@article{527bb1f49bb04279a3af6c1f5d7ffd89,
title = "The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells during Infection and Inflammation",
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 are resistant to the development of allergic lung inflammation. These results identify a central role for DOT1L in Th2 cell lineage commitment and stability and suggest that inhibition of DOT1L may provide a therapeutic strategy to limit type 2 immune responses.",
keywords = "asthma, CD4 T cells, DOT1L, IFN-γ, Th1, Th2, Trichuris muris",
author = "Sebastian Scheer and Jessica Runting and Michael Bramhall and Brendan Russ and Aidil Zaini and Jessie Ellemor and Grace Rodrigues and Judy Ng and Colby Zaph",
note = "Funding Information: We would like to thank Dr. Kim Jacobson for constructive comments and advice on the manuscript. We thank the Monash animal facility, Micromon; the Monash Flow Core facility; and the Monash Bioinformatics platform for their excellent technical support and assistance. We thank Dr. Ron Germain (NIAID) and Dr. Simon Phipps (QIMR Berghofer) for providing 4C13R mice ( Huang et al., 2015 ). This work was supported by NHMRC project grants ( APP1104433 and APP1104466 ) and a Monash platform access grant ( PAG19-0642 ). Graphical Abstract was created using BioRender.com . Funding Information: We would like to thank Dr. Kim Jacobson for constructive comments and advice on the manuscript. We thank the Monash animal facility, Micromon; the Monash Flow Core facility; and the Monash Bioinformatics platform for their excellent technical support and assistance. We thank Dr. Ron Germain (NIAID) and Dr. Simon Phipps (QIMR Berghofer) for providing 4C13R mice (Huang et al. 2015). This work was supported by NHMRC project grants (APP1104433 and APP1104466) and a Monash platform access grant (PAG19-0642). Graphical Abstract was created using BioRender.com. Conceptualization, S.S. B.R. and C.Z.; Methodology, S.S. and C.Z.; Investigation, M.B. J.R. A.Z. J.E. G.R. and J.N.; Writing ? Original Draft, S.S. and C.Z.; Writing ? Review & Editing, S.S. and C.Z.; Funding Acquisition, C.Z. and S.S.; Supervision, S.S. M.B. and C.Z.; Visualization, S.S. and J.R.; Formal Analysis, S.S.; Validation, J.R. M.B. J.E. and S.S. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = dec,
day = "15",
doi = "10.1016/j.celrep.2020.108505",
language = "English",
volume = "33",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}