Abstract
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 (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.
Highlights
Each chromosome is confined to a specific chromosome territory (CT) in the cell nucleus
We report the analysis of high-throughput chromosome conformation capture (Hi-C) data from MCF-7 breast cancer cells: before (0) and after 0:5, 1, 4 and 24 h of E2 stimulation
Similar trends are observed using 3C-qPCR, for two randomly choosen pairs of regions (Figure S4b in File S1). It has been previously shown using another genome-wide technique (ChIA-PET) that E2 drives chromatin interactions in MCF7 cells [19], our results further demonstrate a more pronounced effect of E2 on long-range interactions which are known to play a role in regulating gene expression
Summary
Each chromosome is confined to a specific chromosome territory (CT) in the cell nucleus This spatial organization of genome plays a crucial role in gene regulation and genome stability [1,2,3,4,5]. Using a deeper sequencing than Lieberman et al, Dixon et al identified topologically associating domains (TADs) showing the existence of highly selfinteracting regions bounded by narrow segments [5, 11]. These TADs represent a pervasive structural feature of the genome organization. The high correlation of Hi-C data with the binding of CCCTC-binding factor (CTCF) to the chromatin suggests that CTCF is a major organizer of both the structure of chromosomal fiber within each individual chromosome and of chromosome territories within the cell nucleus [13]
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