Nuclear compartmentalization as a mechanism of quantitative control of gene expression

Bhat, Prashant; Honson, Drew D.; Guttman, Mitchell

doi:10.1038/s41580-021-00387-1

Cited by 170 publications

(138 citation statements)

References 189 publications

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“…Thus, what may be the mechanism(s) underlying the observed 12-hour rhythm of nuclear speckle morphology change? A recent study on LLPS demonstrated that the concentration of scaffolding protein in the condensates can dictate the way by which LLPS occurs ( 15 , 18 ). Simply put, under constant valency condition, a higher concentration of scaffolding protein (within the blue region of the phase diagram) will induce LLPS via spinodal decomposition (thus more diffuse), while a lower concentration (within the red region of the phase diagram) will lead to nucleation (thus rounder) (fig.…”

Section: Resultsmentioning

confidence: 99%

“…One possibility is that nucleation-mediated LLPS will result in many individually isolated condensates, and the barriers of liquid droplets would limit molecular diffusion between dense and dilute phases, while during spinodal decomposition, the connected network-like condensate morphology would greatly favor rapid molecular diffusion within the condensates. The latter would also facilitate the rapid delivery of splicing factors to transcription foci during ER stress to amplify the UPR at the cotranscriptional splicing/transcription elongation stage ( 18 ). Conversely, lower SON expression–associated stagnant nuclear speckles are sequestered away from chromatin and thereby would greatly dampen the UPR ( Figs.…”

Section: Discussionmentioning

confidence: 99%

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Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis

et al. 2022

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Phase separation and biorhythms control biological processes in the spatial and temporal dimensions, respectively, but mechanisms of four-dimensional integration remain elusive. Here, we identified an evolutionarily conserved XBP1s-SON axis that establishes a cell-autonomous mammalian 12-hour ultradian rhythm of nuclear speckle liquid-liquid phase separation (LLPS) dynamics, separate from both the 24-hour circadian clock and the cell cycle. Higher expression of nuclear speckle scaffolding protein SON, observed at early morning/early afternoon, generates diffuse and fluid nuclear speckles, increases their interactions with chromatin proactively, transcriptionally amplifies the unfolded protein response, and protects against proteome stress, whereas the opposites are observed following reduced SON level at early evening/late morning. Correlative Son and proteostasis gene expression dynamics are further observed across the entire mouse life span. Our results suggest that by modulating the temporal dynamics of proteostasis, the nuclear speckle LLPS may represent a previously unidentified (chrono)therapeutic target for pathologies associated with dysregulated proteostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis

et al. 2022

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“…Although the RNA mediated feedback model warrants further investigation, it has implications for possible roles of lncRNAs near enhancers or promoters (Bhat et al 2021, Guttman et al 2009, Ulitsky and Bartel 2013. Interactions of such RNAs with enhancers could stimulate the rate of formation of a condensate resulting in an increase in the frequency and possible size of the associated transcriptional burst.…”

Section: Phillip a Sharp 10mentioning

confidence: 99%

RNA in formation and regulation of transcriptional condensates

Sharp

Chakraborty

Henninger

et al. 2021

RNA

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Macrosopic membraneless organelles containing RNA such as the nucleoli, germ granules and the Cajal body have been known for decades. These biomolecular condensates are liquid-like bodies that can form by a phase transition. Recent evidence has revealed the presence of similar microscopic condensates associated with transcription of genes. This brief article summarizes thoughts about the importance of condensates in regulation of transcription and how RNA molecules, as components of such condensates, control the synthesis of RNA. Models and experimental data suggest that RNAs from enhancers facilitate the formation of a condensate that stabilizes the binding of transcription factors and accounts for a burst of transcription at the promoter. Termination of this burst is pictured as a non-equilibrium feedback loop where additional RNA destabilizes the condensate.

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“…While the ability of HP1a in driving the formation of heterochromatin is clearly demonstrated for embryonic cells Zenk et al (2021) , for the differentiated cells HP1a appears to have different regulatory roles. We note that a detailed mechanistic picture of heterochromatin formation still remains full of puzzles calling for more detailed mechanistic modeling of chromatin Erdel (2020) ; Misteli (2020) ; Itoh et al (2021b) ; Bhat et al (2021) . Besides HP1a the RNA molecules which bind to proteins and phase separate have also been found to have active involvement in the euchromatin domain formation through the microphase separation mechanism ( Hilbert et al (2021) .…”

Section: Introductionmentioning

confidence: 98%

A Liquid State Perspective on Dynamics of Chromatin Compartments

Laghmach

Pierro

Potoyan

2022

Front. Mol. Biosci.

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The interior of the eukaryotic cell nucleus has a crowded and heterogeneous environment packed with chromatin polymers, regulatory proteins, and RNA molecules. Chromatin polymer, assisted by epigenetic modifications, protein and RNA binders, forms multi-scale compartments which help regulate genes in response to cellular signals. Furthermore, chromatin compartments are dynamic and tend to evolve in size and composition in ways that are not fully understood. The latest super-resolution imaging experiments have revealed a much more dynamic and stochastic nature of chromatin compartments than was appreciated before. An emerging mechanism explaining chromatin compartmentalization dynamics is the phase separation of protein and nucleic acids into membraneless liquid condensates. Consequently, concepts and ideas from soft matter and polymer systems have been rapidly entering the lexicon of cell biology. In this respect, the role of computational models is crucial for establishing a rigorous and quantitative foundation for the new concepts and disentangling the complex interplay of forces that contribute to the emergent patterns of chromatin dynamics and organization. Several multi-scale models have emerged to address various aspects of chromatin dynamics, ranging from equilibrium polymer simulations, hybrid non-equilibrium simulations coupling protein binding and chromatin folding, and mesoscopic field-theoretic models. Here, we review these emerging theoretical paradigms and computational models with a particular focus on chromatin’s phase separation and liquid-like properties as a basis for nuclear organization and dynamics.

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Nuclear compartmentalization as a mechanism of quantitative control of gene expression

Cited by 170 publications

References 189 publications

Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis

Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis

RNA in formation and regulation of transcriptional condensates

A Liquid State Perspective on Dynamics of Chromatin Compartments

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