BRCA1 and X-inactivation

Diabetes, Digestive, Kidney Diseases

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Abstract

In female mammals, one X chromosome is silenced in each cell to achieve equivalent X-linked gene dosage between females and males. X inactivation occurs early in mammalian embryogenesis, and in the mouse, the Xist gene is essential for the initiation of X chromosome silencing. When X inactivation is initiated, Xist RNA spreads from its site of transcription to coat the X chromosome, and this cis-spread correlates with the initial transcriptional silencing of the Xi. During the maintenance phase of X inactivation, an accumulation of XIST RNA coats the Xi in somatic cells. Deletion of the XIST/Xist gene in somatic cells does not result in complete reactivation of the Xi. Instead, there is stochastic and infrequent gene reactivation, indicating that Xist acts with other factors to maintain silencing of the Xi.[unreadable] In the past years, we have studied functions of BRCA1 in both germ cells and somatic cells using our BRCA1 mutant mouse models. Our data indicate that BRCA1 is localized in X and Y chromosomes and interacts with ?H2AX indirectly through ATR, and that BRCA1 is responsible for the proper localization of ?H2AX to the XY-body during spermatogenesis. We believe that the disruption of the localization of ?H2AX to XY-body due to the absence of BRCA1 may cause the failure of X-inactivation. [unreadable] [unreadable] However, in somatic cells, we failed to demonstrate a role of BRCA1 in X-inactivation, highlighting a different role of BRCA1 between germ cells and somatic cells in this process. We report that BRCA1 is not enriched on XIST RNA-coated chromatin of the Xi. Reconstitution of BRCA1 in BRCA1mutant cell lines does not affect XIST RNA distribution. Depletion of BRCA1 in wild-type cells does not alter XIST RNA localization. In mouse tumor cells mutant for Brca1, Xist RNA exhibits a normal distribution in 11 of 14 primary tumor lines. A human breast cancer cell line expressing mutant BRCA1 also shows normal XIST RNA distribution in the majority of cells. Finally, dosage compensation in mouse Brca1 mutant embryos and adult mammary tissues is normal. In combination, these results uncover a distinct role of BRCA1 in X-inactivation during spermatogenesis and somatic cells. Thus, although BRCA1 plays an essential role in the X chromosome inactivation, BRCA1 does not regulate XIST RNA localization or its function in X inactivation in somatic cells.