Abstract
Syncytin-2 is encoded by the envelope gene of Endogenous Retrovirus-FRD (ERVFRD-1) and plays a critical role in fusion of placental trophoblasts leading to the formation of the multinucleated syncytiotrophoblast. Its expression is consequently regulated in a strict manner. In the present study, we have identified a forskolin-responsive region located between positions -300 to -150 in the Syncytin-2 promoter region. This 150 bp region in the context of a minimal promoter mediated an 80-fold induction of promoter activity following forskolin stimulation. EMSA analyses with competition experiments with nuclear extracts from forskolin-stimulated BeWo cells demonstrated that the -211 to -177 region specifically bound two forskolin-induced complexes, one of them containing a CRE/AP-1-like motif. Site-directed mutagenesis of the CRE/AP-1 binding site in the context of the Syncytin-2 promoter or a heterologous promoter showed that this motif was mostly essential for forskolin-induced promoter activity. Transfection experiments with dominant negative mutants and constitutively activated CREB expression vectors in addition to Chromatin Immunoprecipitation suggested that a CREB family member, CREB2 was binding and acting through the CRE/AP-1 motif. We further demonstrated the binding of JunD to this same motif. Similar to forskolin and soluble cAMP, CREB2 and JunD overexpression induced Syncytin-2 promoter activity in a CRE/AP-1-dependent manner and Syncytin-2 expression. In addition, BeWo cell fusion was induced by both CREB2 and JunD overexpression, while being repressed following silencing of either gene. These results thereby demonstrate that induced expression of Syncytin-2 is highly dependent on the interaction of bZIP-containing transcription factors to a CRE/AP-1 motif and that this element is important for the regulation of Syncytin-2 expression, which results in the formation of the peripheral syncytiotrophoblast layer.
Highlights
During pregnancy, placental development involves the differentiation of placental trophoblasts into two different pathways, i.e the extravillous cytotrophoblast and the villous cytotrophoblast
Maintenance of the syncytiotrophoblast structure relies on newly fused cytotrophoblasts, a process that is regulated by different transcription factors, growth factors, cytokines, protein kinases and fusogenic proteins such as former envelope (Env) glycoproteins of human Endogenous Retroviruses (ERVs) Syncytin-1 of ERVW-1 and Syncytin-2 of ERVFRD-1
We demonstrate that bZIP transcription factors, such as CREB2 (ATF4) and JunD interact with this region and transactivate promoter activity as well as BeWo cell fusion
Summary
Placental development involves the differentiation of placental trophoblasts into two different pathways, i.e the extravillous cytotrophoblast and the villous cytotrophoblast. Villous cytotrophoblasts possess the ability to fuse with adjacent cells and thereby lead to the formation of the peripheral multinucleated syncytiotrophoblast layer. This layer is essential for proper placental development and for the maintenance of normal pregnancy and fetus development. It is responsible for gas exchange between mother and fetus, feto-maternal immunotolerance, nutrient transport and hormone production [1,2,3,4]. Failure of syncytiotrophoblast formation is associated with different complications, such as pre-eclampsia, one of the most important cause of maternal morbidity and mortality, preterm birth, perinatal death, and intrauterine growth restriction [5]. Maintenance of the syncytiotrophoblast structure relies on newly fused cytotrophoblasts, a process that is regulated by different transcription factors, growth factors, cytokines, protein kinases and fusogenic proteins such as former envelope (Env) glycoproteins of human Endogenous Retroviruses (ERVs) Syncytin-1 of ERVW-1 and Syncytin-2 of ERVFRD-1
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