Long noncoding RNA XIST: Mechanisms for X chromosome inactivation, roles in sex-biased diseases, and therapeutic opportunities

Sexual dimorphism has been reported in various human diseases including autoimmune diseases, neurological diseases, pulmonary arterial hypertension, and some types of cancers, although the underlying mechanisms remain poorly understood. The long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in X chromosome inactivation (XCI) in female placental mammals, a process that ensures the balanced expression dosage of X-linked genes between sexes. XIST is abnormally expressed in many sex-biased diseases. In addition, escape from XIST-mediated XCI and skewed XCI also contribute to sex-biased diseases. Therefore, its expression or modification can be regarded as a biomarker for the diagnosis and prognosis of many sex-biased diseases. Genetic manipulation of XIST expression can inhibit the progression of some of these diseases in animal models, and therefore XIST has been proposed as a potential therapeutic target. In this manuscript, we summarize the current knowledge about the mechanisms for XIST-mediated XCI and the roles of XIST in sex-biased diseases, and discuss potential therapeutic strategies targeting XIST.