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Mechanistic insights in X-chromosome inactivation - PubMed

  • ️Sun Jan 01 2017

Review

Mechanistic insights in X-chromosome inactivation

Zhipeng Lu et al. Philos Trans R Soc Lond B Biol Sci. 2017.

Abstract

X-chromosome inactivation (XCI) is a critical epigenetic mechanism for balancing gene dosage between XY males and XX females in eutherian mammals. A long non-coding RNA (lncRNA), XIST, and its associated proteins orchestrate this multi-step process, resulting in the inheritable silencing of one of the two X-chromosomes in females. The XIST RNA is large and complex, exemplifying the unique challenges associated with the structural and functional analysis of lncRNAs. Recent technological advances in the analysis of macromolecular structure and interactions have enabled us to systematically dissect the XIST ribonucleoprotein complex, which is larger than the ribosome, and its place of action, the inactive X-chromosome. These studies shed light on key mechanisms of XCI, such as XIST coating of the X-chromosome, recruitment of DNA, RNA and histone modification enzymes, and compaction and compartmentalization of the inactive X. Here, we summarize recent studies on XCI, highlight the critical contributions of new technologies and propose a unifying model for XIST function in XCI where modular domains serve as the structural and functional units in both lncRNA-protein complexes and DNA-protein complexes in chromatin.This article is part of the themed issue 'X-chromosome inactivation: a tribute to Mary Lyon'.

Keywords: RNA structure domains; X-chromosome inactivation; XIST; interactome; modularity; topological associating domains.

© 2017 The Author(s).

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Conflict of interest statement

We have no competing interests.

Figures

Figure 1.
Figure 1.

Structural basis of X inactivation: XIST structure and interactions. (a) Summary of mature XIST RNA structures using the human XIST as an example. XIST exons are shown as alternating black and grey rectangles (exons 2–5 are much smaller than 1 and 6). Repeat regions shown in thick blocks were annotated based on Elisaphenko et al. [9]. Each arc represents the base pairing interaction between the two arms of a duplex. Pink rectangles mark the structure domains defined by PARIS. (b) Summary of protein complexes that interact with XIST and their functions. Some of the best-studied examples of XIST interactions are shown. Short vertical arrows indicate known interactions. Question marks indicate that the mechanisms of interactions or functions remain unknown. The WTAP–RBM15–RBM15B complex primarily binds the A-repeat, but also to other regions to a minor extent. (c) The A-repeat forms stochastic inter-repeat duplexes that bind the adapter protein SPEN. (d) Consensus inter-repeat duplex model. The highlighted sequences are the two repeats. The duplex contains eight GC base pairs at the two sides and four forced base pairs in the middle, based on SHAPE reactivity. Domain model of the XIST RNP. (e) Structure model for the interaction between A-repeat and SPEN. (f) Structure model of the XIST RNP. Question marks represent interactions that are unclear or controversial. The size of each domain is not exactly scaled to the real size. The protein complexes are placed closest to their target sites on the XIST RNA. The linker regions among the domains are flexible, so the model here only represents the topology, but not the actual rigid shape. ‘m6A mod’ represents the m6A methylase complex and associated proteins. Figure adapted from Lu et al. [10].

Figure 2.
Figure 2.

Zooming in on chromosome structure on the Xi. (a) (i) Xist RNA FISH in female mouse NPCs showing a cloud of Xist RNA coating the X-chromosome. (ii) DNA FISH on the X-chromosome showing the separation of the Xi into two domains or lobes. The Xa, shown for comparison, shows mixing of the two domains. (b) Allele-specific HiC at 500 kb resolution for the Xi (i) and Xa (ii) in NPCs. The Xi is configured in two megadomains within which TAD structure is lost. The megadomains are separated by the DXZ4 satellite element (blue arrow). A few mini-TADs are re-formed on the Xi (green box). For comparison, the Xa does not have this megadomain structure, but maintains autosome-like TAD structure. (c) Allele-specific ATAC-seq and RNA-seq in NPCs on the Xa (top) and Xi (bottom). There is a global reduction in accessibility and gene expression on the Xi compared to the Xa. Regions that retain acccessibility are located at the promoters and CTCF sites close to escape genes. A cluster of escapees near Mecp2, the Xic and the Kdm5c escape locus, are indicated below. (d) ATAC-see reveals the spatial organization of accessible chromatin in NPCs. Xist RNA FISH cloud falls in a region of depletion of accessible chromatin. (e) Model for how the megadomain structure of the Xi is formed during X inactivation. TADs on the Xa are lost and replaced by two large domains separated by the DXZ4 element. Full-length Xist containing the A-repeat region is required for this restructuring. After X inactivation, small escape TADs form. Within these TADs, escape genes make contact with one another and are regulated at highly proximal CTCF elements. Figures adapted from Giorgetti et al. [68] and Chen et al. [69].

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