DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation

Laura Godfrey, Nicholas T. Crump, Ross Thorne, I-Jun Lau, Emmanouela Repapi, Dimitra Dimou, Alastair L. Smith, Joe R. Harman, Jelena M. Telenius, A. Marieke Oudelaar, Damien J. Downes, Paresh Vyas, Jim R. Hughes and Thomas A. Milne ()
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Laura Godfrey: University of Oxford
Nicholas T. Crump: University of Oxford
Ross Thorne: University of Oxford
I-Jun Lau: University of Oxford
Emmanouela Repapi: University of Oxford
Dimitra Dimou: University of Oxford
Alastair L. Smith: University of Oxford
Joe R. Harman: University of Oxford
Jelena M. Telenius: University of Oxford
A. Marieke Oudelaar: University of Oxford
Damien J. Downes: University of Oxford
Paresh Vyas: University of Oxford
Jim R. Hughes: University of Oxford
Thomas A. Milne: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (H3K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.

Date: 2019
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DOI: 10.1038/s41467-019-10844-3

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