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

The effect of estrogen on chromatin compaction and nuclear organization at subregion 2 of the 16p11.2 RER region. a Map of the 16p11.2 RER subregion 2 showing the location of ER binding sites (red) in MCF7 cells (from [38]). Below, the location of genes in the region is shown from the UCSC Genome Browser NCBI36/hg18 assembly of the human genome. b, c Box plots comparing the distribution of normalized FISH interprobe distances (d2/r2) measured across subregion 2 of the 16p11.2 RER region in ER+ MCF7 (b) and ER− MDAMB231 (c) breast cancer cell lines. Data are shown for cells grown in normal serum, in media stripped of hormone for 3 days (−E2), and after addition of 100 nm estrogen for 24 hours (+E2). n = 60 cells for each sample. d, e The percentage of FISH hybridization signals for subregion 2 of the 16p11.2 RER region found in each of five shells of equal area eroded from the edge of the nucleus (shell 1) through to the nuclear center (shell 5), in MCF7 (d) and MDAMB231 cells (e) grown in normal serum (grey shaded bars), hormone stripped media (−E2, white) and after addition of 100 nm estrogen for 24 hours (+E2, black)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: The effect of estrogen on chromatin compaction and nuclear organization at subregion 2 of the 16p11.2 RER region. a Map of the 16p11.2 RER subregion 2 showing the location of ER binding sites (red) in MCF7 cells (from [38]). Below, the location of genes in the region is shown from the UCSC Genome Browser NCBI36/hg18 assembly of the human genome. b, c Box plots comparing the distribution of normalized FISH interprobe distances (d2/r2) measured across subregion 2 of the 16p11.2 RER region in ER+ MCF7 (b) and ER− MDAMB231 (c) breast cancer cell lines. Data are shown for cells grown in normal serum, in media stripped of hormone for 3 days (−E2), and after addition of 100 nm estrogen for 24 hours (+E2). n = 60 cells for each sample. d, e The percentage of FISH hybridization signals for subregion 2 of the 16p11.2 RER region found in each of five shells of equal area eroded from the edge of the nucleus (shell 1) through to the nuclear center (shell 5), in MCF7 (d) and MDAMB231 cells (e) grown in normal serum (grey shaded bars), hormone stripped media (−E2, white) and after addition of 100 nm estrogen for 24 hours (+E2, black)

Mentions: The association between ER status and RER within subregion 2 suggested that estrogen might be responsible for the observed differences in chromatin compaction. As well as inducing local changes in chromatin modification, ER has been reported to be capable of inducing large-scale visible chromatin de-condensation on an artificial reporter array [37]. Examination of chromatin immunoprecipitation (ChIP)-sequencing data from MCF7 cells [38] revealed seven ER-bound sites within the 400 kb subregion 2 of the 16p11.2 RER region (Fig. 7a). A permutation analysis of 10,000 randomly placed genomic windows of equal size to subregion 2 (~414 kb; using BEDtools v.2.17.0) showed that subregion 2 is among the top 6.2 % of regions in the human genome in terms of enrichment for ER binding sites.Fig. 7


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)

The effect of estrogen on chromatin compaction and nuclear organization at subregion 2 of the 16p11.2 RER region. a Map of the 16p11.2 RER subregion 2 showing the location of ER binding sites (red) in MCF7 cells (from [38]). Below, the location of genes in the region is shown from the UCSC Genome Browser NCBI36/hg18 assembly of the human genome. b, c Box plots comparing the distribution of normalized FISH interprobe distances (d2/r2) measured across subregion 2 of the 16p11.2 RER region in ER+ MCF7 (b) and ER− MDAMB231 (c) breast cancer cell lines. Data are shown for cells grown in normal serum, in media stripped of hormone for 3 days (−E2), and after addition of 100 nm estrogen for 24 hours (+E2). n = 60 cells for each sample. d, e The percentage of FISH hybridization signals for subregion 2 of the 16p11.2 RER region found in each of five shells of equal area eroded from the edge of the nucleus (shell 1) through to the nuclear center (shell 5), in MCF7 (d) and MDAMB231 cells (e) grown in normal serum (grey shaded bars), hormone stripped media (−E2, white) and after addition of 100 nm estrogen for 24 hours (+E2, black)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: The effect of estrogen on chromatin compaction and nuclear organization at subregion 2 of the 16p11.2 RER region. a Map of the 16p11.2 RER subregion 2 showing the location of ER binding sites (red) in MCF7 cells (from [38]). Below, the location of genes in the region is shown from the UCSC Genome Browser NCBI36/hg18 assembly of the human genome. b, c Box plots comparing the distribution of normalized FISH interprobe distances (d2/r2) measured across subregion 2 of the 16p11.2 RER region in ER+ MCF7 (b) and ER− MDAMB231 (c) breast cancer cell lines. Data are shown for cells grown in normal serum, in media stripped of hormone for 3 days (−E2), and after addition of 100 nm estrogen for 24 hours (+E2). n = 60 cells for each sample. d, e The percentage of FISH hybridization signals for subregion 2 of the 16p11.2 RER region found in each of five shells of equal area eroded from the edge of the nucleus (shell 1) through to the nuclear center (shell 5), in MCF7 (d) and MDAMB231 cells (e) grown in normal serum (grey shaded bars), hormone stripped media (−E2, white) and after addition of 100 nm estrogen for 24 hours (+E2, black)
Mentions: The association between ER status and RER within subregion 2 suggested that estrogen might be responsible for the observed differences in chromatin compaction. As well as inducing local changes in chromatin modification, ER has been reported to be capable of inducing large-scale visible chromatin de-condensation on an artificial reporter array [37]. Examination of chromatin immunoprecipitation (ChIP)-sequencing data from MCF7 cells [38] revealed seven ER-bound sites within the 400 kb subregion 2 of the 16p11.2 RER region (Fig. 7a). A permutation analysis of 10,000 randomly placed genomic windows of equal size to subregion 2 (~414 kb; using BEDtools v.2.17.0) showed that subregion 2 is among the top 6.2 % of regions in the human genome in terms of enrichment for ER binding sites.Fig. 7

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