Induction of IGFBP-1 Expression by cAMP Is Associated with Histone Acetylation Status of the Promoter Region in Human Endometrial Stromal Cells

Many genes are up- or down-regulated in human endometrial stromal cells (ESCs) undergoing decidualization. IGF-binding protein-1 (IGFBP-1) and prolactin (PRL) are preferentially expressed during decidualization and are recognized as specific markers of decidualization. This study investigated the involvement of epigenetic mechanisms in the regulation of IGFBP-1 and PRL induction by decidualization in ESCs. ESCs isolated from the proliferative phase endometrium were incubated with cAMP to induce decidualization. Human dermal fibroblasts (HDFs) were used as a nonendometrial control. cAMP induced the expressions of both genes in ESCs but induced the expression of only PRL in HDFs. Histone acetylation levels of the IGFBP-1 promoter region evaluated by chromatin immunoprecipitation assay were higher in ESCs than in HDFs. The IGFBP-1 promoter regions in the two cell types showed similar levels of DNA hypomethylation. The histone acetylation levels and DNA methylation status of the PRL promoter and enhancer regions were similar in the two cell types. cAMP had no significant effects on the histone acetylation levels and DNA methylation status of the IGFBP-1 promoter and the PRL promoter and enhancer regions in ESCs. Cotreatment of HDF with cAMP and histone deacetylase inhibitors induced IGFBP-1 expression, which was accompanied by an increased histone acetylation level and recruitment of CCAAT/enhancer-binding protein-beta to the promoter region. These results show that, during decidualization in ESCs, high histone acetylation status of the promoter regions of IGFBP-1 and PRL is associated with the induction of the IGFBP-1 and PRL genes by making the promoter regions accessible to transcriptional factors. (Endocrinology 153: 5612-5621, 2012)