DNA methylation regulates placental lactogen I gene expression

Expression of rat placental lactogen I is specific to the placenta and neve r expressed in other tissues. To obtain insight into the mechanism of tissu e-specific gene expression, we investigated the methylation status in 3.4 k b of the 5'-flanking region of the rat placental lactogen I gene. We found that the distal promoter region of the rat placental lactogen I gene had mo re potent promoter activity than that of the proximal area alone, which con tains several possible cis-elements. Although there are only 17 CpGs in the promoter region, in vitro methylation of the reporter constructs caused se vere suppression of reporter activity, and CpG sites in the placenta were m ore hypomethylated than other tissues. Coexpression of methyl-CpG-binding p rotein with reporter constructs elicited further suppression of the reporte r activity, whereas treatment with trichostatin A, an inhibitor of histone deacetylase, reversed the suppression caused by methylation. Furthermore, t reatment of rat placental lactogen I nonexpressing BRL cells with 5-aza-2'- deoxycytidine, an inhibitor of DNA methylation, or trichostatin A resulted in the de novo expression of rat placental lactogen I. These results provid e evidence that change in DNA methylation is the fundamental mechanism regu lating the tissue-specific expression of the rat placental lactogen I gene.