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Human Molecular Genetics, 2000, Vol. 9, No. 4 631-636
© 2000 Oxford University Press

ß-globin YAC transgenes exhibit uniform expression levels but position effect variegation in mice

Raouf Alami, John M. Greally1, Keiji Tanimoto2, Steven Hwang1, Yong-Qing Feng, James D. Engel2, Steven Fiering3 and Eric E. Bouhassira+

Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, NY 10461, USA 1Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 2Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, IL and 3Microbiology Department, Dartmouth Medical School, Hanover, NH, USA

Expression of a construct integrated at different genomic locations often varies because of position effects that have been subcategorized as stable (decreased level of expression) and variegating (decreased proportion of expressing cells). It is well established that locus control regions (LCRs) generally overcome position effects in transgenes. However, whether stable and variegated position effects are equally overcome by an intact LCR has not been determined. We report that single-copy yeast artificial chromosome transgenes containing an unmodified human ß-globin locus were not subject to detectable stable position effects but did undergo mild to severe variegating position effects at three of the four non-centromeric integration sites tested. We also find that, at a given integration site, the distance and the orientation of the LCR relative to the regulated gene contributes to the likelihood of variegating position effects, and can affect the magnitude of its transcriptional enhancement. DNase I hypersensitive site (HSS) formation varies with the proportion of expressing cells, not the level of gene expression, suggesting that silencing of the transgene is associated with a lack of HSS formation in the LCR region. We conclude that transcriptional enhancement and variegating position effects are caused by fundamentally different but inter­dependent mechanisms.

+ To whom correspondence should be addressed. Tel: +1 718 430 2188; Fax: +1 718 824 3153; Email: bouhassi@aecom.yu.edu


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