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Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells
Recruitment of transcription machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865474/ https://www.ncbi.nlm.nih.gov/pubmed/26300005 http://dx.doi.org/10.1038/onc.2015.298 |
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author | Hsu, P-Y Hsu, H-K Hsiao, T-H Ye, Z Wang, E Profit, A L Jatoi, I Chen, Y Kirma, N B Jin, V X Sharp, Z D Huang, T H-M |
author_facet | Hsu, P-Y Hsu, H-K Hsiao, T-H Ye, Z Wang, E Profit, A L Jatoi, I Chen, Y Kirma, N B Jin, V X Sharp, Z D Huang, T H-M |
author_sort | Hsu, P-Y |
collection | PubMed |
description | Recruitment of transcription machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 are frequently amplified and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, scattered 20q13 DEREs were mobilized to form regulatory depots for synchronized gene expression of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dysregulated the formation of DERE-involved regulatory depots and transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of proliferation-associated signaling networks, resulting in reduction of cancer cell growth. These findings reveal a formerly uncharacterized feature wherein multiple copies of the amplicon congregate as transcriptional units in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies. |
format | Online Article Text |
id | pubmed-4865474 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48654742016-05-25 Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells Hsu, P-Y Hsu, H-K Hsiao, T-H Ye, Z Wang, E Profit, A L Jatoi, I Chen, Y Kirma, N B Jin, V X Sharp, Z D Huang, T H-M Oncogene Original Article Recruitment of transcription machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 are frequently amplified and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, scattered 20q13 DEREs were mobilized to form regulatory depots for synchronized gene expression of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dysregulated the formation of DERE-involved regulatory depots and transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of proliferation-associated signaling networks, resulting in reduction of cancer cell growth. These findings reveal a formerly uncharacterized feature wherein multiple copies of the amplicon congregate as transcriptional units in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies. Nature Publishing Group 2016-05-05 2015-08-24 /pmc/articles/PMC4865474/ /pubmed/26300005 http://dx.doi.org/10.1038/onc.2015.298 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Hsu, P-Y Hsu, H-K Hsiao, T-H Ye, Z Wang, E Profit, A L Jatoi, I Chen, Y Kirma, N B Jin, V X Sharp, Z D Huang, T H-M Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells |
title | Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells |
title_full | Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells |
title_fullStr | Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells |
title_full_unstemmed | Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells |
title_short | Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells |
title_sort | spatiotemporal control of estrogen-responsive transcription in erα-positive breast cancer cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865474/ https://www.ncbi.nlm.nih.gov/pubmed/26300005 http://dx.doi.org/10.1038/onc.2015.298 |
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