BRCA1, a breast and ovarian tumor suppressor, colocalizes with markers of the inactive X chromosome (Xi) on Xi in female somatic cells and associates with XIST RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma cells lacking BRCA1 show evidence of defects in Xi chromatin structure. Reconstitution of BRCA1-deficient cells with wt BRCA1 led to the appearance of focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1 synthesis in a suitable reporter line led to increased expression of an otherwise silenced Xi-located GFP transgene. These observations suggest that loss of BRCA1 in female cells may lead to Xi perturbation and destabilization of its silenced state.
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We are indebted to Drs. Jeannie Lee and Rudolph Jaenisch for helpful conversations and for important reagents and to Dr. Thomas Jenuwein for sharing his histone H3(me)lys9 antibody with us. We also thank Dr. Mary-Claire King for helpful discussions, Dr. John Pehrson for aliquots of anti-macrohistone H2A1, and Drs. Meg Ryan and Jeanne Bentley Lawrence for human XIST reagents. We are indebted to Drs. Suzette Delaloge, Jean-Christian Sabourin, and Andrea Richardson for providing clinical tumor samples for analysis. This work was supported by grants from the National Cancer Institute, including a Dana-Farber/Harvard SPORE in breast cancer, by a Physician-Scientist Post Doctoral Fellowship from the Howard Hughes Medical Institute (to S.G.), and by the Women's Cancer Program of the Dana-Farber Cancer Institute. J.F. is supported by a grant from ARC.