muhammad Assad Aslam, Mir Farshid Alemdehy, Teun van den Brand, Chelsea McLean, Hanneke Vlaming, Tibor van Welsem, Tessy Korthout, Cesare Lancini, Sjoerd Hendriks, Tomasz Ahrends, Dieke van Dinther, Joke M.M. den Haan, Jannie Borst, Elzo de Wit, Fred van Leeuwen, Heinz Jacobs
bioRxiv 826255; doi: https://doi.org/10.1101/826255

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