Abstract
Perforin gene (
PRF1) transcription regulates perforin expression in NK cells and CTL. Here we identified the locus-wide ensemble of
cis-acting sequences that drives
PRF1 transcription physiologically. By using chromosome transfer, we revealed that de novo activation of a silent
PRF1 locus was controlled by a 150 kb domain comprised of 16 DNase I hypersensitive sites (DHSs). These
cis-acting sequences included a locus control region (LCR) and conferred developmentally appropriate and lineage-specific expression of human perforin from BAC transgenes. The LCR included four distal DHSs that were required for perforin expression from its natural locus, and their engineered deletion from the
PRF1 BAC transgene abolished LCR function and led to rapid gene silencing. Thus, LCR function is central for regulating the developmental and activation-specific
PRF1 promoter activity characteristic of NK cells and CTL.
