Escape from X-chromosome inactivation: from gene discovery to regulatory mechanisms

Early in mammalian development, one of the two X chromosomes in female embryos is largely silenced through X-chromosome inactivation (XCI). Although essential for dosage compensation, XCI is incomplete, with ∼5%-20% of X-linked genes escaping silencing. Escape from XCI represents an important source of sex-biased gene expression and has been increasingly linked to sex differences in development and disease susceptibility. Yet, how a subset of X-linked genes bypass XCI remains poorly understood. Here, we discuss the studies that have revealed the prevalence and variability of XCI escape across genes, tissues, and individuals in both humans and mice. We then summarize current insights into the molecular features and regulatory mechanisms associated with XCI escape, highlighting key questions that remain to be addressed to understand how X-linked gene dosage is regulated and how it contributes to sex-biased biology.