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Estrogen-induced chromatin decondensation and nuclear re-organization linked to regional epigenetic regulation in breast cancer.

Rafique S, Thomas JS, Sproul D, Bickmore WA - Genome Biol. (2015)

Bottom Line: This occurs not only at individual genes, but also over larger chromosomal domains.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK. sehrishrafique@hotmail.com.

ABSTRACT

Background: Epigenetic 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.

Results: We 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.

Conclusions: Our 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.

No MeSH data available.


Related in: MedlinePlus

Properties of RER regions in breast cancer cell lines. Analysis of mean expression (mean z score of genes with significant TCSs) levels in breast cancer cell lines for cluster 1 RER regions (a) and RER regions of clusters 2 and 3 (c). RER regions were subject to hierarchical clustering and cell lines were ordered by their overall level of expression of each RER cluster. Box plots showing mean expression (mean z score of genes with significant TCSs) of RER regions from cluster 1 (b) and clusters 2 and 3 (d) in ER+ (gray) and ER− (white) breast cancer cell lines (*p < 0.05, ***p < 0.001)
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Fig4: Properties of RER regions in breast cancer cell lines. Analysis of mean expression (mean z score of genes with significant TCSs) levels in breast cancer cell lines for cluster 1 RER regions (a) and RER regions of clusters 2 and 3 (c). RER regions were subject to hierarchical clustering and cell lines were ordered by their overall level of expression of each RER cluster. Box plots showing mean expression (mean z score of genes with significant TCSs) of RER regions from cluster 1 (b) and clusters 2 and 3 (d) in ER+ (gray) and ER− (white) breast cancer cell lines (*p < 0.05, ***p < 0.001)

Mentions: For cell line RER regions equivalent to those from tumor RER regions of cluster 1, mean expression levels were higher in ER+ than in ER− cell lines (Fig. 4a, b). The expression of cluster 2 and 3 RER regions was not so well modeled in the cell lines (Fig. 4c, d). This might reflect the fact that the majority of breast cancer cell lines were established from advanced cancers and thus luminal cell lines would be expected to be equivalent to luminal B tumors (which express cluster 1 RER regions) rather than less aggressive luminal A tumors (which express cluster 2 RER regions). Similarly, many ER− breast cancer cell lines are known to reflect the claudin-low, mesenchymal subtype of breast tumor, which is very rare in vivo [20].Fig. 4


Estrogen-induced chromatin decondensation and nuclear re-organization linked to regional epigenetic regulation in breast cancer.

Rafique S, Thomas JS, Sproul D, Bickmore WA - Genome Biol. (2015)

Properties of RER regions in breast cancer cell lines. Analysis of mean expression (mean z score of genes with significant TCSs) levels in breast cancer cell lines for cluster 1 RER regions (a) and RER regions of clusters 2 and 3 (c). RER regions were subject to hierarchical clustering and cell lines were ordered by their overall level of expression of each RER cluster. Box plots showing mean expression (mean z score of genes with significant TCSs) of RER regions from cluster 1 (b) and clusters 2 and 3 (d) in ER+ (gray) and ER− (white) breast cancer cell lines (*p < 0.05, ***p < 0.001)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4536608&req=5

Fig4: Properties of RER regions in breast cancer cell lines. Analysis of mean expression (mean z score of genes with significant TCSs) levels in breast cancer cell lines for cluster 1 RER regions (a) and RER regions of clusters 2 and 3 (c). RER regions were subject to hierarchical clustering and cell lines were ordered by their overall level of expression of each RER cluster. Box plots showing mean expression (mean z score of genes with significant TCSs) of RER regions from cluster 1 (b) and clusters 2 and 3 (d) in ER+ (gray) and ER− (white) breast cancer cell lines (*p < 0.05, ***p < 0.001)
Mentions: For cell line RER regions equivalent to those from tumor RER regions of cluster 1, mean expression levels were higher in ER+ than in ER− cell lines (Fig. 4a, b). The expression of cluster 2 and 3 RER regions was not so well modeled in the cell lines (Fig. 4c, d). This might reflect the fact that the majority of breast cancer cell lines were established from advanced cancers and thus luminal cell lines would be expected to be equivalent to luminal B tumors (which express cluster 1 RER regions) rather than less aggressive luminal A tumors (which express cluster 2 RER regions). Similarly, many ER− breast cancer cell lines are known to reflect the claudin-low, mesenchymal subtype of breast tumor, which is very rare in vivo [20].Fig. 4

Bottom Line: This occurs not only at individual genes, but also over larger chromosomal domains.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.

View Article: PubMed Central - PubMed

Affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK. sehrishrafique@hotmail.com.

ABSTRACT

Background: Epigenetic 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.

Results: We 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.

Conclusions: Our 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.

No MeSH data available.


Related in: MedlinePlus