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

Huai Chin Chiang, Xiaowen Zhang, Jingwei Li, Xiayan Zhao, Jerry Chen, Howard T.H. Wang, Ismail Jatoi, Andrew Brenner, Yanfen Hu, Rong Li

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5086-5099
Number of pages14
JournalNucleic acids research
Volume47
Issue number10
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Genetics

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