Beyond Paraspeckles: Rethinking NEAT1 as Master Regulator of Genome Organization

NEAT1 is among the most extensively studied lncRNAs, classically recognized as the architectural scaffold of nuclear paraspeckles (PSs), membranelles nuclear bodies that assemble through liquid–liquid phase separation to sequester RNA-binding proteins and edited transcripts. Within this framework, NEAT1 was thought to regulate gene expression mainly indirectly, by trapping essential gene regulatory factors within these condensates. Here, we aim to review growing evidence that repositions NEAT1 from a scaffold to an active, highly context-dependent chromatin regulator that finely contributes to genome surveillance and cellular homeostasis. NEAT1 engages chromatin directly by occupying gene regulatory elements and DNA:RNA hybrids, recruiting epigenetic regulators and cooperating with lineage-specific transcription factors. We further examine how such a regulatory NEAT1 activity varies across a broad spectrum of cancerous and non-cancerous diseases. The evidence discussed reframes NEAT1 as an adaptor molecule in transcriptional machinery whose function is deeply influenced by cellular stimuli, interacting partners and chromatin targets accessible in each context. This conceptual shift not only raises new mechanistic questions but also underscores the challenges of therapeutically targeting NEAT1.