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BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells

BRCA1-associated basal-like breast cancer originates from luminal progenitor cells. Breast epithelial cells from cancer-free BRCA1 mutation carriers are defective in luminal differentiation. However, how BRCA1 deficiency leads to lineage-specific differentiation defect is not clear. BRCA1 is implica...

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Autores principales: Chiang, Huai-Chin, Zhang, Xiaowen, Li, Jingwei, Zhao, Xiayan, Chen, Jerry, Wang, Howard T-H, Jatoi, Ismail, Brenner, Andrew, Hu, Yanfen, Li, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547407/
https://www.ncbi.nlm.nih.gov/pubmed/30982901
http://dx.doi.org/10.1093/nar/gkz262
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author Chiang, Huai-Chin
Zhang, Xiaowen
Li, Jingwei
Zhao, Xiayan
Chen, Jerry
Wang, Howard T-H
Jatoi, Ismail
Brenner, Andrew
Hu, Yanfen
Li, Rong
author_facet Chiang, Huai-Chin
Zhang, Xiaowen
Li, Jingwei
Zhao, Xiayan
Chen, Jerry
Wang, Howard T-H
Jatoi, Ismail
Brenner, Andrew
Hu, Yanfen
Li, Rong
author_sort Chiang, Huai-Chin
collection PubMed
description BRCA1-associated basal-like breast cancer originates from luminal progenitor cells. Breast epithelial cells from cancer-free BRCA1 mutation carriers are defective in luminal differentiation. However, how BRCA1 deficiency leads to lineage-specific differentiation defect is not clear. BRCA1 is implicated in resolving R-loops, DNA-RNA hybrid structures associated with genome instability and transcriptional regulation. We recently showed that R-loops are preferentially accumulated in breast luminal epithelial cells of BRCA1 mutation carriers. Here, we interrogate the impact of a BRCA1 mutation-associated R-loop located in a putative transcriptional enhancer upstream of the ERα-encoding ESR1 gene. Genetic ablation confirms the relevance of this R-loop-containing region to enhancer-promoter interactions and transcriptional activation of the corresponding neighboring genes, including ESR1, CCDC170 and RMND1. BRCA1 knockdown in ERα+ luminal breast cancer cells increases intensity of this R-loop and reduces transcription of its neighboring genes. The deleterious effect of BRCA1 depletion on transcription is mitigated by ectopic expression of R-loop-removing RNase H1. Furthermore, RNase H1 overexpression in primary breast cells from BRCA1 mutation carriers results in a shift from luminal progenitor cells to mature luminal cells. Our findings suggest that BRCA1-dependent R-loop mitigation contributes to luminal cell-specific transcription and differentiation, which could in turn suppress BRCA1-associated tumorigenesis.
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spelling pubmed-65474072019-06-13 BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells Chiang, Huai-Chin Zhang, Xiaowen Li, Jingwei Zhao, Xiayan Chen, Jerry Wang, Howard T-H Jatoi, Ismail Brenner, Andrew Hu, Yanfen Li, Rong Nucleic Acids Res Gene regulation, Chromatin and Epigenetics BRCA1-associated basal-like breast cancer originates from luminal progenitor cells. Breast epithelial cells from cancer-free BRCA1 mutation carriers are defective in luminal differentiation. However, how BRCA1 deficiency leads to lineage-specific differentiation defect is not clear. BRCA1 is implicated in resolving R-loops, DNA-RNA hybrid structures associated with genome instability and transcriptional regulation. We recently showed that R-loops are preferentially accumulated in breast luminal epithelial cells of BRCA1 mutation carriers. Here, we interrogate the impact of a BRCA1 mutation-associated R-loop located in a putative transcriptional enhancer upstream of the ERα-encoding ESR1 gene. Genetic ablation confirms the relevance of this R-loop-containing region to enhancer-promoter interactions and transcriptional activation of the corresponding neighboring genes, including ESR1, CCDC170 and RMND1. BRCA1 knockdown in ERα+ luminal breast cancer cells increases intensity of this R-loop and reduces transcription of its neighboring genes. The deleterious effect of BRCA1 depletion on transcription is mitigated by ectopic expression of R-loop-removing RNase H1. Furthermore, RNase H1 overexpression in primary breast cells from BRCA1 mutation carriers results in a shift from luminal progenitor cells to mature luminal cells. Our findings suggest that BRCA1-dependent R-loop mitigation contributes to luminal cell-specific transcription and differentiation, which could in turn suppress BRCA1-associated tumorigenesis. Oxford University Press 2019-06-04 2019-04-15 /pmc/articles/PMC6547407/ /pubmed/30982901 http://dx.doi.org/10.1093/nar/gkz262 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Gene regulation, Chromatin and Epigenetics
Chiang, Huai-Chin
Zhang, Xiaowen
Li, Jingwei
Zhao, Xiayan
Chen, Jerry
Wang, Howard T-H
Jatoi, Ismail
Brenner, Andrew
Hu, Yanfen
Li, Rong
BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells
title BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells
title_full BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells
title_fullStr BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells
title_full_unstemmed BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells
title_short BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells
title_sort brca1-associated r-loop affects transcription and differentiation in breast luminal epithelial cells
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547407/
https://www.ncbi.nlm.nih.gov/pubmed/30982901
http://dx.doi.org/10.1093/nar/gkz262
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