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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

Identifying RER in breast tumors and cancer cell lines. a, c Transcription correlation score (TCS) maps for chromosomes 3 and 16 using data from breast tumors [22] (a) and breast cancer cell lines [20] (c). The horizontal dotted line indicates the significance threshold. Arrows indicate regions containing genes with significant TCSs. b Boxplots showing the distribution of TCSs generated for all genes and for RER genes using two independent breast tumor datasets [22, 23]. d Ideograms showing the location of the 45 RER regions identified in breast tumors (red) and the 71 RER regions identified in breast cancer cell lines (blue)
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Fig1: Identifying RER in breast tumors and cancer cell lines. a, c Transcription correlation score (TCS) maps for chromosomes 3 and 16 using data from breast tumors [22] (a) and breast cancer cell lines [20] (c). The horizontal dotted line indicates the significance threshold. Arrows indicate regions containing genes with significant TCSs. b Boxplots showing the distribution of TCSs generated for all genes and for RER genes using two independent breast tumor datasets [22, 23]. d Ideograms showing the location of the 45 RER regions identified in breast tumors (red) and the 71 RER regions identified in breast cancer cell lines (blue)

Mentions: To identify chromosomal regions containing genes that are coordinately expressed independent of genomic changes in breast cancer, we implemented an approach based on that used to find LRES regions in bladder cancer [19]. We applied this to the analysis of transcription (expression microarray) and copy number (array CGH) from 356 breast tumors [22]. To ensure apparent RER regions were not caused by copy number variation, we excluded from further analysis genes for which a copy number aberration was detected in that sample. A transcription correlation score (TCS) was calculated for each gene to quantify how well its expression correlated with that of its neighbors. This score was the sum of the Spearman rank correlations for a given gene’s expression with that of each of its ten nearest neighbors. TCS maps generated from this tumor set revealed peaks corresponding to potential RER regions (Fig. 1a, arrows; Figure S1 in Additional file 1).Fig. 1


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)

Identifying RER in breast tumors and cancer cell lines. a, c Transcription correlation score (TCS) maps for chromosomes 3 and 16 using data from breast tumors [22] (a) and breast cancer cell lines [20] (c). The horizontal dotted line indicates the significance threshold. Arrows indicate regions containing genes with significant TCSs. b Boxplots showing the distribution of TCSs generated for all genes and for RER genes using two independent breast tumor datasets [22, 23]. d Ideograms showing the location of the 45 RER regions identified in breast tumors (red) and the 71 RER regions identified in breast cancer cell lines (blue)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Identifying RER in breast tumors and cancer cell lines. a, c Transcription correlation score (TCS) maps for chromosomes 3 and 16 using data from breast tumors [22] (a) and breast cancer cell lines [20] (c). The horizontal dotted line indicates the significance threshold. Arrows indicate regions containing genes with significant TCSs. b Boxplots showing the distribution of TCSs generated for all genes and for RER genes using two independent breast tumor datasets [22, 23]. d Ideograms showing the location of the 45 RER regions identified in breast tumors (red) and the 71 RER regions identified in breast cancer cell lines (blue)
Mentions: To identify chromosomal regions containing genes that are coordinately expressed independent of genomic changes in breast cancer, we implemented an approach based on that used to find LRES regions in bladder cancer [19]. We applied this to the analysis of transcription (expression microarray) and copy number (array CGH) from 356 breast tumors [22]. To ensure apparent RER regions were not caused by copy number variation, we excluded from further analysis genes for which a copy number aberration was detected in that sample. A transcription correlation score (TCS) was calculated for each gene to quantify how well its expression correlated with that of its neighbors. This score was the sum of the Spearman rank correlations for a given gene’s expression with that of each of its ten nearest neighbors. TCS maps generated from this tumor set revealed peaks corresponding to potential RER regions (Fig. 1a, arrows; Figure S1 in Additional file 1).Fig. 1

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