Estrogen induces global reorganization of chromatin structure in human breast cancer cells

In the cell nucleus, each chromosome is confined to a chromosome territory. This spatial organization of chromosomes plays a crucial role in gene regulation and genome stability. An additional level of organization has been discovered at the chromosome scale: the spatial segregation into open and closed chromatins to form two genome-wide compartments. Although considerable progress has been made in our knowledge of chromatin organization, a fundamental issue remains the understanding of its dynamics, especially in cancer. To address this issue, we performed genome-wide mapping of chromatin interactions (Hi-C) over the time after estrogen stimulation of breast cancer cells. To biologically interpret these interactions, we integrated with estrogen receptor α (ERα) binding events, gene expression and epigenetic marks. We show that gene-rich chromosomes as well as areas of open and highly transcribed chromatins are rearranged to greater spatial proximity, thus enabling genes to share transcriptional machinery and regulatory elements. At a smaller scale, differentially interacting loci are enriched for cancer proliferation and estrogen-related genes. Moreover, these loci are correlated with higher ERα binding events and gene expression. Taken together these results reveal the role of a hormone--estrogen--on genome organization, and its effect on gene regulation in cancer

Secoisolariciresinol Diglucoside: Relevance to Angiogenesis and Cardioprotection against Ischemia-Reperfusion Injury

ABSTRACT Therapeutic angiogenesis represents a novel approach for the prevention and treatment of ischemic heart disease. This study examined a novel method of stimulating myocardial angiogenesis using secoisolariciresinol diglucoside (SDG), a plant lignan isolated from flaxseed. SDG has been shown to decrease serum cholesterol and reduce the extent of atherosclerosis. In the present study, the angiogenic properties of SDG were investigated in three different models. First, in the in vitro model, human coronary arteriolar endothelial cells (HCAEC) treated with SDG (50 and 100 M) showed a significant increase in tubular morphogenesis compared with control. Western blot analysis indicated an increased expression of vascular endothelial growth factor (VEGF), kinase insert domain-containing receptor (KDR), Flt-1, angiopoietin-1 (Ang-1), Tie-1, and phosphorylated endothelial nitric oxide synthase (p-eNOS) in the SDG-treated cells. Second, in the ex vivo ischemia/reperfusion model, SDG-treated rats (20 mg/kg b.wt./day for 2 weeks orally) showed an increased level of aortic flow and functional recovery after 2 h of reperfusion following 30 min of ischemia compared with the control group [dP/dt (mm Hg/s) of 2110 Ϯ 35 versus 1752 Ϯ 62]. SDG reduced infarct size compared with the control group by 32% (38 versus 26%) and also decreased cardiomyocyte apoptosis. Increased protein expression of VEGF, Ang-1, and p-eNOS was also observed in the SDGtreated group. Third, in the in vivo myocardial infarction model, SDG increased capillary density and myocardial function as evidenced by increased fractional shortening and ejection fraction. In conclusion, these results suggest that SDG has potent angiogenic and antiapoptotic properties that may contribute to its cardioprotective effect in ischemic models. Ischemic heart disease develops as a consequence of coronary atherosclerotic lesion formation. Coronary collateral vessels and microvascular angiogenesis develop as adaptive responses to myocardial ischemia, which ameliorates the function of the damaged heart. Modulation of adaptive response to ischemic heart disease has become a major focus of current research. Therapeutic coronary angiogenesis (sprouting of new vessels at the capillary level) and collateralization (opening of pre-existing vessels) have tremendous therapeutic potential as strategies for treatment of patients with ischemic heart disease, along with traditional coronary interventional therapies such as coronary artery bypass graft (CABG) and percutaneous transluminal coronary intervention (PTCI). Angiogenesis is a complex process that requires growth factors such as vascular endothelial growth factor (VEGF) and the angiopoietin (Ang) systems that directly or indirectly affect the endothelial cells and produce proliferation and differentiation. VEGF is one of the critical factors involved in mobilization and induction of mitosis in endothelial progenitor cells Article, publication date, and citation information can be found a

Functional enrichment clusters of differentially interacting genes after E2 stimulation.

<p>Functional enrichment clusters of differentially interacting genes after E2 stimulation.</p

Influence of E2 on the compartmentalization of genetic and epigenetic regions.

<p>Correlation (absolute value) between compartmentalization and genetic and epigenetic marks, for the chromosome 6. For a better visualization, row values have been scaled (Z-score).</p

Influence of E2 on the polymer behaviour and folding of chromosomes.

<p>a) Power law dependency between intrachromosomal interaction frequency and distance . Interval , kb binning. b) 3D modeling of chromosome 6.</p

Influence of E2 on the spatial proximity between the 17q23 and 20q13 loci.

<p>a) Hi-C interaction heatmap. b) Interphase FISH analysis of THRAP1 [chr17:60019966-60142643] and 20q13 DERE [chr20:54155758-54155858].</p