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Published online before print October 16, 2007, 10.1261/rna.562907
RNA (2007), 13:2287-2299. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 RNA Society.
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Alternately spliced WT1 antisense transcripts interact with WT1 sense RNA and show epigenetic and splicing defects in cancer

Anthony R. Dallosso1, Anne L. Hancock1, Sally Malik1, Ashreena Salpekar1, Linda King-Underwood2, Kathy Pritchard-Jones2, Jo Peters3, Kim Moorwood4, Andrew Ward4, Karim T.A. Malik1, and Keith W. Brown1

1 CLIC Sargent Research Unit, Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom
2 Section of Paediatric Oncology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom
3 MRC Mammalian Genetics Unit, Harwell, Oxfordshire OX11 0RD, United Kingdom
4 Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, United Kingdom

Many mammalian genes contain overlapping antisense RNAs, but the functions and mechanisms of action of these transcripts are mostly unknown. WT1 is a well-characterized developmental gene that is mutated in Wilms’ tumor (WT) and acute myeloid leukaemia (AML) and has an antisense transcript (WT1-AS), which we have previously found to regulate WT1 protein levels. In this study, we show that WT1-AS is present in multiple spliceoforms that are usually expressed in parallel with WT1 RNA in human and mouse tissues. We demonstrate that the expression of WT1-AS correlates with methylation of the antisense regulatory region (ARR) in WT1 intron 1, displaying imprinted monoallelic expression in normal kidney and loss of imprinting in WT. However, we find no evidence for imprinting of mouse Wt1-as. WT1-AS transcripts are exported into the cytoplasm and form heteroduplexes with WT1 mRNA in the overlapping region in WT1 exon 1. In AML, there is often abnormal splicing of WT1-AS, which may play a role in the development of this malignancy. These results show that WT1 encodes conserved antisense RNAs that may have an important regulatory role in WT1 expression via RNA:RNA interactions, and which can become deregulated by a variety of mechanisms in cancer.

Keywords: antisense; RNA; WT1 ; heteroduplex; epigenetics; splicing

Received March 19, 2007 ; accepted August 27, 2007.


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