Paraspeckles are constructed as block copolymer micelles through microphase separation

Abstract

Paraspeckles are constructed by NEAT1_2 architectural long noncoding RNAs and possess characteristic cylindrical shapes with highly ordered internal organization, distinct from typical liquid-liquid phase-separated condensates. We experimentally and theoretically investigated how the shape and organization of paraspeckles are determined. We identified the NEAT1_2 RNA domains responsible for shell localization of the NEAT1_2 ends, which determine the characteristic internal organization. We then applied a theoretical framework using soft matter physics to understand the principles that determine the NEAT1_2 organization, shape, number, and size of paraspeckles. By treating paraspeckles as amphipathic block copolymer micelles, we could explain and predict the experimentally observed behaviors of paraspeckles upon NEAT1_2 domain deletions or transcriptional modulation. Thus, we propose that paraspeckles are block copolymer micelles assembled through microphase separation. This work provides an experimentally-based theoretical framework for the concept that ribonucleoprotein complexes (RNPs) can act as block copolymers to form RNA-scaffolding microphase-separated condensates in cells.