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EPIGENETICS

Many XCI-ting routes to reach the eXACT dose

Nature Cell Biology volume 22, pages 1397–1398 (2020)Cite this article

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X-chromosome inactivation studies have revealed striking species specificities in terms of the players, kinetics and mechanisms. Transcriptomic profiling of human pre‐implantation development and germ cell differentiation suggests a peculiar dosage compensation mechanism with yet undefined contributions from XIST and XACT lncRNAs.

To this aim, Chitiashvili et al. elegantly combined the analysis of human primordial germ cells (hPGCs) from prenatal ovaries and in vitro generated primordial germ-cell-like cells (hPGCLCs). They first demonstrated that hPGCs harbour two Xa, thus confirming that X-chromosome reactivation (XCR), which accompanies the global epigenetic resetting taking place in the germline, occurs from week four of development5. The authors also identified XACT as a marker of hPGCs, both in males and females. XACT is an X-linked, hominoid specific lncRNA, which displays the unique property of coating active X chromosomes in pluripotent stem cells (hPSCs)6,7. Chitiashvili et al. revealed that XACT also accumulates on Xa in hPGCs and that its expression is restricted to cells positive for the pluripotent transcription factor NANOG in pre-and post-implantation epiblasts, in agreement with XACT being regulated by a NANOG-bound enhancer8. The expression pattern of XIST, the trigger of XCI, further draws a parallel between hPSCs and hPGCs: XIST is expressed from both X chromosomes, but its accumulation profile takes the shape of a disperse RNA cloud3,7, which has been linked to the presence of XACT and to a defective ability to trigger XCI in hPSCs. Based on these shared properties, and because embryonic cells can reportedly undergo XCD before XCI, the authors questioned whether and how dosage compensation occurs in hPGCs alongside XCR.

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Fig. 1: Models for X-chromosome activity control during human development.

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  1. Université de Paris, Epigenetics and Cell Fate, CNRS, Paris, France

    Jean-François Ouimette & Claire Rougeulle

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  1. Jean-François Ouimette
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  2. Claire Rougeulle
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Correspondence to Claire Rougeulle.

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Ouimette, JF., Rougeulle, C. Many XCI-ting routes to reach the eXACT dose. Nat Cell Biol 22, 1397–1398 (2020). https://doi.org/10.1038/s41556-020-00608-3

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