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

## TL;DR

This study reveals how S100A9, a protein typically found outside the cell nucleus, moves into the nucleus during childbirth and causes aging of fetal membrane cells by disrupting chromatin structure and activating a genetic element called LINE1.

## Contribution

The novel finding is that nuclear translocation of S100A9 leads to LINE1 de-repression and cellular senescence in amnion fibroblasts at parturition.

## Key findings

- Nuclear translocation of S100A9 causes heterochromatin erosion and LINE1 de-repression in amnion fibroblasts.
- LINE1 retrotransposition activates the cGAS-STING pathway, leading to cellular senescence and secretion of senescence-associated factors.
- In mice, S100A9-induced LINE1 de-repression and senescence can be blocked by inhibiting LINE1 reverse-transcription.

## 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.

This study shows that the classical secretory protein S100 calcium‐binding protein A9 (S100A9) can translocate to the nucleus upon de‐phosphorylation at Thr 113 in human amnion fibroblasts at parturition, where S100A9 induces heterochromatin erosion through segregation of the heterochromatin maintenance protein, resulting inLong Interspersed Nuclear Element‐1 (LINE1) de‐repression. Increased LINE1 retrotransposition causes cellular senescence via activation of the cGAS‐STING‐type I interferon response pathway in human amnion fibroblasts.