Membraneless nuclear organelles and the search for phases within phases

Abstract

Cells are segregated into two distinct compartment groups to optimize cellular function. The first is characterized by lipid membranes that encapsulate specific regions and regulate macromolecular flux. The second, known collectively as membraneless organelles (MLOs), lacks defining lipid membranes and exhibits self‐organizing properties. MLOs are enriched with specific RNAs and proteins that catalyze essential cellular processes. A prominent sub‐class of MLOs are known as nuclear bodies, which includes nucleoli, paraspeckles, and other droplets. These microenvironments contain specific RNAs, exhibit archetypal liquid–liquid phase separation characteristics, and harbor intrinsically disordered, multivalent hub proteins. We present an analysis of nuclear body protein disorder that suggests MLO proteomes are significantly more disordered than structured cellular features. We also outline common MLO ultrastructural features, exemplified by the three sub‐compartments present inside the nucleolus. A core‐shell configuration, or phase within a phase, is displayed by several nuclear bodies and may be functionally important. Finally, we summarize evidence indicating extensive RNA and protein sharing between distinct nuclear bodies, suggesting functional cooperation and similar nucleation principles. Considering the substantial accumulation of specific coding and noncoding RNA classes inside MLOs, evidence that RNA buffers specific phase transition events, and the absence of a clear correlation between total intrinsic protein disorder and MLO accumulation, we conclude that RNA biogenesis may play a key role in MLO formation, internal organization, and function. This article is categorized under: RNA Export and Localization > RNA Localization RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

Expression and phase separation potential of heterochromatin proteins during early mouse development

“…Heterochromatin proteins displayed a significantly higher disorder score, as compared to either a random group of total proteins or nuclear proteins of the same size (median = 0.47, compared with 0.31 and 0.37, respectively; Fig 1A). The median percentage length of disordered domains, measured as percentage of amino acids of the total protein length, was 44% ( Fig 1A), which is similar to the percentages calculated for the proteome of several phase-separated membrane-less organelles and is higher than the value for organised structures such as the proteasome [60]. In addition, the percentage of the protein (length) containing disordered domains was also significantly higher compared with a random (22%) or the nuclear (30%) set of proteins, indicating that heterochromatin proteins are more disordered than a random set of proteins or compared with nuclear proteins in general.…”

Compartment-dependent chromatin interaction dynamics revealed by liquid chromatin Hi-C

“…Possibly these attractions result from co-association of domains with sub-nuclear bodies that themselves appear to form by a process of liquid-liquid phase separation (e.g. (Courchaine et al, 2016;Feric et al, 2016;Larson et al, 2017;Marzahn et al, 2016;Sawyer et al, 2018;Strom et al, 2017;Zhu and Brangwynne, 2015). An example is the interaction between heterochromatic loci driven by multivalent interactions among HP1 proteins and between HP1 proteins and H3K9me3-modified chromatin domains (Larson et al, 2017;Strom et al, 2017).…”

Dynamic Synthetic Cells Based on Liquid–Liquid Phase Separation

“…[156] This hierarchicalo rganisation might allow the spatial orchestration of multistep reactions and has recently been observed in stress granules, [157] nuclear speckles [158] and the nucleolus, [159] where it has been attributedt o balanced surfacet ensionsb etween coexisting liquid phases [159] and/or differences in effective solvationv olumes. Higher-Order Structures and Behaviour 6.1.…”

“…This chemical diversity can produce vacuolisationa nd multiphase structurationw ithin condensates in living cells, in which multiple aqueous phases coexist withoutm ixing. [156] This hierarchicalo rganisation might allow the spatial orchestration of multistep reactions and has recently been observed in stress granules, [157] nuclear speckles [158] and the nucleolus, [159] where it has been attributedt o balanced surfacet ensionsb etween coexisting liquid phases [159] and/or differences in effective solvationv olumes. [160] Reproducings uch am ultilayered organisationi na ll-aqueous synthetic systems is very challenging, due to the low interfacial energies involved.…”