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

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

Sedimentary Environment Influences the Effect of an Infaunal Suspension Feeding Bivalve on Estuarine Ecosystem Function

The suspension feeding bivalve Austrovenus stutchburyi is a key species on intertidal sandflats in New Zealand, affecting the appearance and functioning of these systems, but is susceptible to several environmental stressors including sedimentation. Previous studies into the effect of this species on ecosystem function have been restricted in space and time, limiting our ability to infer the effect of habitat change on functioning. We examined the effect of Austrovenus on benthic primary production and nutrient dynamics at two sites, one sandy, the other composed of muddy-sand to determine whether sedimentary environment alters this key species' role. At each site we established large (16 m2) plots of two types, Austrovenus addition and removal. In winter and summer we deployed light and dark benthic chambers to quantify oxygen and nutrient fluxes and measured sediment denitrification enzyme activity to assess denitrification potential. Rates of gross primary production (GPP) and ammonium uptake were significantly increased when Austrovenus was added, relative to removed, at the sandy site (GPP, 1.5 times greater in winter and summer; ammonium uptake, 8 times greater in summer; 3-factor analysis of variance (ANOVA), p<0.05). Denitrification potential was also elevated in Austrovenus addition plots at the sandy site in summer (by 1.6 times, p<0.1). In contrast, there was no effect of Austrovenus treatment on any of these variables at the muddy-sand site, and overall rates tended to be lower at the muddy-sand site, relative to the sandy site (e.g. GPP was 2.1 to 3.4 times lower in winter and summer, respectively, p<0.001). Our results suggest that the positive effects of Austrovenus on system productivity and denitrification potential is limited at a muddy-sand site compared to a sandy site, and reveal the importance of considering sedimentary environment when examining the effect of key species on ecosystem function