BRCA1-associated R-loop affects transcription and differentiation in breast luminal epithelial cells
| Autor: | Howard T. Wang, Rong Li, Ismail Jatoi, Yanfen Hu, Andrew Brenner, Xiaowen Zhang, Jingwei Li, Xiayan Zhao, Jerry Chen, Huai-Chin Chiang |
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| Rok vydání: | 2019 |
| Předmět: |
Heterozygote
endocrine system diseases Transcription Genetic Carcinogenesis Cellular differentiation Genes BRCA1 Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Genetics medicine Transcriptional regulation Humans Breast Enhancer skin and connective tissue diseases 030304 developmental biology Regulation of gene expression 0303 health sciences Gene knockdown BRCA1 Protein HEK 293 cells Gene regulation Chromatin and Epigenetics Estrogen Receptor alpha Cell Differentiation Epithelial Cells Cell biology Gene Expression Regulation Neoplastic Enhancer Elements Genetic HEK293 Cells Mutation MCF-7 Cells Ectopic expression Female CRISPR-Cas Systems 030217 neurology & neurosurgery Gene Deletion |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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