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

Author

Listed:
  • Joanna Achinger-Kawecka

    (Garvan Institute of Medical Research
    UNSW Sydney)

  • Fatima Valdes-Mora

    (Garvan Institute of Medical Research
    UNSW Sydney)

  • Phuc-Loi Luu

    (Garvan Institute of Medical Research
    UNSW Sydney)

  • Katherine A. Giles

    (Garvan Institute of Medical Research)

  • C. Elizabeth Caldon

    (The Kinghorn Cancer Centre)

  • Wenjia Qu

    (Garvan Institute of Medical Research)

  • Shalima Nair

    (Garvan Institute of Medical Research)

  • Sebastian Soto

    (Garvan Institute of Medical Research)

  • Warwick J. Locke

    (Garvan Institute of Medical Research)

  • Nicole S. Yeo-Teh

    (Garvan Institute of Medical Research)

  • Cathryn M. Gould

    (Garvan Institute of Medical Research)

  • Qian Du

    (Garvan Institute of Medical Research)

  • Grady C. Smith

    (Garvan Institute of Medical Research)

  • Irene R. Ramos

    (John Wayne Cancer Institute)

  • Kristine F. Fernandez

    (The Kinghorn Cancer Centre)

  • Dave S. Hoon

    (John Wayne Cancer Institute)

  • Julia M. W. Gee

    (Cardiff University)

  • Clare Stirzaker

    (Garvan Institute of Medical Research
    UNSW Sydney)

  • Susan J. Clark

    (Garvan Institute of Medical Research
    UNSW Sydney)

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.

Suggested Citation

  • Joanna Achinger-Kawecka & Fatima Valdes-Mora & Phuc-Loi Luu & Katherine A. Giles & C. Elizabeth Caldon & Wenjia Qu & Shalima Nair & Sebastian Soto & Warwick J. Locke & Nicole S. Yeo-Teh & Cathryn M. G, 2020. "Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14098-x
    DOI: 10.1038/s41467-019-14098-x
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    Cited by:

    1. Devin Rocks & Mamta Shukla & Laila Ouldibbat & Silvia C. Finnemann & Achyuth Kalluchi & M. Jordan Rowley & Marija Kundakovic, 2022. "Sex-specific multi-level 3D genome dynamics in the mouse brain," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Zheqi Li & Olivia McGinn & Yang Wu & Amir Bahreini & Nolan M. Priedigkeit & Kai Ding & Sayali Onkar & Caleb Lampenfeld & Carol A. Sartorius & Lori Miller & Margaret Rosenzweig & Ofir Cohen & Nikhil Wa, 2022. "ESR1 mutant breast cancers show elevated basal cytokeratins and immune activation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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