Journal
BREAST CANCER RESEARCH
Volume 21, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13058-019-1132-1
Keywords
BRCA1; Transcription; Super-enhancer; Chromatin looping; Epigenetics; Breast epithelial cells
Categories
Funding
- NIH [CA220578, CA212674, GM114142, U54CA217297, CA214176]
- DOD [W81XWH-17-1-0007]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP170126]
- NIH Postdoctoral Training Grant [T32CA148724]
- NIH-NCI [P30 CA054174]
- NIH Shared Instrument grant [1S10OD021805-01]
- CPRIT Core Facility Award [RP160732]
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BackgroundBRCA1-associated breast cancer originates from luminal progenitor cells. BRCA1 functions in multiple biological processes, including double-strand break repair, replication stress suppression, transcriptional regulation, and chromatin reorganization. While non-malignant cells carrying cancer-predisposing BRCA1 mutations exhibit increased genomic instability, it remains unclear whether BRCA1 haploinsufficiency affects transcription and chromatin dynamics in breast epithelial cells.MethodsH3K27ac-associated super-enhancers were compared in primary breast epithelial cells from BRCA1 mutation carriers (BRCA1(mut/+)) and non-carriers (BRCA1(+/+)). Non-tumorigenic MCF10A breast epithelial cells with engineered BRCA1 haploinsufficiency were used to confirm the H3K27ac changes. The impact of BRCA1 mutations on enhancer function and enhancer-promoter looping was assessed in MCF10A cells.ResultsHere, we show that primary mammary epithelial cells from women with BRCA1 mutations display significant loss of H3K27ac-associated super-enhancers. These BRCA1-dependent super-enhancers are enriched with binding motifs for the GATA family. Non-tumorigenic BRCA1(mut/+) MCF10A cells recapitulate the H3K27ac loss. Attenuated histone mark and enhancer activity in these BRCA1(mut/+) MCF10A cells can be partially restored with wild-type BRCA1. Furthermore, chromatin conformation analysis demonstrates impaired enhancer-promoter looping in BRCA1(mut/+) MCF10A cells.ConclusionsH3K27ac-associated super-enhancer loss is a previously unappreciated functional deficiency in ostensibly normal BRCA1 mutation-carrying breast epithelium. Our findings offer new mechanistic insights into BRCA1 mutation-associated transcriptional and epigenetic abnormality in breast epithelial cells and tissue/cell lineage-specific tumorigenesis.
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