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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 and tumor subtypes. a Unsupervised hierarchical cluster analysis of breast tumor samples for RER regions at 3p14-p21.31 (left) and 16q12.2-q24.1 (right). Heat maps of gene expression z scores with hierarchical clustering of samples (red high expression, green low expression). Genes are ordered by their position in the genome. Subtype information [22] for each tumor sample is identified by the color-coded matrix: luminal A (blue), luminal B (turquoise), ERBB2 (purple), basal (red), normal-like (green). Only genes in the regions with significant TCSs are shown. b As in (a) but for mean expression (mean z score of genes with significant TCSs) for all RER regions in each breast tumor sample, showing clustering of RER regions into three groups. Both the RER regions and samples were subject to hierarchical clustering. c Box plots showing mean expression (mean z score of genes with significant TCSs) of RER regions from clusters 1, 2 and 3 in breast tumors of different subtypes; luminal A (LumA, blue), luminal B (LumB, turquoise), ERBB2 (purple), basal-like (red). **p < 0.01, ***p < 0.001, Wilcoxon test)
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Fig3: Properties of RER regions and tumor subtypes. a Unsupervised hierarchical cluster analysis of breast tumor samples for RER regions at 3p14-p21.31 (left) and 16q12.2-q24.1 (right). Heat maps of gene expression z scores with hierarchical clustering of samples (red high expression, green low expression). Genes are ordered by their position in the genome. Subtype information [22] for each tumor sample is identified by the color-coded matrix: luminal A (blue), luminal B (turquoise), ERBB2 (purple), basal (red), normal-like (green). Only genes in the regions with significant TCSs are shown. b As in (a) but for mean expression (mean z score of genes with significant TCSs) for all RER regions in each breast tumor sample, showing clustering of RER regions into three groups. Both the RER regions and samples were subject to hierarchical clustering. c Box plots showing mean expression (mean z score of genes with significant TCSs) of RER regions from clusters 1, 2 and 3 in breast tumors of different subtypes; luminal A (LumA, blue), luminal B (LumB, turquoise), ERBB2 (purple), basal-like (red). **p < 0.01, ***p < 0.001, Wilcoxon test)

Mentions: To better understand the patterns of coordinate gene expression in relation to tumor biology, we examined heat maps of gene expression data for significant TCS genes in RER domains. For many of these regions, unsupervised hierarchical clustering separated breast tumors by the intrinsic subtypes previously defined by gene expression [30] (e.g., luminal and basal-like) and revealed cases where there is a tumor subtype-specific gene signature (activation or repression) within RER regions. For example, an RER region at 3p14-p21.31 (Fig. 3a) has elevated expression in luminal (ER+) relative to basal tumors (ER−), whereas one at 16q12.2-q24.1 (Fig. 3b) is repressed in luminal ER+ relative to basal type tumors.Fig. 3


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 and tumor subtypes. a Unsupervised hierarchical cluster analysis of breast tumor samples for RER regions at 3p14-p21.31 (left) and 16q12.2-q24.1 (right). Heat maps of gene expression z scores with hierarchical clustering of samples (red high expression, green low expression). Genes are ordered by their position in the genome. Subtype information [22] for each tumor sample is identified by the color-coded matrix: luminal A (blue), luminal B (turquoise), ERBB2 (purple), basal (red), normal-like (green). Only genes in the regions with significant TCSs are shown. b As in (a) but for mean expression (mean z score of genes with significant TCSs) for all RER regions in each breast tumor sample, showing clustering of RER regions into three groups. Both the RER regions and samples were subject to hierarchical clustering. c Box plots showing mean expression (mean z score of genes with significant TCSs) of RER regions from clusters 1, 2 and 3 in breast tumors of different subtypes; luminal A (LumA, blue), luminal B (LumB, turquoise), ERBB2 (purple), basal-like (red). **p < 0.01, ***p < 0.001, Wilcoxon test)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4536608&req=5

Fig3: Properties of RER regions and tumor subtypes. a Unsupervised hierarchical cluster analysis of breast tumor samples for RER regions at 3p14-p21.31 (left) and 16q12.2-q24.1 (right). Heat maps of gene expression z scores with hierarchical clustering of samples (red high expression, green low expression). Genes are ordered by their position in the genome. Subtype information [22] for each tumor sample is identified by the color-coded matrix: luminal A (blue), luminal B (turquoise), ERBB2 (purple), basal (red), normal-like (green). Only genes in the regions with significant TCSs are shown. b As in (a) but for mean expression (mean z score of genes with significant TCSs) for all RER regions in each breast tumor sample, showing clustering of RER regions into three groups. Both the RER regions and samples were subject to hierarchical clustering. c Box plots showing mean expression (mean z score of genes with significant TCSs) of RER regions from clusters 1, 2 and 3 in breast tumors of different subtypes; luminal A (LumA, blue), luminal B (LumB, turquoise), ERBB2 (purple), basal-like (red). **p < 0.01, ***p < 0.001, Wilcoxon test)
Mentions: To better understand the patterns of coordinate gene expression in relation to tumor biology, we examined heat maps of gene expression data for significant TCS genes in RER domains. For many of these regions, unsupervised hierarchical clustering separated breast tumors by the intrinsic subtypes previously defined by gene expression [30] (e.g., luminal and basal-like) and revealed cases where there is a tumor subtype-specific gene signature (activation or repression) within RER regions. For example, an RER region at 3p14-p21.31 (Fig. 3a) has elevated expression in luminal (ER+) relative to basal tumors (ER−), whereas one at 16q12.2-q24.1 (Fig. 3b) is repressed in luminal ER+ relative to basal type tumors.Fig. 3

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