Journal article
SAM-DNMT3A, a strategy for induction of genome-wide DNA methylation, identifies DNA methylation as a vulnerability in ER-positive breast cancers
M Hosseinpour, X Xi, L Liu, L Malaver-Ortega, L Perlaza-Jimenez, JE Joo, HM York, J Beesley, CE Caldon, PA Dugué, JG Dowty, S Arumugam, MC Southey, J Rosenbluh
Nature Communications | NATURE PORTFOLIO | Published : 2024
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-pos..
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Grants
Awarded by Monash University
Funding Acknowledgements
This work was supported by an NHMRC Synergy grant to J.R. and M.C.S. (grant number: 2011329). J.R. is supported by a Victoria Cancer Agency fellowship (grant number: MCRF20035). M.C.S is supported by a Level 3 NHMRC Investigator grant (grant number: GNT2017325). We thank the Functional Genomics Platform, and the Genomics and Bioinformatics Platform at Monash University for help with loss of function screens and data analysis. We thank Phenomics Australia for support of pooled screening experiments. We thank Dr. Gavin Knott (Monash University) for helpful discussions. We thank Prof. Georgia Chenevix-Trench (QIMR), Prof. Roger Reddel (University of Sydney) and Prof. Vilma Band (University of Nebraska) for providing cell lines. We thank Dr. Lochlan Fennell (University of the Sunshine Coast) for help with the HRM assay.