Abstract
BackgroundEpigenetic changes are being increasingly recognized as a prominent feature of cancer. This occurs not only at individual genes, but also over larger chromosomal domains. To investigate this, we set out to identify large chromosomal domains of epigenetic dysregulation in breast cancers.ResultsWe identify large regions of coordinate down-regulation of gene expression, and other regions of coordinate activation, in breast cancers and show that these regions are linked to tumor subtype. In particular we show that a group of coordinately regulated regions are expressed in luminal, estrogen-receptor positive breast tumors and cell lines. For one of these regions of coordinate gene activation, we show that regional epigenetic regulation is accompanied by visible unfolding of large-scale chromatin structure and a repositioning of the region within the nucleus. In MCF7 cells, we show that this depends on the presence of estrogen.ConclusionsOur data suggest that the liganded estrogen receptor is linked to long-range changes in higher-order chromatin organization and epigenetic dysregulation in cancer. This may suggest that as well as drugs targeting histone modifications, it will be valuable to investigate the inhibition of protein complexes involved in chromatin folding in cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0719-9) contains supplementary material, which is available to authorized users.
Highlights
Epigenetic changes are being increasingly recognized as a prominent feature of cancer
Epigenetic alterations have been mostly explored at the single gene level but there are increasing reports of contiguous genes being coordinately repressed in association with tumor progression — a phenomena known as longrange epigenetic silencing (LRES) [2, 3]
To determine whether higher-order chromatin organization is more generally linked to the coordinate dysregulation of genomic regions in breast cancer and whether this is associated with tumor subtype, we have identified regions of regional epigenetic regulation (RER) that are independent of copy number alterations in breast tumors and breast cancer cell lines
Summary
Epigenetic changes are being increasingly recognized as a prominent feature of cancer. Epigenetic alterations have been mostly explored at the single gene level but there are increasing reports of contiguous genes being coordinately repressed in association with tumor progression — a phenomena known as longrange epigenetic silencing (LRES) [2, 3] Both focal and regional epigenetic alterations are likely to contribute to the heterogeneity of cancer. Dysregulated clusters of genes have been reported in association with chromosomal abnormalities [8]; the best described and understood instances of long-range gene dysregulation come from cancer. In these instances, LRES has been most commonly identified by detecting DNA methylation at the promoters of clustered genes [9,10,11,12,13,14].
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