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Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer

Achinger-Kawecka, Joanna, Valdes-Mora, Fatima, Luu, Phuc-Loi, Giles, Katherine A., Caldon, C. Elizabeth, Qu, Wenjia, Nair, Shalima, Soto, Sebastian, Locke, Warwick J., Yeo-Teh, Nicole S., Gould, Cathryn M., Du, Qian, Smith, Grady C., Ramos, Irene R., Fernandez, Kristine F., Hoon, Dave S., Gee, Julia M. W., Stirzaker, Clare and Clark, Susan J. 2020. Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer. Nature Communications 11 (1) , 320. 10.1038/s41467-019-14098-x

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Abstract

Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 21 January 2020
Date of Acceptance: 12 December 2019
Last Modified: 22 Jan 2020 11:45
URI: http://orca-mwe.cf.ac.uk/id/eprint/128892

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