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

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

Author information

1
Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC, 20037, USA.
2
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
3
Department of Chemical Engineering, Virginia Tech, Blacksburg, VA, 24061, USA.
4
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
5
Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
6
Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA. jinv@uthscsa.edu.
7
Department of Anatomy & Cell Biology, School of Medicine & Health Sciences, The George Washington University, Washington, DC, 20037, USA. huy3@gwu.edu.
8
Department of Biochemistry & Molecular Medicine, School of Medicine & Health Sciences, The George Washington University, Washington, DC, 20037, USA. rli69@gwu.edu.

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.

KEYWORDS:

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

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