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  • Review Article
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A guide to membraneless organelles and their various roles in gene regulation

Abstract

Membraneless organelles (MLOs) are detected in cells as dots of mesoscopic size. By undergoing phase separation into a liquid-like or gel-like phase, MLOs contribute to intracellular compartmentalization of specific biological functions. In eukaryotes, dozens of MLOs have been identified, including the nucleolus, Cajal bodies, nuclear speckles, paraspeckles, promyelocytic leukaemia protein (PML) nuclear bodies, nuclear stress bodies, processing bodies (P bodies) and stress granules. MLOs contain specific proteins, of which many possess intrinsically disordered regions (IDRs), and nucleic acids, mainly RNA. Many MLOs contribute to gene regulation by different mechanisms. Through sequestration of specific factors, MLOs promote biochemical reactions by simultaneously concentrating substrates and enzymes, and/or suppressing the activity of the sequestered factors elsewhere in the cell. Other MLOs construct inter-chromosomal hubs by associating with multiple loci, thereby contributing to the biogenesis of macromolecular machineries essential for gene expression, such as ribosomes and spliceosomes. The organization of many MLOs includes layers, which might have different biophysical properties and functions. MLOs are functionally interconnected and are involved in various diseases, prompting the emergence of therapeutics targeting them. In this Review, we introduce MLOs that are relevant to gene regulation and discuss their assembly, internal structure, gene-regulatory roles in transcription, RNA processing and translation, particularly in stress conditions, and their disease relevance.

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Fig. 1: Overview of MLOs of eukaryotic cells.
Fig. 2: MLO formation through various types of multivalent interactions of proteins and RNAs.
Fig. 3: Overview of the function of MLOs relevant to gene regulation.
Fig. 4: The structures and the functions in gene regulation of representative MLOs.
Fig. 5: Stress-induced membraneless organelles in nucleus and cytoplasm.

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Acknowledgements

The authors thank T. Yamamoto, H. Toya, R. Okabe and H. Maita for valuable discussion on the manuscript. This work was supported by Japan Science and Technology Agency (JST) CREST grant no. JPMJCR20E6 (to T.H.) and Japan Society for the Promotion of Science (JSPS) KAKENHI grants nos. 21H05276 (to T.H.), 21H05274 (to S.N.) and 22H02545 (to T.Y.).

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Glossary

Biomolecular condensates

Micron-scale compartments in cells, which are formed by phase separation and lack surrounding membranes; they function to concentrate proteins and nucleic acids.

Charge–π, π–π and dipolar

Types of non-covalent interaction; charge–π and π–π interactions involve an electron-rich π system with charge (anion or cation) or another π system, and dipolar refers to the direct interaction between two magnetic dipoles.

Liquid droplets

Typically liquid particles <500 μm in diameter, rich in proteins and nucleic acids; they form and disperse reversibly in cells in response to environmental changes.

Micellization

A phase separation process distinct from liquid–liquid phase separation (LLPS), in which blocks of copolymers consisting of two or more chemically different polymers joined by covalent bonds form micelles with optimal size and shape in solution.

P-lineage cells

The Caenorhabditis elegans cell lineage forming the germ line; initiated from the posterior daughter cell (P1) that is asymmetrically divided from the one-cell embryo.

Sm-ring protein

A heteroheptameric ring composed of seven Sm proteins (B/B′, D1, D2, D3, E, F and G); common components of spliceosomal U small nuclear RNPs (snRNPs).

U snRNAs

A class of small nuclear RNAs (snRNAs) including U1, U2, U4, U5 and U6 snRNAs that are the major components of the spliceosome.

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Hirose, T., Ninomiya, K., Nakagawa, S. et al. A guide to membraneless organelles and their various roles in gene regulation. Nat Rev Mol Cell Biol 24, 288–304 (2023). https://doi.org/10.1038/s41580-022-00558-8

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