Limits...
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

Gene expression changes in tumors and normal tissue. Box plots show the distribution of mean centered z scores of gene expression in tumor samples and normal breast tissue and breast organoids [28] for genes in the RER regions at 2p24.2-p25.1 (a), 12q15-q21.33 (b) and 16p11.2 (c). Data for tumors are separated according to ER status and Wilcoxon tests were used to determine whether or not there was a significant difference between tumor and normal samples taken together
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Gene expression changes in tumors and normal tissue. Box plots show the distribution of mean centered z scores of gene expression in tumor samples and normal breast tissue and breast organoids [28] for genes in the RER regions at 2p24.2-p25.1 (a), 12q15-q21.33 (b) and 16p11.2 (c). Data for tumors are separated according to ER status and Wilcoxon tests were used to determine whether or not there was a significant difference between tumor and normal samples taken together

Mentions: We compared gene expression levels in the RER regions in breast tumors with those in bulk normal breast tissues, using datasets from [28, 29] that also include expression data derived from breast organoid preparations which are enriched in the epithelial cells known to give rise to tumors. There were examples where RER region expression was significantly (p < 0.05) up-regulated in ER− and down-regulated in ER+ tumors (2p24.2-p25.1; Fig. 2a), or vice versa (18q12.3-q21.32), relative to normal tissue or organoids. An RER region at 12q15-q21.33 (Fig. 2b) was down-regulated relative to normal only in ER− tumors and one at 14q23.3-q32.11 had a similar pattern only in ER+ tumors. Elevated expression in ER− tumors only (i.e., no significant change in ER+ tumors) relative to normal organoid was seen in two instances (16q12.2-q24.1 and 20q13.2-q13.33). Expression was up-regulated in ER+ tumors only, relative to normal, in a total of 12 RER regions, (e.g., RER region 16p11.2; Fig. 2c). Finally, expression was up-regulated in both tumor types relative to normal in 13 RER regions.Fig. 2


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)

Gene expression changes in tumors and normal tissue. Box plots show the distribution of mean centered z scores of gene expression in tumor samples and normal breast tissue and breast organoids [28] for genes in the RER regions at 2p24.2-p25.1 (a), 12q15-q21.33 (b) and 16p11.2 (c). Data for tumors are separated according to ER status and Wilcoxon tests were used to determine whether or not there was a significant difference between tumor and normal samples taken together
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Gene expression changes in tumors and normal tissue. Box plots show the distribution of mean centered z scores of gene expression in tumor samples and normal breast tissue and breast organoids [28] for genes in the RER regions at 2p24.2-p25.1 (a), 12q15-q21.33 (b) and 16p11.2 (c). Data for tumors are separated according to ER status and Wilcoxon tests were used to determine whether or not there was a significant difference between tumor and normal samples taken together
Mentions: We compared gene expression levels in the RER regions in breast tumors with those in bulk normal breast tissues, using datasets from [28, 29] that also include expression data derived from breast organoid preparations which are enriched in the epithelial cells known to give rise to tumors. There were examples where RER region expression was significantly (p < 0.05) up-regulated in ER− and down-regulated in ER+ tumors (2p24.2-p25.1; Fig. 2a), or vice versa (18q12.3-q21.32), relative to normal tissue or organoids. An RER region at 12q15-q21.33 (Fig. 2b) was down-regulated relative to normal only in ER− tumors and one at 14q23.3-q32.11 had a similar pattern only in ER+ tumors. Elevated expression in ER− tumors only (i.e., no significant change in ER+ tumors) relative to normal organoid was seen in two instances (16q12.2-q24.1 and 20q13.2-q13.33). Expression was up-regulated in ER+ tumors only, relative to normal, in a total of 12 RER regions, (e.g., RER region 16p11.2; Fig. 2c). Finally, expression was up-regulated in both tumor types relative to normal in 13 RER regions.Fig. 2

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