August 24, 2009
Aurora B Answers XIST-ential Question
Mitotic release of chromatin-binding RNA gives insight into X chromosome silencing
Early in development, mammalian female cells counteract their double dose of X chromosomes by coating one of them with a large RNA named XIST. The RNA binds to the same X chromosome from which it is transcribed and initiates a series of events leading to the chromosome's permanent silencing. In the August 24, 2009 issue of the Journal of Cell Biology, Hall et al. exploit the fact that XIST temporarily dissociates from the X chromosome during mitosis and find that Aurora B kinase helps regulate the RNA's chromatin binding.
Hall and colleagues found that treating cells with an inhibitor of protein phosphatase 1 (PP1) caused XIST to be released from the Xi in interphase cells. PP1 usually keeps the kinase Aurora B in check until the start of mitosis, so the team wondered whether XIST's premature release was driven by increased Aurora B activity. XIST was no longer released in interphase cells if PP1 and Aurora B were both inhibited. Moreover, inhibiting Aurora B with either drugs or a specific siRNA caused XIST to be retained on the Xi even in mitotic cells.
Lawrence says that the team was excited to identify Aurora B as a regulator of XIST. Their previous studies had suggested that a broader chromatin organizer might control XIST binding, particularly during cancer when the regulation of XIST and the Xi often goes awry. Aurora B fits the bill perfectly as it localizes to the chromosome arms at prophase, phosphorylates several chromatin proteins including histone H3, and is frequently activated in cancer cells.
It remains unclear exactly how Aurora B promotes XIST's loss from the Xi. "There are probably multiple places that XIST anchors to chromatin," says Lawrence. "In order to release it, you have to modify multiple points." Further studies on the mitotic loss of XIST should help identify these different anchor points and determine how they are modified to promote or block RNA binding.
XIST may, in fact, represent a broader class of noncoding RNAs that associate with and regulate heterochromatin. "We hope that manipulating binding in vivo provides a new way to study RNA"“chromatin interactions that other labs will build on," says Lawrence. "It will be interesting to determine if these other RNAs mirror the behavior of XIST and are controlled by the same mechanism."
Hall, L.L., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200811143
Image Caption: Although XIST initiates the silencing of the chromosome, the RNA (green) is temporarily released during mitosis (left). By manipulating XIST binding in vivo, Hall et al. discover that Aurora B kinase regulates the RNA's association with chromatin: XIST is retained on the X chromosome in mitotic cells lacking Aurora B (right). Credit: Hall, L.L., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200811143
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