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 (MALAT1KD) 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 MALAT1KD, whereas EZH2 disruption phenocopies MALAT1KD, 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.