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Molecular and Cellular Biology, September 2004, p. 7855-7862, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.7855-7862.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

An Antisense RNA Regulates the Bidirectional Silencing Property of the Kcnq1 Imprinting Control Region

Noopur Thakur,1,{dagger} Vijay Kumar Tiwari,1,{dagger} Helene Thomassin,2 Radha Raman Pandey,1 Meena Kanduri,1 Anita Göndör,1 Thierry Grange,2 Rolf Ohlsson,1 and Chandrasekhar Kanduri1*

Department of Development and Genetics, Evolution Biology Centre, Uppsala University, Uppsala, Sweden,1 Institut Jacques Monod, CNRS, Universites Paris 6-7, Paris, France2

Received 10 May 2004/ Returned for modification 17 June 2004/ Accepted 28 June 2004

The Kcnq1 imprinting control region (ICR) located in intron 10 of the Kcnq1 gene is unmethylated on the paternal chromosome and methylated on the maternal chromosome and has been implicated in the manifestation of parent-of-origin-specific expression of six neighboring genes. The unmethylated Kcnq1 ICR harbors bidirectional silencer activity and drives expression of an antisense RNA, Kcnq1ot1, which overlaps the Kcnq1 coding region. To elucidate whether the Kcnq1ot1 RNA plays a role in the bidirectional silencing activity of the Kcnq1 ICR, we have characterized factor binding sites by genomic footprinting and tested the functional consequence of various deletions of these binding sites in an episome-based system. Deletion of the elements necessary for Kcnq1ot1 promoter function resulted in the loss of silencing activity. Furthermore, interruption of Kcnq1ot1 RNA production by the insertion of a polyadenylation sequence downstream of the promoter also caused a loss of both silencing activity and methylation spreading. Thus, the antisense RNA plays a key role in the silencing function of the ICR. Double-stranded RNA (dsRNA)-mediated RNA interference is unlikely to be involved, as the ICR is active irrespective of the simultaneous production of dsRNA from the genes it silences.

* Corresponding author. Mailing address: Department of Development and Genetics, Evolution Biology Centre, Uppsala University, Norbyvägen 18A, S-752 36 Uppsala, Sweden. Phone: 0046 70 9600450. Fax: 0046 18 4712678. E-mail: kanduri.chandrasekhar{at}ebc.uu.se.

{dagger} N.T. and V.K.T. contributed equally to this work.

Molecular and Cellular Biology, September 2004, p. 7855-7862, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.7855-7862.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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