Paraspeckles are constructed as block copolymer micelles

Abstract

Paraspeckles are constructed by NEAT1_2 architectural long noncoding RNAs. Their characteristic cylindrical shapes, with highly ordered internal organization, distinguish them 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. Using the soft matter physics, we then applied a theoretical framework to understand the principles that determine NEAT1_2 organization as well as 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 a type of microphase separation, micellization. This work provides an experimentbased theoretical framework for the concept that ribonucleoprotein complexes (RNPs) can act as block copolymers to form RNAscaffolding biomolecular condensates with optimal sizes and structures in cells.

RNA binding is essential for NONO condensates to modulate pre-mRNA processing of super enhancer-associated genes in neuroblastoma

“…In the two main steps of paraspeckle formation, first, DBHS proteins, including NONO, bind and stabilise NEAT1 lncRNA. Secondly, FUS binds and carries out phase separation dependent on its prion-like domain (Yamazaki, Yamamoto et al, 2021). Whilst a role for NONO-driven phase separation in paraspeckle formation is yet to be established, NONO phase separation is required for radiation-induced DNA damage repair (Fan et al, 2021).…”

Promyelocytic leukemia nuclear body-like structures can assemble in mouse oocytes

“…A recent study employing polymer physics proposed a model for the organization of paraspeckles, another core-shell-type nuclear body. The report showed that parts of the building domains of the scaffold molecules (long non-coding RNAs) are mutually repulsive when positioned at the surface of paraspeckle, which accordingly determines the dynamics (size, number, and distribution) of the nuclear body; however, these repulsive domains are not required for the assembly of paraspeckle itself ( Yamazaki et al, 2021 ). Notably, SUMOylation is dispensable for the formation of PML-NBs ( Sahin et al, 2014 ).…”

Function moves biomolecular condensates in phase space

“…[107] Paraspeckles resemble block copolymer micelles driven by differences in hydrophilicity along the NEAT1 chain. [108] Similarly, the lncRNA Xist, along with its protein interactome, forms compartments around the X chromosome, leading to its compaction and subsequent inactivation, potentially via phase separation. [109,110] These observations suggest that the cell harnesses the inherent separation of DNA and RNA for various functions.…”