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, 9 (12), 190213

Localized Accumulation of Xist RNA in X Chromosome Inactivation

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Localized Accumulation of Xist RNA in X Chromosome Inactivation

Neil Brockdorff. Open Biol.

Abstract

The non-coding RNA Xist regulates the process of X chromosome inactivation, in which one of the two X chromosomes present in cells of early female mammalian embryos is selectively and coordinately shut down. Remarkably Xist RNA functions in cis, affecting only the chromosome from which it is transcribed. This feature is attributable to the unique propensity of Xist RNA to accumulate over the territory of the chromosome on which it is synthesized, contrasting with the majority of RNAs that are rapidly exported out of the cell nucleus. In this review I provide an overview of the progress that has been made towards understanding localized accumulation of Xist RNA, drawing attention to evidence that some other non-coding RNAs probably function in a highly analogous manner. I describe a simple model for localized accumulation of Xist RNA and discuss key unresolved questions that need to be addressed in future studies.

Keywords: X chromosome inactivation; chromatin; epigenetic; long non-coding RNA.

Conflict of interest statement

I declare I have no competing interests.

Figures

Figure 1.
Figure 1.
Xist RNA clouds detected using RNA-FISH. The examples shown each illustrate a single XX cell nucleus at interphase. The Xist RNA-FISH signal is shown in yellow and the DNA counterstain, DAPI, in blue. Using conventional widefield microscopy (left) Xist RNA signal appears as a cluster of large foci occupying a discrete nuclear domain. Super-resolution 3D-SIM (right) resolves the Xist RNA signal as punctate foci thought to represent single Xist RNA molecules (arrowheads).
Figure 2.
Figure 2.
Proposed model for the interplay between SAF-A/hnRNPU and CIZ1 (a) and/or alternative anchoring factors (b) in localized accumulation of Xist RNA. (a) SAF-A/hnRNPU monomers bind to Xist RNA molecules that are diffusing within inter-chromatin (inter-chr) spaces (left panel, arrows), triggering ATP-dependent SAF-A/hnRNPU polymerization (right panel). CIZ1 bound to the Xist E-repeat (Rep-E) anchors the Xist molecule through an interaction with the polymerized SAF-A/hnRNPU scaffold. (b) Other anchoring factors not present in lymphocytes or fibroblasts function redundantly with CIZ1. Illustrated here a putative anchoring factor (unknown) binds to the Xist A-repeat (Rep-A) and interacts with the polymerized SAF-A/hnRNPU scaffold. The factor functions additively with CIZ1 which is present and bound to Xist RNA in all cell types. The overall effect is an increased strength of Xist RNA anchoring relative to (a), where only CIZ1 is present.
Figure 3.
Figure 3.
A simplified model for localized accumulation of Xist RNA. Depiction of an interphase nucleus (NE = nuclear envelope), with individual chromosomes indicated with a fixed number of putative anchoring sites (top). In the expanded view (bottom left panel) the Xi chromosome is shown with the majority of Xist RNA molecules anchored at perichromatin sites (left panel). The model proposes that Xist RNA accumulation is centred on the site of synthesis with the range being determined by the abundance (product of synthesis and turnover rates) and the strength of anchoring. The number of putative anchoring sites is considered as constant. Decreasing abundance or increasing anchoring strength are predicted to reduce the local accumulation range from the site of synthesis (bottom centre panel). Conversely, increasing abundance or reducing anchoring strength are predicted to result in expanded Xist RNA accumulation beyond the Xi territory (bottom right panel).
Figure 4.
Figure 4.
Models for the translocation of Xist RNA molecules. (a) Individual Xist RNA molecules diffuse away from the transcription site, moving through inter-chromatin (inter-chr) spaces in directions indicated with arrows (left panel, molecules labelled 1–3). Individual molecules are restrained at defined sites through interactions between polymerized SAF-A/hnRNPU and Xist-anchoring factors as proposed in figure 2 (left panel, molecule labelled 4). Non-anchored molecules diffuse further and then either anchor at distant sites (right panel, molecules 1 and 3) or continue to diffuse (right panel, molecule 2). Depending on anchoring dynamics (dwell time) and RNA turnover, Xist RNA molecules may undergo cycles of anchor release (right panel, molecule 4). (b) An alternative model for the translocation of Xist RNA molecules. Xist RNA is anchored in close proximity to the transcription site (left panel, molecules 1 and 2) and dynamic movements of the chromatin (dashed arrow) transfer anchored molecules from one site to another (right panel, molecule 2). Other newly transcribed Xist molecules then anchor (right panel, molecule 3) and can undergo translocation to alternative sites as a result of different dynamic chromatin movements.

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