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Science 31 October 2008:
Vol. 322. no. 5902, pp. 750 - 756
DOI: 10.1126/science.1163045
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Reports

Polycomb Proteins Targeted by a Short Repeat RNA to the Mouse X Chromosome

Jing Zhao,1,2,3 Bryan K. Sun,1,2,3 Jennifer A. Erwin,1,2,3 Ji-Joon Song,2,3 Jeannie T. Lee1,2,3*

To equalize X-chromosome dosages between the sexes, the female mammal inactivates one of her two X chromosomes. X-chromosome inactivation (XCI) is initiated by expression of Xist, a 17-kb noncoding RNA (ncRNA) that accumulates on the X in cis. Because interacting factors have not been isolated, the mechanism by which Xist induces silencing remains unknown. We discovered a 1.6-kilobase ncRNA (RepA) within Xist and identified the Polycomb complex, PRC2, as its direct target. PRC2 is initially recruited to the X by RepA RNA, with Ezh2 serving as the RNA binding subunit. The antisense Tsix RNA inhibits this interaction. RepA depletion abolishes full-length Xist induction and trimethylation on lysine 27 of histone H3 of the X. Likewise, PRC2 deficiency compromises Xist up-regulation. Therefore, RepA, together with PRC2, is required for the initiation and spread of XCI. We conclude that a ncRNA cofactor recruits Polycomb complexes to their target locus.

1 Howard Hughes Medical Institute, Boston, MA 02115, USA.
2 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02493, USA.
3 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

* To whom correspondence should be addressed. E-mail: lee{at}molbio.mgh.harvard.edu

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