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

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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 This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Development
Evolution of imprinted and random X‐chromosome inactivation (XCI) in mammals. Phylogenetic tree illustrating the appearance of the two major forms of XCI, imprinted and random (iXCI and rXCI, respectively), across species. In Eutheria, rXCI coincides with the emergence of Xist, while in Metatheria iXCI evolution is marked by the appearance of Rsx. iXCI is also found in mice and cows, where it concerns extraembryonic annexes and pre‐implantation development. The time of divergence is estimated in Mya. The sex chromosome composition is also indicated for each species.
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Developmental pattern of Xist expression, coating, and X‐silencing in females of three eutherian species (mouse, human, and rabbit). In mice, Xist imprinted expression from the Xp starts at the 2 to 4‐cell stage transition, with Xist transcripts coating the future (paternal) Xi. From the 8‐cell to the morula stage, the paternal X is progressively inactivated. At the blastocyst stage, the paternal X undergoes reactivation in the inner cell mass (ICM), so that both X chromosomes are now active. By contrast, the Xp remains inactivated in the trophoblast. Random XCI follows in the ICM, whereby the paternal and the maternal Xs have the same probability of being inactivated. This random pattern of inactivation is epigenetically maintained through cell divisions in the post‐implantation embryo and in the adult. In humans, XIST is not imprinted and its expression is detectable from both X chromosomes from the 4–8 cell stage. It is unknown whether XIST coats the chromosomes at these stages. It does, however, at the morula stage, but the chromosomes remain transcriptionally active. This configuration persists in the blastocyst, in embryonic as well as extra‐embryonic lineages. Later on, XIST expression and coating are restricted to a single X chromosome and accompanied by X transcriptional repression. In rabbits, like in humans, the two X chromosomes are active in the early cleavage stages. Punctate Xist expression is detectable from both Xs from the 8‐cell stage. Xist accumulation initiates in the morula and is more prominent in the blastocyst, coinciding with transcriptional inactivation. Importantly, a significant portion of blastocyst cells show biallelic Xist coating, which is accompanied in this case by the silencing of both X chromosomes. Only later is the situation resolved, finally resulting in inactivation of a single X in the adult. This inactivation is believed to be random, but this requires further investigation. The timing of zygotic genome activation (ZGA) is indicated for each species.
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X‐linked noncoding elements involved in the control of X‐chromosome inactivation (XCI) in mouse and human. (a) Top panels: representation of the mouse X chromosome, with zooms of the regions that control XCI in the mouse. The X inactivation center (Xic), located in XqD, harbors protein‐coding genes (in black) as well as lncRNA genes (in blue). Firre, located in XqA5, also has XCI‐related function (see below). Middle panel: schematic tridimensional structure of the Xic, partitioned in two topologically associated domains (TADs). The Tsix TAD includes repressors of XCI (in red), while the Xist TAD encompasses XCI activators (in green). Linx is represented by dotted lines as its function is yet to be determined. Bottom panel: depiction of the mechanisms of action of lncRNA transcripts involved in the control of XCI. Firre encodes a lncRNA involved in Xi perinucleolar localization and maintenance of XCI. LncRNAs of the Xic are important for XCI initiation. Tsix blocks Xist accumulation on the Xa, while Jpx, Ftx, RepA, and XistAR favor Xist expression on the Xi through diverse mechanisms. (b) Same as (a) for the humans. The XIC locus is located in Xq13 while XACT maps to Xq23. The diagonal bars represent a break in the scale (top panels). Within the XIC, the region upstream of XIST displays relative conservation compared to the mouse, both at the levels of gene content and for what concerns its 3D organization (TAD). Nevertheless, the function of putative XIST regulators such as JPX and FTX remains to be investigated. In contrast, the downstream region corresponding to the TSIX TAD shows a lesser degree of conservation. XACT is found in human only and could be required to counteract XIST expression, activity or accumulation.
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Xist structure and function. (a) Structure of the mouse and human Xist/XIST genes, with exons represented as boxes and introns as lines. Conserved repeat elements (A–F) are drawn in color, in scale. The table depicts some of the properties of these repeat elements. (b) Functions, activities and interactors of Xist RNA repeat elements as characterized in the mouse. The A‐repeat recruits several proteins involved in X‐chromosome silencing and is also required for spreading along the chromosome; The B‐repeat interacts with Jarid2, a PRC2 cofactor, thus participating to Xi chromatin remodeling. The C‐repeat could be important for Xist tethering to the Xi, possibly via its interaction with the transcription factor YY1. The E‐repeat also mediates Xist tethering to the Xi by interacting with HNRNPU (whose interaction with Xist also depends on the A‐repeat). The F‐repeat is, like the B‐repeat, is also critical for Jarid2 recruitment.
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RNA in Disease and Development > RNA in Development
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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