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Novel players in X inactivation: insights into Xist-mediated gene silencing and chromosome conformation

Abstract

The nuclear long noncoding RNA (lncRNA) Xist ensures X-chromosome inactivation (XCI) in female placental mammals. Although Xist is one of the most intensively studied lncRNAs, the mechanisms associated with its capacity to trigger chromosome-wide gene silencing, the formation of facultative heterochromatin and an unusual 3D conformation of the inactive X chromosome (Xi) have remained elusive. Now researchers have identified novel functional partners of Xist in a series of breakthrough studies, using unbiased techniques to isolate Xist-bound proteins, as well as forward genetic screens. In addition, important insights into the 3D organization of Xi and its relation to gene expression have been obtained. In this Review, we discuss how this new information is providing a recipe for deciphering XCI mechanisms by which a multitasking RNA can structurally and functionally transform an active chromosome into uniquely organized facultative heterochromatin.

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Figure 1: Structure and functions of mouse Xist RNA.
Figure 2: Proteomic and forward genetic screens used to identify Xist silencing partners.
Figure 3: Functions of Xist RNA silencing partners for XCI.
Figure 4: Distinct topology of the Xa versus the Xi, and the influence of DXZ4 and Xist deletions.

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Acknowledgements

We thank I. Pinheiro, E. Nora and S.F. de Almeida for their critical reading of the manuscript. This work was supported by Fundação para a Ciência e Tecnologia (grants PTDC/BEX-BCM/2612/2014 and IF/00242/2014 to S.T.d.R.). Research in the Heard laboratory was supported by Labex DEEP (ANR-11-LBX-0044), part of the IDEX Idex PSL (ANR-10-IDEX-0001-02 PSL), ERC Advanced Investigator award 250367 and “La Ligue Contre le Cancer” (Equipe Labelisée).

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da Rocha, S., Heard, E. Novel players in X inactivation: insights into Xist-mediated gene silencing and chromosome conformation. Nat Struct Mol Biol 24, 197–204 (2017). https://doi.org/10.1038/nsmb.3370

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