BRCA1 mutations attenuate super-enhancer function and chromatin looping in haploinsufficient human breast epithelial cells

Breast Cancer Res. 2019 Apr 17;21(1):51. doi: 10.1186/s13058-019-1132-1.


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.

Keywords: BRCA1; Breast epithelial cells; Chromatin looping; Epigenetics; Super-enhancer; Transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Biomarkers, Tumor
  • Cell Line
  • Cell Transformation, Neoplastic / genetics
  • Chromatin / genetics*
  • Chromatin Immunoprecipitation
  • Computational Biology / methods
  • Enhancer Elements, Genetic*
  • Epithelial Cells / metabolism*
  • Genes, BRCA1*
  • Genomic Instability
  • Haploinsufficiency*
  • High-Throughput Nucleotide Sequencing
  • Histones
  • Humans
  • Mammary Glands, Human / metabolism*
  • Mutation*
  • Nucleotide Motifs
  • Protein Binding


  • Biomarkers, Tumor
  • Chromatin
  • Histones