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Human Molecular Genetics, 2003, Vol. 12, No. 3 283-294
© 2003 Oxford University Press

A differentially methylated region within the gene Kcnq1 functions as an imprinted promoter and silencer

Debora Mancini-DiNardo{dagger}, Scott J.S. Steele{dagger}, Robert S. Ingram and Shirley M. Tilghman*

Howard Hughes Medical Institute and Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA

Received September 19, 2002; Accepted November 26, 2002

The imprinted gene cluster on mouse distal chromosome 7 contains a differentially methylated CpG island that maps within the Kcnq1 gene that has been shown to be required for the imprinting of multiple genes. To evaluate models for how this imprinting control region (ICR) regulates imprinting, we have characterized it structurally and functionally. We show that the region contains a promoter for a paternally expressed anti-sense transcript, Kcnq1ot1, and we define the extent of the minimal promoter. We describe three paternal-specific nuclease hypersensitive sites immediately upstream from the start site and show that they are required for full promoter activity. The expression of Kcnq1ot1 during pre- and postnatal development is compared to that of other imprinted genes in its vicinity, Cdnkn1c and Kcnq1. The lack of coordination in their expression tends to rule out an enhancer competition model for the action of the ICR in imprinting control. Using a stable transfection assay we show that the region contains a position-independent and orientation-independent silencer. We propose, on the basis of these findings, that the Kcnq1 ICR functions as a silencer on the paternal chromosome to effect the repression of neighboring genes.

* To whom correspondence should be addressed at: Tel: +1 6092582900; Fax: +1 6092583345; Email: stilghman{at}molbio.princeton.edu

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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