Escape from X inactivation in mice and humans

Abstract

A subset of X-linked genes escapes silencing by X inactivation and is expressed from both X chromosomes in mammalian females. Species-specific differences in the identity of these genes have recently been discovered, suggesting a role in the evolution of sex differences. Chromatin analyses have aimed to discover how genes remain expressed within a repressive environment.

Figure 1

More genes escape X inactivation in humans than in the mouse. Distribution of genes subject to X inactivation (blue) and of 'escape' genes (orange) in human and mouse. The position of the pseudoautosomal regions (PAR1 and 2 in human, PAR in mouse), of the centromeres (cen, purple bar), and of the X-inactivation center encoding the long noncoding RNA XIST/Xist (black bar) are indicated. Note that as the centromere is located at one end of the mouse X chromosome, there is no short arm or long arm. Data from Carrel and Willard [12] and Yang et al. [13].

Figure 2

Silenced and escape regions have distinct chromatin marks. (a) Chromatin containing escape genes is excluded from the condensed heterochromatic body of the Xi. In mouse, individual escape genes are surrounded by inactivated chromatin. In contrast, human escape genes exist in domains comprising clusters of genes. Orange bars represent escape genes and blue bars inactivated genes. (b) Silenced chromatin in the Xi is coated by Xist RNA potentially via specific DNA motifs (green). Repressive histone modifications and histone variants (for example, H3K27me3, H3K9me3, H4K20me3, and macroH2A1) are recruited and DNA methylation modifies the CpG islands. This type of chromatin structure prevents transcription (blue bar below). In contrast, escape gene regions are enriched for permissive histone marks (for example, H3K4me3, and H3 and H4 acetylation) and RNA polymerase II (RNA pol II) and are hypomethylated at their CpG islands. Insulator sites bound by the insulator protein CTCF, together with unknown factors (as denoted by the '?'), may separate inactivated genes (blue bar) from active genes (orange bar). CTCF binding may block CpG methylation and the spread of repressive chromatin and/or may organize the chromatin into loops.