Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 13, Pages 5160-5165Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0801048105
Keywords
transcriptional regulation; chromatin conformation; gene repression; mammary gland; breast cancer
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Funding
- MRC [G9826944] Funding Source: UKRI
- Medical Research Council [G9826944] Funding Source: researchfish
- Medical Research Council [G9826944] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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The 85-kb breast cancer-associated gene BRCA1 is an established tumor suppressor gene, but its regulation is poorly understood. We demonstrate by gene conformation analysis in both human cell lines and mouse mammary tissue that gene loops are imposed on BRCA1 between the promoter, introns, and terminator region. Significantly, association between the BRCA1 promoter and terminator regions change upon estrogen stimulation and during lactational development. Loop formation is transcription-dependent, suggesting that transcriptional elongation plays an active role in BRCA1 loop formation. We show that the BRCA1 terminator region can suppress estrogen-induced transcription and so may regulate BRCA1 expression. Significantly, BRCA1 promoter and terminator interactions vary in different breast cancer cell lines, indicating that defects in BRCA1 chromatin structure may contribute to clysregulated expression of BRCA1 seen in breast tumors.
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