BRCA1 mutations attenuate super-enhancer function and chromatin looping in haploinsufficient human breast epithelial cells
| dc.contributor.author | Zhang, Xiaowen | en |
| dc.contributor.author | Wang, Yao | en |
| dc.contributor.author | Chiang, Huai-Chin | en |
| dc.contributor.author | Hsieh, Yuan-Pang | en |
| dc.contributor.author | Lu, Chang | en |
| dc.contributor.author | Park, Ben H. | en |
| dc.contributor.author | Jatoi, Ismail | en |
| dc.contributor.author | Jin, Victor X. | en |
| dc.contributor.author | Hu, Yanfen | en |
| dc.contributor.author | Li, Rong | en |
| dc.contributor.department | Chemical Engineering | en |
| dc.date.accessioned | 2019-04-22T11:41:16Z | en |
| dc.date.available | 2019-04-22T11:41:16Z | en |
| dc.date.issued | 2019-04-17 | en |
| dc.date.updated | 2019-04-21T03:17:19Z | en |
| dc.description.abstract | Background BRCA1-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. Methods H3K27ac-associated super-enhancers were compared in primary breast epithelial cells from BRCA1 mutation carriers (BRCA1mut/+) 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. Results Here, 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 BRCA1mut/+ MCF10A cells recapitulate the H3K27ac loss. Attenuated histone mark and enhancer activity in these BRCA1mut/+ MCF10A cells can be partially restored with wild-type BRCA1. Furthermore, chromatin conformation analysis demonstrates impaired enhancer-promoter looping in BRCA1mut/+ MCF10A cells. Conclusions H3K27ac-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. | en |
| dc.description.version | Published version | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.citation | Breast Cancer Research. 2019 Apr 17;21(1):51 | en |
| dc.identifier.doi | https://doi.org/10.1186/s13058-019-1132-1 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/89071 | en |
| dc.language.iso | en | en |
| dc.rights | Creative Commons Attribution 4.0 International | en |
| dc.rights.holder | The Author(s) | en |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en |
| dc.title | BRCA1 mutations attenuate super-enhancer function and chromatin looping in haploinsufficient human breast epithelial cells | en |
| dc.title.serial | Breast Cancer Research | en |
| dc.type | Article - Refereed | en |
| dc.type.dcmitype | Text | en |