RNA polymerase II clusters form in line with liquid phase wetting of chromatin

Pancholi, Agnieszka; Klingberg, Tim; Zhang, Weichun; Prizak, Roshan; Mamontova, Irina; A, Noa; Ay, Kobitski; Nienhaus, G. Ulrich; Zaburdaev,; Hilbert, Lennart

doi:10.1101/2021.02.03.429626

Cited by 3 publications

(2 citation statements)

References 70 publications

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“…3k-m ). To determine whether PP may also influence the wetting of genomic DNA by nuclear speckles 56 , we further added mouse genomic DNA into the droplet solution. In accordance with observations in intact cells, nuclear speckle condensates largely don’t mix with, but can wet the DNA ( Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Dion,

Tao,

Chambers

et al. 2024

Preprint

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Current treatments targeting individual protein quality control have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common upstream druggable target capable of global proteostasis modulation. Building on our prior research establishing nuclear speckles as pivotal organelles responsible for global proteostasis transcriptional control, we aim to alleviate proteinopathies through nuclear speckle rejuvenation. We identified pyrvinium pamoate as a small-molecule nuclear speckle rejuvenator that enhances protein quality control while suppressing YAP1 signaling via decreasing the surface tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, pyrvinium pamoate reduced tauopathy and alleviated retina degeneration by promoting autophagy and ubiquitin-proteasome system. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were also observed in human tauopathies. Our study uncovers novel therapeutic targets for tackling protein misfolding disorders within an expanded proteostasis framework encompassing nuclear speckles and YAP1.

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Section: Resultsmentioning

confidence: 99%

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Dion,

Tao,

Chambers

et al. 2024

Preprint

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“…Condensate-like behavior can be observed on scales starting at the single-molecule level, such as the sequence-dependent condensation of the Klf4 TF on its recognition sequence at sub-saturated concentrations to reinforce selective binding, which operates at a larger scale than DNA absorbance of proteins but at a smaller scale than true phase separation [ 28 ]. At the scale of single- or dimerized molecules, the binding of TFs to DNA can be a form of ‘wetting’, as protein complexes adhere to nucleosome-free regions of chromatin [ 29 ]. This is the initiating factor of any TC, as the sequence-specific binding of one or more TFs to their target motifs throughout the genome is obligatory before recruitment of RNAPII and other factors is possible.…”

Section: Condensates Are a Fundamental Aspect Of Nuclear Organization...mentioning

confidence: 99%

Transcriptional condensates and phase separation: condensing information across scales and mechanisms

Demmerle

Hao

Cai

2023

Nucleus

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Transcription is the fundamental process of gene expression, which in eukaryotes occurs within the complex physicochemical environment of the nucleus. Decades of research have provided extreme detail in the molecular and functional mechanisms of transcription, but the spatial and genomic organization of transcription remains mysterious. Recent discoveries show that transcriptional components can undergo phase separation and create distinct compartments inside the nucleus, providing new models through which to view the transcription process in eukaryotes. In this review, we focus on transcriptional condensates and their phase separation-like behaviors. We suggest differentiation between physical descriptions of phase separation and the complex and dynamic biomolecular assemblies required for productive gene expression, and we discuss how transcriptional condensates are central to organizing the three-dimensional genome across spatial and temporal scales. Finally, we map approaches for therapeutic manipulation of transcriptional condensates and ask what technical advances are needed to understand transcriptional condensates more completely.

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Spatially coherent diffusion of human RNA Pol II depends on transcriptional state rather than chromatin motion

Barth

Shaban

2022

Preprint

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Gene transcription by RNA polymerase II (RNAP II) is a tightly regulated process in the genomic, temporal, and spatial context. Transcriptionally active genes often spatially cluster at RNA Pol II foci, called transcription factories, causing long-range interactions between distal sites of the genome. Recently, we have shown that chromatin exhibits spatially long-range coherently moving regions over the entire nucleus and transcription enhances this long-range correlated DNA movement. Yet, it remains unclear how the mobility of RNA Pol II molecules are affected by transcription regulation and whether this response depends on the coordinated chromatin movement. We applied our Dense Flow reConstruction and Correlation method to analyze nucleus-wide coherent movements of RNA Pol II in living human cancer cells. We quantify the spatial correlation length of RNA Pol II in the context of DNA motion. Like DNA, we observe a spatially coherent movement of RNA Pol II molecules. However, the correlation extends over ~1 μm, considerably less than for DNA, suggesting that spatially coherent RNA Pol II motion does not solely result from the underlying DNA motion. In contrast to DNA, inducing transcription in quiescent cells decreased the coherent motion of RNA Pol II, while the inhibition of transcription elongation by using DRB slightly increased coherent RNA Pol II motion. The spatially coherent movement of RNA Pol II domains is affected by transcriptional state and largely independent of the underlying chromatin domains. Our results suggest that RNA Pol II domains can cause the emergence of spatially correlated chromatin motion spanning several micrometers.

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RNA polymerase II clusters form in line with liquid phase wetting of chromatin

Cited by 3 publications

References 70 publications

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Transcriptional condensates and phase separation: condensing information across scales and mechanisms

Spatially coherent diffusion of human RNA Pol II depends on transcriptional state rather than chromatin motion

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