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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287835 | GEO | 2025/06/16

REPOSITORIES: GEO

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Project description:The process of parturition involves the complex interplay of factors that changes the excitability and contractile activity of the uterus. We have compared the relative gene expression profile of myometrium from rats before parturition (21 days pregnant) and during delivery using high-density DNA microarray. Of 8740 sequences available in the array a total of 3782 were detected as present. From the sequences that were significantly altered, 59 genes were upregulated and 82 genes were downregulated. We were able to detect changes in genes described to have altered expression level at term including connexin 43 and 26, cyclo-oxygenase 2 and oxytocin receptor as well as novel genes that have been not previously associated with parturition. Quantitative real time PCR on selected genes further confirmed the microarray data. Here we report for the first time that aquaporin5 (AQP5), a member of aquaporin (AQP) water channel family, was dramatically downregulated during parturition (~100 fold by microarray and ~50 fold by Real Time PCR). The emerging profile highlights biochemical cascades occurring in a period of about 36 hours that triggers parturition and the initiation of myometrium reverse remodeling after partum. The microarray analysis uncovered genes that were previously suspected to play a role in parturition. This regulation involves genes from immune/inflammatory response, steroid/lipids metabolism, calcium homeostasis, cell volume regulation, cell signaling, cell division, and tissue remodeling, suggesting the presence of multiple and redundant mechanisms altered in the process of birth. Experiment Overall Design: Uteri were dissected from late pregnant rats (21 days, LP) (three individuals, two replicates of sample 1) and rats during labor (DL) after the expulsion of the second pup (three individuals, two replicates of sample 1). After dissection, uteri were placed immediately in cold Ca2+-free PBS buffer and peripheral large blood vessels, external surrounding connective tissue and placenta were removed. The endometrium superficial layer was separated by gentle scraping. The myometrium was weighted, finely minced and homogenized with a polytron (Polytron PT3000, Brinkmann, Switzerland).

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

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