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Molecular anatomy of the architectural NEAT1 noncoding RNA: The domains, interactors, and biogenesis pathway required to build phase‐separated nuclear paraspeckles

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Abstract Long noncoding RNAs (lncRNAs) are extremely diverse and have various significant physiological functions. lncRNAs generally associate with specific sets of RNA‐binding proteins (RBPs) to form functional ribonucleoprotein (RNP) complexes. NEAT1 is a highly abundant lncRNA in the mammalian cell nucleus that associates with specific RBPs to form NEAT1 RNPs. Intriguingly, cellular NEAT1 RNPs are extraordinarily large and can be detected using an optical microscope. These gigantic RNPs, so‐called paraspeckles, are a type of membraneless nuclear body. Paraspeckles contain approximately 50 NEAT1 RNA molecules together with characteristic RBPs possessing aggregation‐prone prion‐like domains. Paraspeckle formation proceeds on the nascent NEAT1 transcript in conjunction with NEAT1 biogenesis, which exhibits various features that differ from those exhibited by mRNA biogenesis, including a lack of introns, noncanonical 3′ end formation, and nuclear retention. These unique features may be required for the mechanism of paraspeckle formation. NEAT1 possesses three distinct RNA domains (A, B, and C), which function in stabilization (A), isoform switching (B), and paraspeckle assembly (C). In particular, the central C domain contains smaller subdomains that are high‐affinity binding sites for the essential paraspeckle proteins (NONO and SFPQ) that subsequently polymerize along NEAT1. Subsequent recruitment of additional essential PSPs (FUS and RBM14) induces liquid–liquid phase separation to build a massive paraspeckle structure. Thus, the molecular anatomy of the NEAT1 arcRNA provides an ideal model to understand how lncRNAs form the functional RNP machinery. This article is characterized under: RNA Export and Localization > Nuclear Export/Import RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
The NEAT1 arcRNA in paraspeckle nuclear bodies. (a) NEAT1 is essential for paraspeckle integrity. The paraspeckles visualized by immunostaining of NONO (green signals in WT) are abolished by NEAT1 depletion (NEAT1 KO). Scale bar: 5 μm. (b) The upper image shows the fine structure of mouse paraspeckles determined by super‐resolution microscopy. Paraspeckle substructures were detected by RNA‐FISH with NEAT1 antisense RNA probes (NEAT1_5′ and NEAT1_3′: green; NEAT1_m: magenta). The lower image shows a schematic model of the core‐shell arrangement of paraspeckle components. Scale bar: 500 nm. (c) NEAT1 isoforms synthesized by alternative 3′ end processing. NEAT1_2 possesses non‐polyadenylated 3′TH. The positions of RNA‐FISH probes used in B (5′, m, and 3′) are shown
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An updated model of paraspeckle formation. The NONO/SFPQ dimer primarily associates with the C1 and C2 subdomains of NEAT1_2 and subsequently polymerizes via the CC extended domains to form the NEAT1_2 RNP platform. PLD proteins (FUS and RBM14) associate with this platform to form the NEAT1_2 RNP complex. NEAT1_2 RNAs bundle to form larger complexes in which LLPS is induced to sequestrate more complexes to eventually form an intact paraspeckle
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LLPS is a driving force of paraspeckle formation. (a) The basic concept of LLPS. LLPS is driven by multivalent interactions between proteins containing intrinsically disordered PLDs. (b) The PLDs of FUS and RBM14 are required for in vitro phase separation and in vivo paraspeckle formation. The domain structures of FUS and RBM are shown at the top. The consensus sequence in each PLD is shown in the middle
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The modular domain structure of the human NEAT1_2 arcRNA. The three distinct domains (A, B, and C) and three subdomains within the C domain are shown, and their respective functions are indicated. The position of each domain relative to the 5′ end (kb) is also shown. The structure of mini‐NEAT1 is also shown. The dashed lines represent the deleted regions
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Paraspeckle formation proceeds via two distinct steps. The essential factors for paraspeckle formation are shown
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes
RNA Export and Localization > Nuclear Export/Import

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