Journal
CELL REPORTS
Volume 33, Issue 11, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108505
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Funding
- NHMRC [APP1104433, APP1104466]
- Monash platform access grant [PAG19-0642]
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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. DOT1 L-dependent dimethylation of lysine 79 of histone H3 (H3K79me2) is associated with lineage-specific gene expression. However, DOT1L-deficient Th cells overproduce I FN-gamma under lineage-specific and lineage-promiscuous conditions. Consistent with the increased I FN-gamma 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.
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