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

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 CTCFbound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ERregulated 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.

Genome-Wide Estrogen Receptor Activity in Breast Cancer

“…The relevance of these long-range chromatin interactions to breast cancer is demonstrated by work showing that aberrant genomic amplification of ER-occupied enhancers can negatively impact on survival and therapy response through the formation of novel rogue long-range target-promoter interactions ( 54-56 ). Furthermore, an altered chromatin organization pattern ( 51 ) and differential chromatin interactions both within and between topologically associating domains were found to be associated with endocrine resistance ( 57 ), indicating that 3D epigenome dysregulation is a common feature of transformed cells and of treatment-refractory breast cancer.…”

“…Recently, the existence of this cyclic ER binding to chromatin was called into question ( 177 ). However, the method used by Holding et al relies on using the insulator protein CTCF to normalize the ER chromatin profile, with multiple studies showing interconnectivity between these 2 proteins ( 57 , 178-180 ), thereby potentially confounding the resolution of the normalization approach. In addition, it is unclear whether the lack of cycling observed by Holding et al is a phenomenon linked to the specific method used (ie, ChIP-seq might lack the resolution required to observe cycling) or a more general conclusion.…”

Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level

“…Recent studies of allele-specific methylation indicate that genomic loci stochastically switch between two metastable states -completely methylated, or completely unmethylated 24 . These bistable switches play an important role in cancer and drug resistance through the generation of phenotypic heterogeneity 25,26 . Epigenetic switching also plays a critical role in T-cell fate specification 27 .…”

Crosstalk between microRNA expression and DNA methylation drive the hormone-dependent phenotype of breast cancer

“…i) Hierarchical clustering of methylation levels of CpG cluster 2 (n=12 706). j) Boxplot showing average DNA methylation of Cluster 2 CpGs when Oslo2 tumors were separated into lymphocyte infiltration quartile groups from low (1) to high (4). Wilcoxon rank-sum p-values (two-group comparisons) and Kruskal-Wallis p-values (three or more groups) are indicated.…”