XIST

XIST, or X-inactive specific transcript, is a long noncoding RNA encoded by the XIST gene within the X-inactivation center on the X chromosome. It is central to X chromosome inactivation (XCI), the dosage-compensation process that equalizes gene expression between XX females and XY males in placental mammals. In female cells, XIST is upregulated on the chromosome destined to become inactive and spreads in cis along that chromosome to establish a transcriptionally silent, heterochromatic state.

Mechanism and structure: XIST RNA coats the inactive X chromosome and recruits chromatin-modifying complexes that promote gene silencing. Key players include Polycomb repressive complexes, which deposit repressive histone marks such as H3K27me3, and silencing factors like SPEN/SHARP. The RNA contains several repeat regions (A to F); the A-repeat is essential for silencing, while other repeats contribute to localization, spreading, and stabilization of the inactive state. Maintenance of XCI involves ongoing chromatin modifications and DNA methylation to preserve silencing through subsequent cell divisions.

Regulation and variation: XIST expression is regulated by the X-inactivation center and the antisense transcript TSIX, which antagonizes XIST. XCI is established during early development and is typically random in the placental lineage of many species, though imprinted XCI occurs in certain tissues or species-specific contexts. In humans, XCI is initiated with XIST activity, while different species may utilize related or distinct regulatory mechanisms.

Clinical and research relevance: Aberrant XIST expression or XCI can be associated with X chromosome aneuploidies and certain cancers. XIST remains a major focus in developmental biology, stem cell research, and studies of epigenetic regulation and dosage compensation.