Nuclear Translocation of S100A9 Triggers Senescence of Human Amnion Fibroblasts by De‐Repressing LINE1 Via Heterochromatin Erosion at Parturition

Abstract Aging of the fetal membranes participates in labor onset. However, the underlying mechanism is poorly understood. Here, we identify that the classical secretory protein S100 calcium‐binding protein A9 (S100A9), upon de‐phosphorylation at Thr 113, translocates to the nuclei of amnion fibroblasts of the human fetal membranes, where S100A9 causes heterochromatin erosion via segregation of heterochromatin maintenance proteins, resulting in Long Interspersed Nuclear Element‐1 (LINE1) de‐repression at parturition. Increased LINE1 retrotransposition further activates the type I interferon response via the cGAS‐STING pathway, thereby leading to amnion fibroblast senescence with consequent increased secretion of components associated with senescence‐associated secretory phenotype. Mouse studies show that intra‐amniotic injection of vector specifically expressing S100A9 in the nucleus induces preterm birth along with LINE1 de‐repression and increased cellular senescence in the fetal membranes, which is blocked by inhibition of LINE1 reverse‐transcription. Together, these findings highlight that nuclear‐translocated S100A9 acts as a heterochromatin disruptor to de‐repress LINE1 which subsequently triggers amnion fibroblast senescence at parturition.