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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

RER regions and TADs do not overlap. Diagrams of the RER regions at 6q23 (top) and 16p11.2 (bottom), showing the extent of the two RER regions and the location of TADs in the T47D breast cancer line (purple), IMR90 fibroblasts (red) and human ESCs (blue). TAD data are from [43, 44]
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Fig8: RER regions and TADs do not overlap. Diagrams of the RER regions at 6q23 (top) and 16p11.2 (bottom), showing the extent of the two RER regions and the location of TADs in the T47D breast cancer line (purple), IMR90 fibroblasts (red) and human ESCs (blue). TAD data are from [43, 44]

Mentions: The median size of the RER regions that we identified in breast cancer cells lines is similar (900 kb) to the average size of TADs that have been defined in mammalian genomes from the ligation frequencies in Hi-C and 5C experiments [42]. Indeed, it has been suggested that TAD structure allows for coordinate gene regulation [7]. Hi-C analysis is not available for the breast cancer cell lines that we have analyzed by FISH here, but overall TAD structure is remarkably similar between very diverse human cell types. Therefore, we analyzed the degree of overlap between the RER regions defined here and TADs identified in human embryonic stem cells (hESCs) and IMR90 fibroblasts [43] as well as in the T47D breast cancer cell line [44]. The latter cell line does not show an RER phenotype at the 16p11.2 locus in our analysis (Fig. 5c), but extensive coordinate gene regulation in response to progesterone in these cells is reported to generally occur within TADs. However, even using a relaxed threshold of 80 % overlap between a RER region and a single TAD, we found that few of our RER regions correspond to single TAD domains; six (23 %) for TADs in hESCs, eight (31 %) for IMR90 and ten (38.5 %) for T47D (Fig. 8a). Bootstrapping with randomly repositioned RER domains shows that this overlap is not significantly different to that expected by chance. Subregion 2 of the 16p11.2 RER region — the main focus of study in this manuscript — spans a TAD boundary in hESCs and IMR90 cells, but is contained within one larger TAD from the T47D breast cancer cell lines (Fig. 8b). We conclude that our breast cancer RER regions do not correspond to TADs. However, we cannot exclude the possibility that this is because our analyses of RER regions and TADs are based on data from different cell lines or potentially because TADs are disrupted in cancer.Fig. 8


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)

RER regions and TADs do not overlap. Diagrams of the RER regions at 6q23 (top) and 16p11.2 (bottom), showing the extent of the two RER regions and the location of TADs in the T47D breast cancer line (purple), IMR90 fibroblasts (red) and human ESCs (blue). TAD data are from [43, 44]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig8: RER regions and TADs do not overlap. Diagrams of the RER regions at 6q23 (top) and 16p11.2 (bottom), showing the extent of the two RER regions and the location of TADs in the T47D breast cancer line (purple), IMR90 fibroblasts (red) and human ESCs (blue). TAD data are from [43, 44]
Mentions: The median size of the RER regions that we identified in breast cancer cells lines is similar (900 kb) to the average size of TADs that have been defined in mammalian genomes from the ligation frequencies in Hi-C and 5C experiments [42]. Indeed, it has been suggested that TAD structure allows for coordinate gene regulation [7]. Hi-C analysis is not available for the breast cancer cell lines that we have analyzed by FISH here, but overall TAD structure is remarkably similar between very diverse human cell types. Therefore, we analyzed the degree of overlap between the RER regions defined here and TADs identified in human embryonic stem cells (hESCs) and IMR90 fibroblasts [43] as well as in the T47D breast cancer cell line [44]. The latter cell line does not show an RER phenotype at the 16p11.2 locus in our analysis (Fig. 5c), but extensive coordinate gene regulation in response to progesterone in these cells is reported to generally occur within TADs. However, even using a relaxed threshold of 80 % overlap between a RER region and a single TAD, we found that few of our RER regions correspond to single TAD domains; six (23 %) for TADs in hESCs, eight (31 %) for IMR90 and ten (38.5 %) for T47D (Fig. 8a). Bootstrapping with randomly repositioned RER domains shows that this overlap is not significantly different to that expected by chance. Subregion 2 of the 16p11.2 RER region — the main focus of study in this manuscript — spans a TAD boundary in hESCs and IMR90 cells, but is contained within one larger TAD from the T47D breast cancer cell lines (Fig. 8b). We conclude that our breast cancer RER regions do not correspond to TADs. However, we cannot exclude the possibility that this is because our analyses of RER regions and TADs are based on data from different cell lines or potentially because TADs are disrupted in cancer.Fig. 8

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