SAM-DNMT3A, a strategy for induction of genome-wide DNA methylation, identifies DNA methylation as a vulnerability in ER-positive breast cancers
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.
Authors
- Pierre‐Antoine Dugué (ORCID: https://orcid.org/0000-0003-2736-3023)
- Catherine Elizabeth Caldon (ORCID: https://orcid.org/0000-0003-1392-3472)
- Joseph Rosenbluh
- Mahnaz Hosseinpour (ORCID: https://orcid.org/0000-0003-4787-1965)
- Senthil Arumugam (ORCID: https://orcid.org/0000-0001-6733-4679)
- Harrison M. York (ORCID: https://orcid.org/0000-0002-4534-8188)
- Luis F. Malaver‐Ortega (ORCID: https://orcid.org/0000-0002-0433-9752)
- Jihoon E. Joo (ORCID: https://orcid.org/0000-0003-3331-5335)
- Melissa C. Southey (ORCID: https://orcid.org/0000-0002-6313-9005)
- Xinqi Xi
- Laura Perlaza-Jiménez (ORCID: https://orcid.org/0000-0002-8511-1134)
- Ling Liu (ORCID: https://orcid.org/0009-0001-3822-1111)
- James G. Dowty (ORCID: https://orcid.org/0000-0003-2383-0886)
Institutions
- Garvan Institute of Medical Research (AU)
- The University of Melbourne (AU)
- Cancer Council Victoria (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Discovery Institute (US)
- Australian Regenerative Medicine Institute (AU)
- Monash Medical Centre (AU)
- Monash Health (AU)
- The Kinghorn Cancer Centre (AU)
- Monash University (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1038/s41467-024-54824-8
- Citations
- 1
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.23
Funders
- Victorian Cancer Agency
- Marshfield Clinic Research Foundation
- QIMR Berghofer Medical Research Institute
- Monash University
- University of the Sunshine Coast
- National Health and Medical Research Council