Dosage compensation and gene expression on the mammalian X chromosome: one plus one does not always equal two

Abstract

Counting chromosomes is not just simple math. Although normal males and females differ in sex chromosome content (XY vs. XX), X chromosome imbalance is tolerated because dosage compensation mechanisms have evolved to ensure functional equivalence. In mammals this is accomplished by two processes--X chromosome inactivation that silences most genes on one X chromosome in females, leading to functional X monosomy for most genes in both sexes, and X chromosome upregulation that results in increased gene expression on the single active X in males and females, equalizing dosage relative to autosomes. This review focuses on genes on the X chromosome, and how gene content, organization and expression levels can be influenced by these two processes. Special attention is given to genes that are not X inactivated, and are not necessarily fully dosage compensated. These genes that "escape" X inactivation are of medical importance as they explain phenotypes in individuals with sex chromosome aneuploidies and may impact normal traits and disorders that differ between men and women. Moreover, escape genes give insight into how X chromosome inactivation is spread and maintained on the X.

Fig. 1

XCI models to incorporate escape gene regulation. a Genomic sequences or boundary elements may regulate inactive X expression and differ in their proximity to escape gene domains. i) Inactive X heterochromatin (gray circles) is propagated from “way stations” (green ovals) and encompasses X inactivated genes (yellow). In this model, escape genes (blue) reside too far from way stations to be inactivated. Although not shown, a variation of this model is that specific escape sequences could lie too far from inactivated genes to impart an effect (Carrel et al. 2006; McNeil et al. 2006). Nevertheless, regulatory elements that rely on distance to distinguish genes cannot account for the close juxtaposition of some escape and inactivated genes (Tsuchiya et al. 2004; Carrel and Willard 2005), but could explain large Mb sized domains with large transition regions elsewhere on the X. ii) Sequences such as insulators, boundary elements or barriers (red octagon) flank coordinately regulated genes and protect them from silencing. This model, or at least this model with respect to the CTCF protein (Filippova et al. 2005), also cannot fully explain escape gene expression (Ciavatta et al. 2006). iii) Incorporation of both models; way stations propagate XCI which is prevented from reaching escape genes by boundary elements. b Three-dimensional organization of X-linked genes can further affect escape gene expression (Chaumeil et al. 2006). A cross-section of the inactive X is enlarged. Both active (blue) and inactive (yellow) genes lie at the periphery of the XIST-delineated inactive X territory (gray). Non-genic and repeat sequences (black line) reside largely within the XIST compartment. Exterior positioning of escape genes is facilitated by boundary elements (red) and/or excessive distance from way stations (green)