IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-10844-3.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-10844-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-019-10844-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10844-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.