Structural aspects of the inactive X chromosome

Abstract

A striking difference between male and female nuclei was recognized early on by the presence of a condensed chromatin body only in female cells. Mary Lyon proposed that X inactivation or silencing of one X chromosome at random in females caused this structural difference. Subsequent studies have shown that the inactive X chromosome (Xi) does indeed have a very distinctive structure compared to its active counterpart and all autosomes in female mammals. In this review, we will recap the discovery of this fascinating biological phenomenon and seminal studies in the field. We will summarize imaging studies using traditional microscopy and super-resolution technology, which revealed uneven compaction of the Xi. We will then discuss recent findings based on high-throughput sequencing techniques, which uncovered the distinct three-dimensional bipartite configuration of the Xi and the role of specific long non-coding RNAs in eliciting and maintaining this structure. The relative position of specific genomic elements, including genes that escape X inactivation, repeat elements and chromatin features, will be reviewed. Finally, we will discuss the position of the Xi, either near the nuclear periphery or the nucleolus, and the elements implicated in this positioning.This article is part of the themed issue 'X-chromosome inactivation: a tribute to Mary Lyon'.

Keywords: X chromosome; X inactivation; chromatin; nucleus.

Figure 1.

(a,b) Allelic intrachromosomal contact maps reveal the bipartite structure of the Xi in mouse F₁ brain tissue (spretus Xi). (a) A heat map of the Pearson correlation of contact counts within 1 Mb windows along the Xa obtained from BL6-specific in situ DNase Hi-C reads shows compartments and TAD structures typically found in autosomes. (b) As in (a) but for spretus-specific reads showing the two superdomains of preferential interaction along the Xi. (c,d) Three-dimensional models inferred from the contact maps in (a) and (b), respectively, provide a visualization of the two distinct X-chromosome structures. The location of the Dxz4 locus (within the hinge region) is indicated by the ringed point. The red to blue shading runs from the centromere to telomere. (Adapted from [47].)

Figure 2.

(a,b) Imaging of the Xi preferred locations near the nuclear periphery (a) or the nucleolus (b). (a) Example of a nucleus from an XXX individual after immunostaining for H3K27me3 shows two Barr bodies at different locations at the periphery of the nucleus. (b) Example of a nucleus stained with DAPI (blue) after immunostaining for nucleophosmin (red) and RNA-FISH for Xist to mark the Xi (green). Note that Xist RNA surrounds the nucleolus. (c,d) Hypothetical models of positioning of the Xi near the periphery which may be facilitated by the lamin B receptor (c) or near the nucleolus which may be facilitated by Dxz4 and Firre lncRNA loci CTCF and cohesin (d). (Adapted from [96].)