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

dc.contributor.authorZhang, Xiaowenen
dc.contributor.authorWang, Yaoen
dc.contributor.authorChiang, Huai-Chinen
dc.contributor.authorHsieh, Yuan-Pangen
dc.contributor.authorLu, Changen
dc.contributor.authorPark, Ben H.en
dc.contributor.authorJatoi, Ismailen
dc.contributor.authorJin, Victor X.en
dc.contributor.authorHu, Yanfenen
dc.contributor.authorLi, Rongen
dc.contributor.departmentChemical Engineeringen
dc.date.accessioned2019-04-22T11:41:16Zen
dc.date.available2019-04-22T11:41:16Zen
dc.date.issued2019-04-17en
dc.date.updated2019-04-21T03:17:19Zen
dc.description.abstractBackground 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.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationBreast Cancer Research. 2019 Apr 17;21(1):51en
dc.identifier.doihttps://doi.org/10.1186/s13058-019-1132-1en
dc.identifier.urihttp://hdl.handle.net/10919/89071en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.holderThe Author(s)en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleBRCA1 mutations attenuate super-enhancer function and chromatin looping in haploinsufficient human breast epithelial cellsen
dc.title.serialBreast Cancer Researchen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
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