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

Expression of a construct integrated at different genomic locations often v aries because of position effects that have been subcategorized as stable ( decreased level of expression) and variegating (decreased proportion of exp ressing cells). It is well established that locus control regions (LCRs) ge nerally overcome position effects in transgenes, However, whether stable an d variegated position effects are equally overcome by an intact LCR has not been determined, We report that single-copy yeast artificial chromosome tr ansgenes containing an unmodified human beta-globin locus were not subject to detectable stable position effects but did undergo mild to severe varieg ating position effects at three of the four non-centromeric integration sit es 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 t he likelihood of variegating position effects, and can affect the magnitude of its transcriptional enhancement, DNase I hypersensitive site (HSS) form ation 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 d ifferent but interdependent mechanisms.