Phase separated microenvironments inside the cell nucleus are linked to disease and regulate epigenetic state, transcription and RNA processing

Sawyer, Iain A.; Bártek, Jiří; Dundr, Miroslav

doi:10.1016/j.semcdb.2018.07.001

Cited by 74 publications

(59 citation statements)

References 106 publications

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“…It is therefore very likely that these specific Sir3-Sir3 interactions build-up molecular bridges between Sir3-bound regions, in agreement with in vitro studies (Adkins et al 2009;Georgel et al 2001;McBryant et al 2008). In this case, specific Sir3-Sir3 interactions between arrays of Sir3 molecules associated with subtelomeres, the rDNA or internal regions would rather form a dynamic, gel like, network structure rather that a liquid droplet as proposed for other type of nuclear foci (Sawyer et al 2019). However further work is needed to decipher the physical nature of these foci.…”

Section: Mechanisms Of Sir3 Mediated Trans-interactionssupporting

confidence: 74%

The silencing factor Sir3 is a molecular bridge that sticks together distant loci

Ruault

Scolari

Lazar‐Stefanita

et al. 2020

Preprint

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ABSTRACTPhysical contacts between distant loci contribute to regulate genome function. However, the molecular mechanisms responsible for settling and maintaining such interactions remain poorly understood. Here we investigate the well conserved interactions between heterochromatin loci. In budding yeast, the 32 telomeres cluster in 3-5 foci in exponentially growing cells. This clustering is functionally linked to the formation of heterochromatin in subtelomeric regions through the recruitment of the silencing complex SIR composed of Sir2/3/4. Combining microscopy and Hi-C on strains expressing different alleles of SIR3, we show that the binding of Sir3 directly promotes long range contacts between distant regions, including the rDNA, telomeres, and internal Sir3 bound sites. Furthermore, we unveil a new property of Sir3 in promoting rDNA compaction. Finally, using a synthetic approach we demonstrate that Sir3 can bond loci belonging to different chromosomes together, when targeted to these loci, independently of its interaction with its known partners (Rap1, and Sir4), Sir2 activity or chromosome context. Altogether these data suggest that Sir3 represents an uncommon example of protein able to bridge directly distant loci.

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Section: Mechanisms Of Sir3 Mediated Trans-interactionssupporting

confidence: 74%

The silencing factor Sir3 is a molecular bridge that sticks together distant loci

Ruault

Scolari

Lazar‐Stefanita

et al. 2020

Preprint

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“…Overall, the impact of phosphorylation on less‐prominent nuclear body dynamics, rather than the excellent work performed to identify novel regulators of nuclear body assembly, may be an interesting avenue of research. Our understanding of how and why these structures physically interact will be illuminated by SRM co‐localization of proteins enriched in separate nuclear bodies, and a better grasp of their ability to supply or sequester components (Sawyer, Bartek, & Dundr, ). The frequent physical association between the Cajal body and the HLB may represent a good model for further analysis of internuclear body surface interaction dynamics by SRM (Albrecht et al, ; Sawyer, Hager, & Dundr, ; Wang et al, ).…”

Section: Mlo Cooperativity and Rna/protein Sharingmentioning

confidence: 99%

Membraneless nuclear organelles and the search for phases within phases

2018

Self Cite

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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

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“…Components of membraneless RNA-filled nuclear bodies do not mix with the nucleoplasm because they undergo liquid-liquid phase separation (LLPS). Nuclear bodies, the best known examples of LLPS in the nucleus to date, phase-separate from the nucleoplasm due to multivalent weak interactions between RNA and RBPs [12,14,30,31,104,105]. The ability of RNA to form extensive secondary structures and establish multivalent interactions, and its net negative charge make RNA a potent modulator of LLPS.…”

Section: Role Of Rna In Ctcf-mediated Chromatin Organizationmentioning

confidence: 99%

Architectural RNA in chromatin organization

Thakur

Henikoff

2020

Biochemical Society Transactions

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RNA plays a well-established architectural role in the formation of membraneless interchromatin nuclear bodies. However, a less well-known role of RNA is in organizing chromatin, whereby specific RNAs have been found to recruit chromatin modifier proteins. Whether or not RNA can act as an architectural molecule for chromatin remains unclear, partly because dissecting the architectural role of RNA from its regulatory role remains challenging. Studies that have addressed RNA's architectural role in chromatin organization rely on in situ RNA depletion using Ribonuclease A (RNase A) and suggest that RNA plays a major direct architectural role in chromatin organization. In this review, we will discuss these findings, candidate chromatin architectural long non-coding RNAs and possible mechanisms by which RNA, along with RNA binding proteins might be mediating chromatin organization.

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Phase separated microenvironments inside the cell nucleus are linked to disease and regulate epigenetic state, transcription and RNA processing

Cited by 74 publications

References 106 publications

The silencing factor Sir3 is a molecular bridge that sticks together distant loci

The silencing factor Sir3 is a molecular bridge that sticks together distant loci

Membraneless nuclear organelles and the search for phases within phases

Architectural RNA in chromatin organization

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