When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

Abstract

A tribute to Mary Lyon was held in October 2016. Many remarked about Lyon's foresight regarding many intricacies of the X-chromosome inactivation process. One such example is that a year after her original 1961 hypothesis she proposed that genes with Y homologues should escape from X inactivation to achieve dosage compensation between males and females. Fifty-five years later we have learned many details about these escapees that we attempt to summarize in this review, with a particular focus on recent findings. We now know that escapees are not rare, particularly on the human X, and that most lack functionally equivalent Y homologues, leading to their increasingly recognized role in sexually dimorphic traits. Newer sequencing technologies have expanded profiling of primary tissues that will better enable connections to sex-biased disorders as well as provide additional insights into the X-inactivation process. Chromosome organization, nuclear location and chromatin environments distinguish escapees from other X-inactivated genes. Nevertheless, several big questions remain, including what dictates their distinct epigenetic environment, the underlying basis of species differences in escapee regulation, how different classes of escapees are distinguished, and the roles that local sequences and chromosome ultrastructure play in escapee regulation.This article is part of the themed issue 'X-chromosome inactivation: a tribute to Mary Lyon'.

Keywords: X-chromosome inactivation; epigenetic regulation; escapee; inactive X chromosome; lupus; sexual dimorphism.

Figure 1.

Frequencies, expression patterns and sources of variable escape. (a) Summary of select XCI surveys. XCI states are coloured red (subject), yellow (variable escape) and green (escape). A lighter green denotes the frequency of bi-allelic genes reported in single-cell RNA-seq surveys, but does not consider cellular heterogeneity as a source of variable escape. The number of genes listed is as reported in the indicated references and may not necessarily correlate with more recent genome annotations (e.g. [31]). Abbreviations include: tissues, blood (Bl), brain (Br), spleen (S) and ovary (O), trophectoderm stem cells (TSC), neuronal precursor cells (NPC); approaches, allele-specific expression (ASE), allelic imbalance (AI). (b) Variable escape between individuals or between tissues can exhibit a bimodal pattern of inactive X expression levels, but more frequently represents a continuum. Inactive X expression for each sample is generally measured relative to active X levels (Xi/Xa) with XCI status depending, in part, on criteria for escape. (c) Classification of escape genes and contributing factors. Cellular heterogeneity probably impacts both constitutive escapees and variable escape genes. Variable escapees may be akin to facultative escape and in addition to tissue-specific regulators and ultrastructure could be impacted by factors influencing epigenetic states or developmental timing. As discussed in text, the constitutive escapees are controlled by intrinsic elements and also factors that influence the local chromatin neighbourhood of which known contributors are cited, although additional factors are probably involved.