DNA methylation pattern of a tandemly repeated LacZ transgene indicates that most copies are silent

The Pgk-1,2-LacZ transgene consists of the ubiquitously-expressed Pgk-1 pro moter driving expression of the E. coli lacZ reporter gene. We studied the expression of this transgene in a mouse strain carrying 8-9 tandem copies o f this construct, When inherited through the male germ line, the transgene was expressed in all tissues examined but when inherited through the female germ line, the transgene became irreversibly inactivated. The lacZ region is a CpG-rich island that was essentially entirely methylated in all copies of the silent, maternally-inherited transgene. At the active transgenic lo cus, all but one of the copies were entirely methylated, This one unmethyla ted copy was adjacent to the cellular DNA and was presumed to be the expres sed transgene copy, These results suggest that the tandem repeats of transg enes become silenced by a mechanism associated with DNA methylation and tha t proximity to the cellular genome may be important in maintaining expressi on against the spread of inactivation from the adjacent silent transgenes. Dev Dyn 1999;215:126-138. (C) 1999 Wiley-Liss, Inc.