Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization

Sanders, David W.; Kedersha, Nancy; Lee, Daniel S.W.; Strom, Amy R.; Drake, Victoria J.; Riback, Joshua A.; Bracha, Dan; Eeftens, Jorine M.; Iwanicki, Allana; Wang, Alicia; Wei, Ming; Whitney, Gena; Lyons, Shawn M.; Anderson, Paul; Jacobs, William M.; Ivanov, Pavel; Brangwynne, Clifford P.

doi:10.1016/j.cell.2020.03.050

Cited by 672 publications

(865 citation statements)

References 109 publications

(158 reference statements)

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“…The protein interaction network for our SG and PB components is also consistent with recent studies where graph theory approaches have been used to provide a mechanistic understanding of how multivalent RNA binding proteins promote liquid-liquid phase separation (LLPS) (Guillen-Boixet, Kopach et al, 2020, Sanders, Kedersha et al, 2020, Yang, Mathieu et al, 2020. We find numerous multivalent proteins that may act as hubs to promote PB and SG formation (Fig.…”

Section: Discussionsupporting

confidence: 87%

Integrated multi-omics reveals common properties underlying stress granule and P-body formation

Kershaw

Nelson

Lui

et al. 2020

Preprint

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Non-membrane-bound compartments such as P-bodies (PBs) and stress granules (SGs) play important roles in the regulation of gene expression following environmental stresses. We have systematically determined the protein and mRNA composition of PBs and SGs formed in response to a common stress condition imposed by glucose depletion. We find that high molecular weight (HMW) complexes exist prior to glucose depletion that may act as seeds for the further condensation of proteins forming mature PBs and SGs. Both before and after glucose depletion, these HMW complexes are enriched for proteins containing low complexity and RNA binding domains. The mRNA content of these HMW complexes is enriched for long, structured mRNAs that become more poorly translated following glucose depletion.Many proteins and mRNAs are shared between PBs and SGs including several multivalent RNA binding proteins that may promote condensate interactions during liquid-liquid phase separation. Even where the precise identity of mRNAs and proteins localizing to PBs and SGs is distinct, the mRNAs and proteins share common biophysical and chemical features that likely trigger their phase separation.

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Section: Discussionsupporting

confidence: 87%

Integrated multi-omics reveals common properties underlying stress granule and P-body formation

Kershaw

Nelson

Lui

et al. 2020

Preprint

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“…PHC1 shows similar phase separation behaviour, while it lacks a significant IDR. This is consistent with recent work showing that while weak interactions between IDRs can drive phase-separation in certain systems (39-44), a more complicated picture is emerging for multicomponent systems in living cells(28,45).…”

supporting

confidence: 92%

“…IDRs), characteristic of proteins driving phase separation ( Figure 1B,E,H,K). The presence of oligomerization domains is particularly interesting, given recent studies highlighting the role of oligomerization in driving phase separation of condensates such as stress granules and nucleoli (28,29). To understand the potential role of Polycomb protein oligomerization in promoting phase separation, we utilized the recently-developed Corelet system (30), a light-activated oligomerization platform ( Figure 1A).…”

Section: Canonical Prc1 Subunits Form Condensatesmentioning

confidence: 99%

“…Instead, Cbx2 may acts as a localizing "seed" on the chromatin, and through its interactions with the other phase separation-prone PRC1 subunits, particularly Bmi1 and PHC1, locally amplifies valence to drive formation of a larger condensate. This local valence is further amplified through oligomerization domains on Bmi1 and PHC1, which together with RNF2 appear to serve as valence-amplifying "nodes" (28,35,49,50).…”

Section: Prc1 Condensates Lead To Chromatin Compactionmentioning

confidence: 99%

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Epigenetic memory as a time integral over prior history of Polycomb phase separation

Eeftens

Kapoor

Brangwynne

2020

Preprint

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Structural organization of the genome into transcriptionally active euchromatin and silenced heterochromatin is essential for eukaryotic cell function. Heterochromatin is a more compact form of chromatin, and is associated with characteristic post- translational histone modifications and chromatin binding proteins. Phase-separation has recently been suggested as a mechanism for heterochromatin formation, through condensation of heterochromatin associated proteins. However, it is unclear how phase-separated condensates can contribute to stable and robust repression, particularly for heritable epigenetic changes. The Polycomb complex PRC1 is known to be key for heterochromatin formation, but the multitude of Polycomb proteins has hindered our understanding of their collective contribution to chromatin repression. Here, we take a quantitative live cell imaging approach to show that PRC1 proteins form multicomponent condensates through hetero-oligomerization. They preferentially seed at H3K27me3 marks, and subsequently write H2AK119Ub marks. Using optogenetics to nucleate local Polycomb condensates, we show that Polycomb phase separation can induce chromatin compaction, but phase separation is dispensable for maintenance of the compacted state. Our data are consistent with a model in which the time integral of historical Polycomb phase separation is progressively recorded in repressive histone marks, which subsequently drive chromatin compaction. These findings link the equilibrium thermodynamics of phase separation with the fundamentally non-equilibrium concept of epigenetic memory.

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“…Numerous ribonucleoprotein and nucleoprotein complexes spontaneously selfassemble into non-membrane bound cellular bodies, or biomolecular condensates, via liquid-liquid phase separation (Banani et al, 2017). The canonical examples of RNA-protein bodies include the nucleolus in the nucleus (Brangwynne et al, 2011;Feric et al, 2016) as well as P-granules (Brangwynne et al, 2009) and stress granules in the cytoplasm (Guillén-Boixet et al, 2020;Molliex et al, 2015;Sanders et al, 2020;Yang et al, 2020). In addition, DNA-protein complexes can phase separate in the nucleus, such as the heterochromatin protein HP1a in the context of heterochromatin (Larson et al, 2017;Strom et al, 2017), histones to form chromatin domains (Gibson et al, 2019;Sanulli et al, 2019), or super-enhancers which form active transcriptional hubs (Sabari et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Self-assembly of multi-component mitochondrial nucleoids via phase separation

Feric

Demarest

Tian

et al. 2019

Preprint

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Mitochondria contain an autonomous and spatially segregated genome. The organizational unit of mitochondrial genomes is the nucleoid which consists of mitochondrial DNA (mtDNA) and associated architectural proteins. The physical properties and mechanisms of assembly of mitochondrial nucleoids remain largely unclear. Here, we show that mitochondrial nucleoids form by phase separation. Mitochondrial nucleoids exhibit morphological features, coarsening behavior, and dynamics of phase-separated structures in vitro and in vivo. The major mtDNA-binding protein TFAM spontaneously phase separates in vitro into viscoelastic droplets with slow internal dynamics, and the combination of TFAM and mtDNA is sufficient to promote the in vitro formation of multiphase structures with gel-like properties, which recapitulate the in vivo behavior of mitochondrial nucleoids in live human cells. Enlarged phase-separated mitochondrial nucleoids are present in the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) and altered mitochondrial nucleoid structure is accompanied by mitochondrial dysfunction. These results identify phase separation as the physical mechanism driving the organization of mitochondrial nucleoids, and they have ramifications for mitochondrial function.

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Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization

Cited by 672 publications

References 109 publications

Integrated multi-omics reveals common properties underlying stress granule and P-body formation

Integrated multi-omics reveals common properties underlying stress granule and P-body formation

Epigenetic memory as a time integral over prior history of Polycomb phase separation

Self-assembly of multi-component mitochondrial nucleoids via phase separation

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