Proviral position effects: possible probes for genes that suppress transcription

Rous sarcoma virus, an oncogenic avian retrovirus, readily causes morphological transformation of chick cells, but in infected rat cells transformation is rare because proviral transcription is inefficient. This constraint is not due to a lack of positive transcriptional factors, or an excess of negative ones, but reflects the site of proviral integration in rat cell DNA. In most sites the provirus is almost invariably silent, in others it is correspondingly active, whilst in a third category expression fluctuates in concert with transitions in chromatin structure. Transcriptional fluctuations are mediated both by flanking cell DNA in cis and by trans-acting cell genes, suggesting that proviral position effects are sensors for genes that down-regulate transcription, perhaps by determining chromatin configuration. We have tried to identify such genes by gene transfer, karyology and insertional mutagenesis. The variable success of these three approaches indicates that the transcriptional down-regulator(s) need act only transiently. This is consistent with a function that operates in ontogeny or differentiation to down-regulate genes whose silence is then perpetuated by other means. The loss of such functions may predispose to neoplasia.