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Kcnq1ot1/Lit1 Noncoding RNA Mediates Transcriptional Silencing by Targeting to the Perinucleolar Region ^,

Faizaan Mohammad,^1, Radha Raman Pandey,^1, Takashi Nagano,³ Lyubomira Chakalova,³ Tanmoy Mondal,¹ Peter Fraser,³ and Chandrasekhar Kanduri^1,2*

Department of Genetics and Pathology, Dag Hammarskölds Väg 20, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden,¹ Department of Genetics and Development, Norbyvägen 18A, Uppsala University, S-75236 Uppsala, Sweden,² Laboratory of Chromatin and Gene Expression, Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom³

Received 21 December 2007/ Returned for modification 6 February 2008/ Accepted 15 February 2008

The Kcnq1ot1 antisense noncoding RNA has been implicated in long-range bidirectional silencing, but the underlying mechanisms remain enigmatic. Here we characterize a domain at the 5' end of the Kcnq1ot1 RNA that carries out transcriptional silencing of linked genes using an episomal vector system. The bidirectional silencing property of Kcnq1ot1 maps to a highly conserved repeat motif within the silencing domain, which directs transcriptional silencing by interaction with chromatin, resulting in histone H3 lysine 9 trimethylation. Intriguingly, the silencing domain is also required to target the episomal vector to the perinucleolar compartment during mid-S phase. Collectively, our data unfold a novel mechanism by which an antisense RNA mediates transcriptional gene silencing of chromosomal domains by targeting them to distinct nuclear compartments known to be rich in heterochromatic machinery.

Published ahead of print on 25 February 2008.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors contributed equally to this article.