Mechanism of histone lysine-specific demethylase LSD1 in regulating trophoblast syncytialization

Proper placental development and function are essential for a successful pregnancy. A key process in human placental development involves trophoblast syncytialization, forming the crucial maternal-fetal interface responsible for nutrient exchange, hormone secretion, and immune regulation during pregnancy. However, the molecular mechanisms regulating this vital process remain poorly understood. Here, we utilize multiple trophoblast cell models to elucidate the essential role of the lysine-specific demethylase 1 (LSD1) in multinucleated syncytiotrophoblast (STB) formation. Deficiency of LSD1 significantly hinders STB differentiation in human trophoblast cells. Mechanistically, impaired LSD1 enzyme activity leads to the de-repression of endogenous retroviruses (ERVs), triggering cytoplasmic accumulation of double-stranded RNA (dsRNA). dsRNA accumulation activates the interferon pathway and upregulates the interferon-induced genes, like IFITM2/3, which act as downstream effectors to restrict STB differentiation. Our findings establish a previously unrecognized role of ERV-dsRNA-IFN pathway in LSD1-mediated trophoblast syncytialization, and identify IFITM2/3 as key mediators linking aberrant interferon signaling activation to impaired STB formation during placental development.