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Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors

Saunderson, Emily A., Stepper, Peter, Gomm, Jennifer J., Hoa, Lily, Morgan, Adrienne, Allen, Michael D., Jones, J. Louise, Gribben, John G., Jurkowski, Tomasz P. ORCID: and Ficz, Gabriella 2017. Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors. Nature Communications 8 (1) , 1450. 10.1038/s41467-017-01078-2

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Aberrant promoter DNA hypermethylation is a hallmark of cancer; however, whether this is sufficient to drive cellular transformation is not clear. To investigate this question, we use a CRISPR-dCas9 epigenetic editing tool, where an inactive form of Cas9 is fused to DNA methyltransferase effectors. Using this system, here we show simultaneous de novo DNA methylation of genes commonly methylated in cancer, CDKN2A, RASSF1, HIC1 and PTEN in primary breast cells isolated from healthy human breast tissue. We find that promoter methylation is maintained in this system, even in the absence of the fusion construct, and this prevents cells from engaging senescence arrest. Our data show that the key driver of this phenotype is repression of CDKN2A transcript p16 where myoepithelial cells harbour cancer-like gene expression but do not exhibit anchorage-independent growth. This work demonstrates that hit-and-run epigenetic events can prevent senescence entry, which may facilitate tumour initiation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 5 February 2019
Date of Acceptance: 16 August 2017
Last Modified: 25 Oct 2022 13:08

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