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

Author

Listed:
  • 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
    University of Oxford)

  • A. Marieke Oudelaar

    (University of Oxford
    University of Oxford)

  • Damien J. Downes

    (University of Oxford)

  • Paresh Vyas

    (University of Oxford
    Oxford University Hospitals NHS Foundation Trust)

  • Jim R. Hughes

    (University of Oxford
    University of Oxford)

  • Thomas A. Milne

    (University of Oxford)

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.

Suggested Citation

  • 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 & Pare, 2019. "DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10844-3
    DOI: 10.1038/s41467-019-10844-3
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    Cited by:

    1. Derek H. Janssens & Melodie Duran & Dominik J. Otto & Weifang Wu & Yiling Xu & Danielle Kirkey & Charles G. Mullighan & Joanna S. Yi & Soheil Meshinchi & Jay F. Sarthy & Kami Ahmad & Steven Henikoff, 2024. "MLL oncoprotein levels influence leukemia lineage identities," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Siobhan Rice & Thomas Jackson & Nicholas T. Crump & Nicholas Fordham & Natalina Elliott & Sorcha O’Byrne & Maria del Mar Lara Fanego & Dilys Addy & Trisevgeni Crabb & Carryl Dryden & Sarah Inglott & D, 2021. "A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    3. Gayan I. Balasooriya & David L. Spector, 2022. "Allele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Shaela Wright & Xujie Zhao & Wojciech Rosikiewicz & Shelby Mryncza & Judith Hyle & Wenjie Qi & Zhenling Liu & Siqi Yi & Yong Cheng & Beisi Xu & Chunliang Li, 2023. "Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Nicholas T. Crump & Alastair L. Smith & Laura Godfrey & Ana M. Dopico-Fernandez & Nicholas Denny & Joe R. Harman & Joseph C. Hamley & Nicole E. Jackson & Catherine Chahrour & Simone Riva & Siobhan Ric, 2023. "MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Shengyong Yu & Chunhua Zhou & Jiangping He & Zhaokai Yao & Xingnan Huang & Bowen Rong & Hong Zhu & Shijie Wang & Shuyan Chen & Xialian Wang & Baomei Cai & Guoqing Zhao & Yuhan Chen & Lizhan Xiao & He , 2022. "BMP4 drives primed to naïve transition through PGC-like state," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. Paola Cattaneo & Michael G. B. Hayes & Nina Baumgarten & Dennis Hecker & Sofia Peruzzo & Galip S. Aslan & Paolo Kunderfranco & Veronica Larcher & Lunfeng Zhang & Riccardo Contu & Gregory Fonseca & Sim, 2022. "DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    8. Kate M. MacDonald & Shirony Nicholson-Puthenveedu & Maha M. Tageldein & Sarika Khasnis & Cheryl H. Arrowsmith & Shane M. Harding, 2023. "Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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