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
Received Date: 12th November 19
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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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.