Chromatin organisation in breast cancer
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Epigenetic misregulation of gene expression is known to be an important feature in cancer. This has mainly been studied at the level of changes in DNA methylation and histone modifications at individual genes. In this thesis I have set out to investigate whether there are long-range changes in chromatin structure linked to altered gene expression in breast cancer. From large published datasets, I used a computational approach to identify large genomic regions which are coordinately misregulated in breast cancer independent of copy number aberrations (genomic effects). I found 26 regions of co-ordinate regulation of neighbouring genes that are consistent between breast tumours and breast cancer cell lines. These regions had different expression phenotypes (activation, repression, no change) compared to normal breast and also with tumour subtype (luminal vs basal and ER status). The regions of epigenetic regulation (RER) identified in breast cancer were mostly cancer type specific. I investigated the mechanism of long-range misregulation at one such region on chromosome 16p11.2 which is aberrantly activated in breast cancer. Interestingly, in estrogen-receptor positive (ER+ve) cells, genes in this region are upregulated relative to estrogen receptor negative (ER-ve) cells. Using fluorescence in situ hybridisation (FISH) I found that in ER+ve breast cancer cell lines and tumour tissue this region is in a more decondensed chromatin architecture than in ER-ve cell lines and tumour tissue. Furthermore this region was very compact in a normal breast epithelial cell line and breast tissue corresponding to what would be expected from the expression data. Estrogen was found to play a key role in maintaining the aberrant decondensation of chromatin at this locus on chr16p11.2, as shown by compaction of the region by starving ER+ve cells of estrogen and decompaction upon subsequent estrogen treatment. Interestingly there was also an estrogen mediated repositioning of the 16p11.2 RER domain away from the nuclear centre in hormone starved conditions and towards the centre upon estrogen stimulation. Together these results show that estrogen is key to regulating the changes in nuclear organisation and chromatin decompaction at this locus, which are associated with aberrant patterns of gene expression in ER+ve breast cancer.