Sequence and chromosomal context effects on variegated expression of keratin 5/lacZ constructs in stratified epithelia of transgenic mice

The expression of transgene loci in mammals often occurs in a heterocellula r fashion resulting in variegated patterns of expression. We have examined the effect of chromosomal integration site, copy number, and transcriptiona lly activating sequences on the variegation of a keratin 5-lacZ (K5Z) const ruct in the stratified epithelia of transgenic mice. lacZ expression in the se mice is always mosaic, and the beta -gal activity per cell is usually hi gher in the lines with a higher proportion of expressing cells. Similar con structs, in which cDNAs were exchanged by lacZ sequences, showed no variega tion. Also, when a strongly active, nonvariegating construct was coinjected with K5Z most transgenic lines showed an almost homogeneous lacZexpression . The comparison of transgene arrays of different copies inserted at the sa me locus (obtained by using a lox/Cre system) showed that the reduction of copy number does not lead to an increase in the proportion of cells that ex press the transgene. Finally, in most of the variegating or nonexpressing l ines the transgenes were located both at inter-mediate positions and at per itelomeric regions in the long chromosome arms. These findings suggest that the probability and efficiency of expression of K5Z genes depend on both l ong range chromosomal influences and on sequences in the transgene array.