Variable escape from X-chromosome inactivation: identifying factors that tip the scales towards expression

Abstract

In humans over 15% of X-linked genes have been shown to 'escape' from X-chromosome inactivation (XCI): they continue to be expressed to some extent from the inactive X chromosome. Mono-allelic expression is anticipated within a cell for genes subject to XCI, but random XCI usually results in expression of both alleles in a cell population. Using a study of allelic expression from cultured lymphoblasts and fibroblasts, many of which showed substantial skewing of XCI, we recently reported that the expression of genes lies on a contiunuum between those that are subject to inactivation, and those that escape. We now review allelic expression studies from mouse, and discuss the variability in escape seen in both humans and mice in genic expression levels, between X chromosomes and between tissues. We also discuss current knowledge of the heterochromatic features, DNA elements and three-dimensional topology of the inactive X that contribute to the balance of expression from the otherwise inactive X chromosome.

Keywords: RNA-seq; XIST; allelic imbalance; boundary elements; dosage compensation; epigenetic marks; waystations.

Figure 1

Variability in dosage compensation on the X chromosome. A: The X and Y chromosomes evolved from an ancestral pair of autosomes. After their divergence, expression of X-linked genes from the Xa was increased, and the majority of genes were silenced on the Xi. Note that only a subset of genes is illustrated in all figures. B: Not all genes that escape from XCI show the same level of expression. Longer arrows denote higher Xi expression but expression is still not equal to the Xa. C: A gene may escape from XCI on certain X chromosomes but not others. To simplify, variable Xi expression levels are not shown in parts (C) and (D). D: Escape from XCI may occur only in certain tissues for some genes. E: The level of skewing of XCI, as illustrated by grey and white circles, differs between females and tissues. As escape from inactivation can differ between X chromosomes (shown in C), skewing will alter the overall expression level.

Figure 2

Features contributing to escape from XCI. A: STS was the first non-PAR gene found to escape from XCI in humans, and maps of genes escaping XCI show that genes with the least divergence from the Y are most likely to escape from XCI. B: Genes, which escape from XCI differ with respect to inactive (yellow hexagons) and active (green stars) chromatin marks as well as the presence of XIST RNA (blue wavy line) and promoter DNAm (white lollipops = unmethylated, black lollipops = methylated). C: DNA sequences such as waystations (pink triangles), escape elements (orange ovals) and boundary elements (maroon hexagons) have been hypothesised to account for genes that are subject to and escape from XCI. D: The three dimensional structure of the Xi appears to bring together genes that escape from XCI and to involve XIST (blue wavy lines) and PRC2 (tan ovals) in the spread of XCI. E: Together all the above features influence whether a gene is subject to, or can escape from, XCI. There does not appear to be a definitive set of features that cause a gene to escape from XCI, rather, it is likely a combination of multiple features that determines the degree to which escape occurs.