X-inactive-specific transcript: a long noncoding RNA with a complex role in sex differences in human disease

• Published in: Biology of sex differences 2024-12, Vol.15 (1), p.101-16
• Main Authors: Predescu, Dan N, Mokhlesi, Babak, Predescu, Sanda A
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Anopheles; Antisense RNA; Autoimmunity; Chromatin; Chromosomes, Human, X - genetics; Development and progression; Disease - genetics; Embryonic development; Epigenetic inheritance; Female; Genes; Genetic aspects; Genetic engineering; Genetic transcription; Genetically modified organisms; Humans; Male; Nervous system diseases; Review; RNA, Long Noncoding - genetics; Sex Characteristics; Sex chromosomes; Sexually dimorphic diseases; X Chromosome Inactivation; XIST, gene silencing
• ISSN: 2042-6410; 2042-6410
• DOI: 10.1186/s13293-024-00681-5

In humans, the X and Y chromosomes determine the biological sex, XX specifying for females and XY for males. The long noncoding RNA X-inactive specific transcript (lncRNA XIST) plays a crucial role in the process of X chromosome inactivation (XCI) in cells of the female, a process that ensures the balanced expression of X-linked genes between sexes. Initially, it was believed that XIST can be expressed only from the inactive X chromosome (Xi) and is considered a typically female-specific transcript. However, accumulating evidence suggests that XIST can be detected in male cells as well, and it participates in the development of cancers and other human diseases by regulating gene expression at epigenetic, chromatin remodeling, transcriptional, and translational levels. XIST is abnormally expressed in many sexually dimorphic diseases, including autoimmune and neurological diseases, pulmonary arterial hypertension (PAH), and some types of cancers. However, the underlying mechanisms are not fully understood. Escape from XCI and skewed XCI also contributes to sex-biased diseases and their severity. Interestingly, in humans, similar to experimental animal models of human disease, the males with the XIST gene activated display the sex-biased disease condition at a rate close to females, and significantly greater than males who had not been genetically modified. For instance, the men with supernumerary X chromosomes, such as men with Klinefelter syndrome (47, XXY), are predisposed toward autoimmunity similar to females (46, XX), and have increased risk for strongly female biased diseases, compared to 46, XY males. Interestingly, chromosome X content has been linked to a longer life span, and the presence of two chromosome X contributes to increased longevity regardless of the hormonal status. In this review, we summarize recent knowledge about XIST structure/function correlation and involvement in human disease with focus on XIST abnormal expression in males. Many human diseases show differences between males and females in penetrance, presentation, progression, and survival. In humans, the X and Y sex chromosomes determine the biological sex, XX specifying for females and XY for males. This numeric imbalance, two X chromosomes in females and only one in males, known as sex chromosome dosage inequality, is corrected in the first days of embryonic development by inactivating one of the X chromosomes in females. While this "dosage compensation" should in theory solv