Objective: Histone methyltransferases are emerging targets for epigenetic therapy. DOT1L (disruptor of telomeric silencing 1-like) is the H3K79 methylation writer. We investigated its role in the development of intimal hyperplasia (IH). Approach and Results: IH was induced via balloon angioplasty in rat carotid arteries. DOT1L and its catalytic products H3K79me2 and H3K79me3 (immunostaining) increased by 4.69 ±0.34, 2.38 ±0.052, and 3.07 ±0.27 fold, respectively, in injured (versus uninjured)

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... rotid arteries at post-injury day 7. DOT1L silencing via shRNA-lentivirus infusion in injured arteries reduced DOT1L, H3K79me2, and IH at day 14 by 54.5%, 37.1%, and 76.5%, respectively. Moreover, perivascular administration of a DOT1L-selective inhibitor (EPZ5676) reduced H3K79me2, H3K79me3, and IH by 56.1%, 58.6%, and 39.9%, respectively. Conclusions: DOT1L inhibition mitigates the development of IH.