A novel disrupter of telomere silencing 1-like (DOT1L) interaction is required for signal transducer and activator of transcription 1 (STAT1)-activated gene expression.

gene expression is both rapid and transient and requires dynamic post-translational modification of the chromatin template. Previously, we showed that following IFN-γ treatment, trimethylation of histone H3 at lysine 79 (H3K79me3) is rapidly and highly induced in the 5'-end of the gene interferon regulatory factor 1 (IRF1), but the role of this histone modification was unexplored. Here we report that DOT1L, the non-SET domain containing methyltransferase that modifies Lys-79, is localized across IRF1 in the uninduced state and is not further recruited by IFN-γ induction. depletion of DOT1L prevents the induction of H3K79me3 and lowers the transcription of IRF1 2-fold, as expected. Surprisingly, binding to its DNA recognition element near the IRF1 promoter is diminished 2-fold in the DOT1L-depleted cell line. In vivo and in vitro protein interaction assays reveal a interaction. Domain mapping identifies the middle region of DOT1L (amino acids 580-1183) as the duanyu18131 interaction domain. Overexpression of the DOT1L duanyu18131 interaction domain represses IRF1 transcription (2-fold) and interferes with duanyu18131 DNA binding at IRF1 and endogenous DOT1L histone methyltransferase activity. Collectively, our findings reveal a novel interaction that is required for the regulation gene expression.

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