The A-repeat links ASF/SF2-dependent Xist RNA processing with random choice during X inactivation

The Xist noncoding RNA is a key component in silencing of one X chromosome in female mammalian cells as part of the process of dosage compensation. Now a previously described repeat element in Xist, the A-repeat, is shown to bind the splicing factor ASF/SF2, and it is further shown that normal Xist processing may be involved in stochastically determining which X is inactivated. One X chromosome, selected at random, is silenced in each female mammalian cell. Xist encodes a noncoding RNA that influences the probability that the cis -linked X chromosome will be silenced. We found that the A-repeat, a highly conserved element within Xist , is required for the accumulation of spliced Xist RNA. In addition, the A-repeat is necessary for X-inactivation to occur randomly. In combination, our data suggest that normal Xist RNA processing is important in the regulation of random X-inactivation. We propose that modulation of Xist RNA processing may be part of the stochastic process that determines which X chromosome will be inactivated.