Function and evolution of the long noncoding RNA circuitry orchestrating X‐chromosome inactivation in mammals

Abstract

X-chromosome inactivation (XCI) is a chromosome-wide regulatory process that ensures dosage compensation for X-linked genes in Theria. XCI is established during early embryogenesis and is developmentally regulated. Different XCI strategies exist in mammalian infraclasses and the regulation of this process varies also among closely related species. In Eutheria, initiation of XCI is orchestrated by a cis-acting locus, the X-inactivation center (Xic), which is particularly enriched in genes producing long noncoding RNAs (lncRNAs). Among these, Xist generates a master transcript that coats and propagates along the future inactive X-chromosome in cis, establishing X-chromosome wide transcriptional repression through interaction with several protein partners. Other lncRNAs also participate to the regulation of X-inactivation but the extent to which their function has been maintained in evolution is still poorly understood. In Metatheria, Xist is not conserved, but another, evolutionary independent lncRNA with similar properties, Rsx, has been identified, suggesting that lncRNA-mediated XCI represents an evolutionary advantage. Here, we review current knowledge on the interplay of X chromosome-encoded lncRNAs in ensuring proper establishment and maintenance of chromosome-wide silencing, and discuss the evolutionary implications of the emergence of species-specific lncRNAs in the control of XCI within Theria. WIREs RNA 2016, 7:702-722. doi: 10.1002/wrna.1359 For further resources related to this article, please visit the WIREs website.

New Advances in Human X Chromosome Status from a Developmental and Stem Cell Biology

“…Murine XCI consists of a series of events orchestrated by a single locus, known as the X Inactivation Center (XIC). Chronologically, it was demonstrated that the murine XIC and chromosome interactions at XIC count the number of X chromosomes (15), select the X chromosome to be inactivated (X i )(14, 16), propagate stable heterochromatin on the X i (17–19), and direct the localization of the stable X i heterochromatin to the lamina (20). These complex events are orchestrated by the XIC through the actions and interactions of multiple long non-coding RNAs, proteins, and functional elements encoded therein.…”

“…There are two chromatin domains, known as Topologically Associated Domains, or TADs, that comprise the XIC. These TADs are thought to have directly opposing functions, which are mediated by the distinct genomic elements present in each; the Tsix TAD mediates XCI repression, and the Xist TAD mediates XCI progression(17). …”

“…Nanog, Oct4, and Sox2 mark the naïve state and collectively repress the ubiquitin ligase Rnf12 (21) that lies in the Xist TAD (17), prior to dosage compensation. As naïve state TFs become depleted, Rnf12 is activated and marks Rex1 for degradation (21).…”

“…Rex1 is another naïve TF that, along with KLF4 and c-Myc, activates the lncRNA Tsix (21). Tsix is the key repressor of Xist function in mice and negatively regulates Xist expression in cis (17). On the active X chromosome, the Xite element in the Tsix TAD promotes the expression of Tsix in cis (17, 21), in turn generating Tsix expression asymmetry(22), facilitating the inactivation of the Tsix-null X chromosome.…”

“…Tsix is the key repressor of Xist function in mice and negatively regulates Xist expression in cis (17). On the active X chromosome, the Xite element in the Tsix TAD promotes the expression of Tsix in cis (17, 21), in turn generating Tsix expression asymmetry(22), facilitating the inactivation of the Tsix-null X chromosome. However, the process of this transition from biallelic to monoallelic Tsix expression has not been fully explained.…”