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

被引：99

作者：

Achinger-Kawecka, Joanna ^{[1
,2
]}

Valdes-Mora, Fatima ^{[1
,2
]}

Luu, Phuc-Loi ^{[1
,2
]}

Giles, Katherine A. ^{[1
]}

Caldon, C. Elizabeth ^{[3
]}

Qu, Wenjia ^{[1
]}

Nair, Shalima ^{[1
]}

Soto, Sebastian ^{[1
]}

Locke, Warwick J. ^{[1
]}

Yeo-Teh, Nicole S. ^{[1
]}

Gould, Cathryn M. ^{[1
]}

Du, Qian ^{[1
]}

Smith, Grady C. ^{[1
]}

Ramos, Irene R. ^{[4
]}

Fernandez, Kristine F. ^{[3
]}

Hoon, Dave S. ^{[4
]}

Gee, Julia M. W. ^{[5
]}

Stirzaker, Clare ^{[1
,2
]}

Clark, Susan J. ^{[1
,2
]}

机构：

[1] Garvan Inst Med Res, Epigenet Res Lab, Genom & Epigenet Theme, Sydney, NSW 2010, Australia

[2] UNSW Sydney, St Vincents Clin Sch, Fac Med, Sydney, NSW 2010, Australia

[3] Kinghorn Canc Ctr, Canc Theme, Sydney, NSW 2010, Australia

[4] John Wayne Canc Inst, Dept Translat Mol Med, Santa Monica, CA USA

[5] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Breast Canc Mol Pharmacol Grp, Cardiff CF10 3NB, Wales

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

英国医学研究理事会;

关键词：

DIFFERENTIAL EXPRESSION ANALYSIS; GENE-EXPRESSION; GENOME; ORGANIZATION; TAMOXIFEN; DOMAINS; REORGANIZATION; DISRUPTION; ACTIVATION; PRINCIPLES;

D O I：

10.1038/s41467-019-14098-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

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