Human chorionic gonadotropin (hCG) is composed of a common α subunit and a placenta-specific β subunit. Importantly, hCG is highly expressed in the differentiated and multinucleated syncytiotrophoblast, which is formed via trophoblast cell fusion and stimulated by cAMP. Although the ubiquitous AP2 transcription factors, TFAP2A and TFAP2C, may regulate hCGβ expression, it remains unclear how cAMP stimulates placenta-specific hCGβ gene expression and trophoblastic differentiation. Here we demonstrated that the placental Glial Cells Missing 1 (GCM1) transcription factor binds to a highly conserved promoter region in all the six hCGβ paralogues by ChIP-chip analysis. We further showed that cAMP stimulates GCM1 and the CBP coactivator to activate hCGβ promoter through a GCM1-binding site (GBS1), which also constitutes a previously-identified AP2 site. Given that TFAP2C may compete with GCM1 for GBS1, cAMP enhances the association between hCGβ promoter and GCM1, but not TFAP2C. Indeed, the hCG-cAMP-PKA signaling pathway also stimulates Ser269 and Ser275 phosphorylation in GCM1, which recruits CBP to mediate GCM1 acetylation and stabilization. Consequently, hCG stimulates the expression of GCM1 target genes, including the syncytin-1 fusogenic protein, to promote placental cell fusion. Our study reveals a positive feedback loop between GCM1 and hCG regulating placental hCGβ expression and cell differentiation.
Reproductive Disturbances, Pituitary Lactotrope Adenomas, and Mammary Gland Tumors in Transgenic Female Mice Producing High Levels of Human Chorionic Gonadotropin
