Connecting chromatin to cell invasion: MALAT1–PRC2 complex epigenetically controls trophoblast activity via FRMD8–ADAM17–protease inhibitor circuit

Scrupulous trophoblast invasion is pivotal for successful placentation; its insufficiency results in preeclampsia (PE) and intrauterine growth restriction (IUGR). Although the long non-coding RNA (lncRNA) MALAT1 has been implicated in placental pathologies, its regulatory role in trophoblast biology remains incompletely understood. We demonstrate MALAT1's nuclear predominance in highly invasive mouse trophoblast giant cells (TGC) and human HTR-8/SVneo cells. MALAT1 knockdown ( MALAT1 KD ) upregulates the proximal gene FRMD8 , which stabilizes the membrane-bound sheddase ADAM17 and enhances its proteolytic activity. Paradoxically, this increased protease activity elevates protease inhibitor levels, impairing trophoblast migration and invasion. Mechanistically, RNA pull-down, RIP, and ChIP-PCR assays reveal MALAT1 interacts with Polycomb Repressive Complex 2 (PRC2) components to transcriptionally repress FRMD8 . Pharmacological ADAM17 inhibition rescues the anti-invasive phenotype of MALAT1 KD , whereas EZH2 disruption phenocopies MALAT1 KD , establishing a MALAT1–PRC2–FRMD8–ADAM17 axis. Our findings reveal an unconventional epigenetic regulation axis governing trophoblast invasion by fine-tuning protease inhibitor expression, offering mechanistic insights into placental development and identifying potential therapeutic targets for pregnancy-related disorders. • MALAT1 predominates nuclei of mouse and human invasive trophoblast lineages. • MALAT1 silences proximal gene FRMD8 by recruiting PRC2 to its promoter. • MALAT1 knockdown mediated FRMD8 derepression increases ADAM17 sheddase activity. • Elevated ADAM17 enzymatic activity at the membrane upregulates key protease inhibitors. • MALAT1 potentiates trophoblast invasion by epigenetically controlling cell surface proteolysis.