Regulation of human trophoblast syncytialization by histone demethylase LSD1

Abstract

A successful pregnancy is critically dependent upon proper placental development and function, beginning with differentiation of human trophoblast cells. At the final stage of trophoblast differentiation, the human placenta contains a cell population called syncytiotrophoblasts which provide the exchange surface between the mother and the fetus. However, molecular regulation of syncytiotrophoblast development is poorly understood. In this study, we explored the regulatory pathway of lysine-specific demethylase 1 (LSD1), in combination with transcription factor GATA2 and cellular signaling, in human trophoblast syncytialization. Using cell culture models, we show that LSD1 is important for human trophoblast syncytialization. Cellular signaling, such as the activation of protein kinase A, together with LSD1 contribute to the recruitment of GATA2 at the Syncytin-1 and Syncytin-2 loci. Loss of LSD1 in trophoblast cells impairs GATA2 function, histone modifications and RNA polymerase II recruitment at Syncytin-1 and -2 loci leading to their transcriptional repression and impaired syncytialization. In summary, our data reveals a regulatory pathway demonstrating that LSD1 is essential for human trophoblast syncytialization.