A repressive role of enhancer of zeste homolog 2 in 11β-hydroxysteroid dehydrogenase type 2 expression in the human placenta

The expression of 11-hydroxysteroid dehydrogenase type 2 (11-HSD2), which acts as a placental glucocorticoid barrier, is silenced in cytotrophoblasts but substantially up-regulated during syncytialization. However, the repressive mechanism of 11-HSD2 expression before syncytialization and how this repression is lifted during syncytialization remain mostly unresolved. Here we found that enhancer of zeste homolog 2 (EZH2) accounts for the silence of 11-HSD2 expression via trimethylation of histone H3 lysine 27 at the promoter of the 11-HSD2 gene. Further studies revealed that, upon syncytialization, human chorionic gonadotropin reduced the phosphorylation of retinoblastoma protein (pRB) via activation of the cAMP/PKA pathway, which sequesters E2F transcription factor 1 (E2F1), the transcription factor for EZH2 expression. As a result of inactivation of the pRB-E2F1-EZH2 pathway, the repressive marker trimethylation of histone H3 lysine 27 at the 11-HSD2 promoter is removed, which leads to the robust expression of 11-HSD2 during syncytialization.