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

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. Dowty, Senthil Arumugam, Melissa C. Southey () and Joseph Rosenbluh ()
Additional contact information
Mahnaz Hosseinpour: Monash University
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
James G. Dowty: The University of Melbourne
Senthil Arumugam: Monash University
Melissa C. Southey: Monash University
Joseph Rosenbluh: Monash University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54824-8

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