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Counting on Xist

Nature Genetics volume 19, pages 211–212 (1998)Cite this article

The defining requirement of dosage-compensation mechanisms is the need for a cell to recognize sex-chromosome dosage (X or XX) and respond to equalize expression levels of critical X-linked genes between the sexes. In mammals, dosage compensation is achieved by X-chromosome inactivation, which is unique among compensation mechanisms in having to distinguish between the two types of X chromosome — one destined to become active and the other inactive — within the same nucleus. This presents two challenges: how to achieve inactivation in cis on one X without affecting gene activity on the other X and how to recognize the number of X chromosomes in a cell in order to determine how many and which X chromosome(s) should be inactivated.

Insight into the first step has emerged with the characterizatoin of Xist, a gene within the X-inactivation centre. Xist is both necessary and sufficient for X inactivation and encodes a large structural RNA that coats the inactive X chromosome1,2,3. Prior to inactivation, Xist is transcribed from all X chromosomes. At the onset of inactivation, however, the steady-state levels of Xist RNA increase and the transcript coats the X chromosome that is then inactivated. While Xist expression is maintained from the inactive X, it is turned off altogether on the active X. Recent studies have demonstrated that this transition is mediated by stabilization of Xist transcripts on the X that will become inactive, but not on other X chromosome (which remains active; Refs 4,5). This, then, brings us to the second challenge: how does the cell know whether to stabilize Xist RNA and on how many Xs?

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Figure 1: Diagram of the Xist mutations targeted by Clerc and Avner8 and their effects on X inactivation.
Figure 2: Schematic representation of three general models proposed for the initiation of X inactivation and the establishment of active (Xa) and inactive (Xi) X chromosomes.

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Authors and Affiliations

  1. Department of Genetics, Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, 44106, Ohio, USA

    Laura Carrel & Huntington F. Willard

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  1. Laura Carrel
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  2. Huntington F. Willard
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Carrel, L., Willard, H. Counting on Xist. Nat Genet 19, 211–212 (1998). https://doi.org/10.1038/878

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