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Human Molecular Genetics, 2001, Vol. 10, No. 14 1455-1464
© 2001 Oxford University Press

An element in intron 1 of the CFTR gene augments intestinal expression in vivo

Rebecca K. Rowntree, Georges Vassaux1, Tarra L. McDowell, Steve Howe1, Amanda McGuigan1, Marios Phylactides, Clare Huxley1 and Ann Harris+

Paediatric Molecular Genetics, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK and 1Section of Cell and Molecular Biology, Division of Biomedical Sciences, Imperial College School of Medicine, London SW7 2AZ, UK

The elements controlling the complex developmental and tissue-specific expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene lie outside the basal promoter region and have not been characterized. We previously identified a tissue-specific DNase I hypersensitive site (DHS) in intron 1 (185 + 10 kb) of the CFTR gene. Here we show that removal of the core element abolishes the activity of this DHS in transient transfection assays of reporter/enhancer gene constructs. We then compared expression from a 310 kb yeast artificial chromosome (YAC) that contains the entire CFTR gene with expression from the same YAC from which the DHS element had been deleted. Stable transfection of a human colon carcinoma cell line showed that transcription from the deleted YAC was reduced by ~60%. In transgenic mice, deletion of the intron 1 DHS had no effect on expression in the lung, but reduced expression in the intestine by ~60%. Thus, the regulatory element associated with the intron 1 DHS is tissue-specific and is required for normal CFTR expression levels in the intestinal epithelium in vivo.

+ To whom correspondence should be addressed. Fax: +44 1865 222626; Email: aharris@molbiol.ox.ac.ukPresent addresses:Georges Vassaux, ICRF Molecular Oncology Unit, ICSM at Hammersmith Hospital, Du Cane Road, London W12 ONN, UKTarra L. McDowell, MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UKAmanda McGuigan, Biological Services Unit, Hodgkin Building, King’s College, London SE1 9RT, UK


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