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SAM-DNMT3A, a strategy for induction of genome-wide DNA methylation, identifies DNA methylation as a vulnerability in ER-positive breast cancers

Author

Listed:
  • Mahnaz Hosseinpour

    (Monash University
    Monash University
    The University of Melbourne)

  • Xinqi Xi

    (Monash University)

  • Ling Liu

    (Monash University)

  • Luis Malaver-Ortega

    (Monash University)

  • Laura Perlaza-Jimenez

    (Monash University)

  • Jihoon E. Joo

    (The University of Melbourne)

  • Harrison M. York

    (Monash University)

  • Jonathan Beesley

    (QIMR Berghofer Medical Research Institute)

  • C. Elizabeth Caldon

    (Garvan Institute of Medical Research)

  • Pierre-Antoine Dugué

    (Monash University
    Cancer Council Victoria
    The University of Melbourne)

  • James G. Dowty

    (The University of Melbourne)

  • Senthil Arumugam

    (Monash University
    Monash University)

  • Melissa C. Southey

    (Monash University
    The University of Melbourne
    Cancer Council Victoria)

  • Joseph Rosenbluh

    (Monash University
    Monash University)

Abstract

DNA methylation is an epigenetic mark that plays a critical role in regulating gene expression. DNA methyltransferase (DNMT) inhibitors, inhibit global DNA methylation and have been a key tool in studies of DNA methylation. A major bottleneck is the lack of tools to induce global DNA methylation. Here, we engineered a CRISPR based approach, that we initially designed, to enable site-specific DNA methylation. Using the synergistic activation mediator (SAM) system, we unexpectedly find that regardless of the targeted sequence any sgRNA induces global genome-wide DNA methylation. We term this method SAM-DNMT3A and show that induction of global DNA methylation is a unique vulnerability in ER-positive breast cancer suggesting a therapeutic approach. Our findings highlight the need of caution when using CRISPR based approaches for inducing DNA methylation and demonstrate a method for global induction of DNA methylation.

Suggested Citation

  • Mahnaz Hosseinpour & Xinqi Xi & Ling Liu & Luis Malaver-Ortega & Laura Perlaza-Jimenez & Jihoon E. Joo & Harrison M. York & Jonathan Beesley & C. Elizabeth Caldon & Pierre-Antoine Dugué & James G. Dow, 2024. "SAM-DNMT3A, a strategy for induction of genome-wide DNA methylation, identifies DNA methylation as a vulnerability in ER-positive breast cancers," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54824-8
    DOI: 10.1038/s41467-024-54824-8
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