Abstract
Author SummaryIn placental mammal females, Xist RNA is crucial for inactivation of one of the two X chromosomes in order to maintain proper X chromosome dosage. It is known that the conserved A region of Xist RNA, which contains eight or nine repeated elements, plays an essential role in this process, however, little is known about its structure and mechanism of action. By using chemical and enzymatic probes, as well as FRET experiments, we performed the first experimental analysis of the solution structure of the entire Xist A region. Both mouse and human A regions were found to form two long stem-loop structures each containing four repeats. In contrast to previous predictions, interactions take place both between repeats and between repeats and spacers. Affinity-purification of RNA-protein complexes formed by incubation of RNA in mouse ES cell nuclear extract, followed by mass spectrometry and antibody-based analyses of their protein contents, showed that the isolated 4-repeat structures from the A region can recruit components of the PRC2 complex that is needed for X chromosome inactivation. However, association of one component of this complex, Suz12, was more efficient when the entire A region was used.
Highlights
In mammals, the transcriptional silencing of one of the two X chromosomes in female cells (X chromosome inactivation, XCI) ensures sex chromosome dosage compensation [1]
X-specific transcript (Xist) RNA is crucial for inactivation of one of the two X chromosomes in order to maintain proper X chromosome dosage
It is known that the conserved A region of Xist RNA, which contains eight or nine repeated elements, plays an essential role in this process, little is known about its structure and mechanism of action
Summary
The transcriptional silencing of one of the two X chromosomes in female cells (X chromosome inactivation, XCI) ensures sex chromosome dosage compensation [1]. Once acquired early in development, the inactivated state is faithfully inherited through successive cell divisions. XCI initiation is associated with increased Xist RNA transcription. Whilst first retained near its transcription site, Xist RNA spreads along the entire X chromosome from which it has been transcribed [2,3,4,5] whilst, a series of epigenetic marks, which include the repressive histone modifications H3K27me, H3K9me, are recruited to the presumptive inactive X chromosome. Xist RNA is a long noncoding RNA (17 kb in length in the mouse), which is capped, spliced, and polyadenylated. Little is known about its structure and mechanism of action
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