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The lysine methyltransferase DOT1L controls CD4+ T cell-dependent immunity and inflammation

View ORCID ProfileS. Scheer, View ORCID ProfileM. Bramhall, J. Runting, B. Russ, Q. Zhang, S. F. Flanigan, A. Zaini, J. Ellemor, G. Rodrigues, J. Ng, C. Davidovich, View ORCID ProfileC. Zaph
doi: https://doi.org/10.1101/821348
S. Scheer
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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  • For correspondence: colby.zaph@monash.edu sebastian.scheer@monash.edu
M. Bramhall
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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J. Runting
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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B. Russ
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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Q. Zhang
2Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton VIC 3800, Australia
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S. F. Flanigan
2Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton VIC 3800, Australia
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A. Zaini
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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J. Ellemor
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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G. Rodrigues
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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J. Ng
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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C. Davidovich
2Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton VIC 3800, Australia
3EMBL-Australia and the ARC Centre of Excellence in Advanced Molecular Imaging, Clayton, VIC 3800, Australia
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C. Zaph
1Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton VIC 3800, Australia
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  • ORCID record for C. Zaph
  • For correspondence: colby.zaph@monash.edu sebastian.scheer@monash.edu
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Abstract

CD4+ T helper (Th) cell differentiation is controlled by lineage-specific expression of transcription factors and effector proteins, as well as silencing of lineage-promiscuous genes. Lysine methyltransferases (KMTs) comprise a major class of epigenetic enzymes that are emerging as important regulators of Th cell biology. Here, we show that the KMT DOT1L regulates Th cell function and lineage integrity. DOT1L-dependent dimethylation of lysine 79 of histone H3 (H3K79me2) is associated with lineage-specific gene expression. However, DOT1L-deficient Th cells overproduce IFN-γ under lineage-specific and lineage-promiscuous conditions. Consistent with the increased IFN-γ response, mice with a T cell-specific deletion of DOT1L are susceptible to infection with the helminth parasite Trichuris muris and resistant to the development of allergic lung inflammation. These results identify a central role for DOT1L in Th cell lineage commitment and stability, and suggest that inhibition of DOT1L may provide a novel therapeutic strategy to limit type 2 immune responses.

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  • ↵† Lead contact

  • Expanded Discussion. New Figure included. Author list updated. Supplemental file added.

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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 14, 2019.
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The lysine methyltransferase DOT1L controls CD4+ T cell-dependent immunity and inflammation
S. Scheer, M. Bramhall, J. Runting, B. Russ, Q. Zhang, S. F. Flanigan, A. Zaini, J. Ellemor, G. Rodrigues, J. Ng, C. Davidovich, C. Zaph
bioRxiv 821348; doi: https://doi.org/10.1101/821348
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The lysine methyltransferase DOT1L controls CD4+ T cell-dependent immunity and inflammation
S. Scheer, M. Bramhall, J. Runting, B. Russ, Q. Zhang, S. F. Flanigan, A. Zaini, J. Ellemor, G. Rodrigues, J. Ng, C. Davidovich, C. Zaph
bioRxiv 821348; doi: https://doi.org/10.1101/821348

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