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Review
. 2020 Dec 8;15(6):1220-1232.
doi: 10.1016/j.stemcr.2020.10.011. Epub 2020 Nov 19.

Chromatin-Associated Membraneless Organelles in Regulation of Cellular Differentiation

Markus Grosch  1 , Sebastian Ittermann  1 , Dmitry Shaposhnikov  1 , Micha Drukker  2
Affiliations
Review

Chromatin-Associated Membraneless Organelles in Regulation of Cellular Differentiation

Markus Grosch et al. Stem Cell Reports. .

Abstract

Membrane-free intracellular biocondensates are enclosures of proteins and nucleic acids that form by phase separation. Extensive ensembles of nuclear "membraneless organelles" indicate their involvement in genome regulation. Indeed, nuclear bodies have been linked to regulation of gene expression by formation of condensates made of chromatin and RNA processing factors. Important questions pertain to the involvement of membraneless organelles in determining cell identity through their cell-type-specific composition and function. Paraspeckles provide a prism to these questions because they exhibit striking cell-type-specific patterns and since they are crucial in embryogenesis. Here, we outline known interactions between paraspeckles and chromatin, and postulate how such interactions may be important in regulation of cell fate transitions. Moreover, we propose long non-coding RNAs (lncRNAs) as candidates for similar regulation because many form foci that resemble biocondensates and exhibit dynamic patterns during differentiation. Finally, we outline approaches that could ascertain how chromatin-associated membraneless organelles regulate cellular differentiation.

Keywords: NEAT1; RNA-binding protein; biocondensates; chromatin; differentiation; lncRNA; membraneless organelles; paraspeckles; phase separation; pluripotent stem cells.

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Figures

Figure 1
Figure 1
Hypothesized Modes of Regulation That Could Affect the Functions of Nuclear Membraneless Organelles (A) A schematic illustration of paraspeckle assembly and disassembly as an example of a nuclear membraneless organelle that forms by nuclear liquid-liquid phase separation (LLPS). Paraspeckle assembly relies on lncRNA NEAT1_2, chromatin factors, and RBPs, such as SFPQ, and NONO. The figure illustrates that the RNA-binding protein TDP-43 undergoes LLPS in paraspeckles during the differentiation of PSCs, which thereby affects its function. Nucleus of human fibroblast on top to illustrate phase-separated lncRNA complexes with RBPs and chromatin factors. NEAT1_2 probe is depicted in red and DAPI DNA stain in blue. Scale bar: 10 μm. (B) Principal modes of regulation that affect nuclear membraneless organelles with possible functional cell-type-specific outcomes: left, the interactions of membraneless organelles with chromatin factors expressed and positioned in the genome in a cell-specific manner; middle, the number of condensates formed in a cell-type-specific manner; and right, the cell-type-specific composition of membraneless organelles.
Figure 2
Figure 2
The Interactome of Paraspeckles and NEAT1_2 NEAT1 is predominantly associated with transcription start and termination sites (West et al., 2014), and it interacts with a network of RBPs and chromatin factors. NEAT1 binding to dsDNA is likely mediated via the formation of sequence-specific RNA:DNA triple-helix structures (Sentürk Cetin et al., 2019). Proteins that are known to localize in paraspeckles (Naganuma et al., 2012) are classified in functional categories as indicated at the bottom right corner of the figure. Hypothesized connections between chromatin factors that are known to localize to paraspeckles, known effects of NEAT1/paraspeckles on the chromatin, and the functions of the respective chromatin factors are shown.
Figure 3
Figure 3
The Number of Paraspeckles Relies on Nucleus Size and Stage-Specific Regulation Paraspeckles are highly abundant at the four-cell stage before being downregulated upon blastocyst differentiation. Germ layer differentiation is accompanied by an increase in the number of paraspeckles and mature cell types exhibit paraspeckle numbers that often correspond to the size of their nuclei.
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