Nucleus-localized S100A9 triggers senescence of human amnion fibroblasts as a heterochromatin buster at parturition

Aging in the amnion is considered to trigger and intensify inflammation for the initiation of labor. However, the inducers of amnion cell senescence await to be identified. Here, we unexpectedly observe that S100A9, a classical cytokines, also localizes in the nucleus of human amnion fibroblasts (hAFs), and reveal that nucleus-localized S100A9 (nS100A9) abundance in hAFs increases at parturition and that nS100A9 triggers hAFs senescence. Mechanistically, nS100A9 interacts with heterochromatin proteins, preventing them from binding and maintaining condensed heterochromatin, resulting in heterochromatin erosion, LINE1 de-repression, and type I interferon response activation via the cGAS-STING pathway. Moreover, we demonstrate that dephosphorylation of S100A9 at Thr 113 is required for its nuclear translocation. Mouse studies show that intra-amniotic injection of nS100A9 induces preterm birth along with LINE1 activation, which is blocked by reverse-transcriptase inhibitor. Together, these findings highlight a novel role for S100A9 as a heterochromatin buster that triggers hAFs aging at parturition. Overall design: RNA sequencing of human amnion fibroblasts treated with or without nS100A9 overexpression