Structure-function relationships in mitochondrial transcriptional condensates

Feric, Marina; Sarfallah, Azadeh; Dar, Furqan; Temiakov, Dmitry; Pappu, Rohit V.; Misteli, Tom

doi:10.1101/2021.12.30.474545

Cited by 3 publications

(10 citation statements)

References 77 publications

(139 reference statements)

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“…A possible example of this scenario is the handover of mtRNA from the mtnucleoid into an adjacent mtRNA granule. [56,61] Removal of RNA may be also facilitated by the action of transcription termination factors -for example, rho-factor in bacteria, [99] polyA signals in conjunction with exonuclease Xrn2 in eukaryotic cells, [100] and MTERF in mt-nucleoids [101] -which contribute to the detachment of the polymerase and thus separation of nascent RNA from the DNA strand. Additionally, RNA-binding proteins immediately coat nascent RNA to form hnRNPs [102] in the nucleus, potentially providing altered energetics to facilitate escape of bound RNA from the transcriptional condensate.…”

Section: Separating the Genome From Its Rna Products: Removing Rna Fr...mentioning

confidence: 99%

“…For instance, the nucleolus contains a drop-withina-drop morphology, [11] whereas mt-transcriptional condensates are heterogeneous. [58,61] These complex structures may arise, in part, from differences in miscibility between the components (Figure 2A).…”

Section: Origin Of Structural Heterogeneity: Differences In Component...mentioning

confidence: 99%

“…For example, mt‐transcriptional condensates are highly viscoelastic, and they correspondingly exhibit decreased transcription rates. [ 61 ] Moreover, both recruitment and assembly of transcription machinery, particularly at promoter pause sites, tend to be the rate‐limiting steps for transcription in the nucleus; once in the elongation phase, Pol II moves rapidly along the DNA strand, synthesizing a transcript at a rate of >1 kb per minute. [ 89 ] Longer times for molecules to rearrange and assemble into functional transcription complexes in the condensate may therefore reduce the frequency of transcription events.…”

Section: Kindling Function Inside Condensates: Reaction Rates Versus ...mentioning

confidence: 99%

“…Computational modeling suggests that these vesicles are non‐equilibrium structures that become dynamically arrested upon the accumulation of RNA in vitro, whereas removal of nascent RNA, as occurs in vivo, supports the prototypical droplet‐like mt‐nucleoids. [ 61 ] Notably, vesicle‐like morphologies have been observed in vitro for other protein‐nucleic acid systems [ 62–64 ] and even in vivo, [ 65 ] suggesting vesicles represent another fundamental state of (ribo)nucleoprotein condensates that the cell could potentially sample (Figure 1F).…”

Section: Transcriptional Condensates In Nucleoidsmentioning

confidence: 99%

“…For instance, the nucleolus contains a drop‐within‐a‐drop morphology, [ 11 ] whereas mt‐transcriptional condensates are heterogeneous. [ 58,61 ] These complex structures may arise, in part, from differences in miscibility between the components (Figure 2A). Based on in vitro and in vivo observations, DNA and RNA appear to have minimal affinity for each other, most likely as a result of electrostatic repulsion arising from the negative charge along their respective backbones.…”

Section: Origin Of Structural Heterogeneity: Differences In Component...mentioning

confidence: 99%

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Function moves biomolecular condensates in phase space

Feric

Misteli

2022

BioEssays

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Phase separation underlies the formation of biomolecular condensates. We hypothesize the cellular processes that occur within condensates shape their structural features. We use the example of transcription to discuss structure-function relationships in condensates. Various types of transcriptional condensates have been reported across the evolutionary spectrum in the cell nucleus as well as in mitochondrial and bacterial nucleoids. In vitro and in vivo observations suggest that transcriptional activity of condensates influences their supramolecular structure, which in turn affects their function. Condensate organization thus becomes driven by differences in miscibility among the DNA and proteins of the transcription machinery and the RNA transcripts they generate. These considerations are in line with the notion that cellular processes shape the structural properties of condensates, leading to a dynamic, mutual interplay between structure and function in the cell.

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Section: Separating the Genome From Its Rna Products: Removing Rna Fr...mentioning

confidence: 99%

Section: Origin Of Structural Heterogeneity: Differences In Component...mentioning

confidence: 99%

Section: Kindling Function Inside Condensates: Reaction Rates Versus ...mentioning

confidence: 99%

Section: Transcriptional Condensates In Nucleoidsmentioning

confidence: 99%

Section: Origin Of Structural Heterogeneity: Differences In Component...mentioning

confidence: 99%

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Function moves biomolecular condensates in phase space

Feric

Misteli

2022

BioEssays

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May the force be with you: Nuclear condensates function beyond transcription control

et al. 2023

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Over the past decade, research has revealed biomolecular condensates' relevance in diverse cellular functions. Through a phase separation process, they concentrate macromolecules in subcompartments shaping the cellular organization and physiology. In the nucleus, biomolecular condensates assemble relevant biomolecules that orchestrate gene expression. We here hypothesize that chromatin condensates can also modulate the nongenetic functions of the genome, including the nuclear mechanical properties. The importance of chromatin condensates is supported by the genetic evidence indicating that mutations in their members are causative of a group of rare Mendelian diseases named chromatinopathies (CPs). Despite a broad spectrum of clinical features and the perturbations of the epigenetic machinery characterizing the CPs, recent findings highlighted negligible changes in gene expression. These data argue in favor of possible noncanonical functions of chromatin condensates in regulating the genome's spatial organization and, consequently, the nuclear mechanics. In this review, we discuss how condensates may impact nuclear mechanical properties, thus affecting the cellular response to mechanical cues and, eventually, cell fate and identity.Chromatin condensates organize macromolecules in the nucleus orchestrating the transcription regulation and mutations in their members are responsible for rare diseases named chromatinopathies. We argue that chromatin condensates, in concert with the nuclear lamina, may also govern the nuclear mechanical properties affecting the cellular response to external cues.

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Mesoscale structure–function relationships in mitochondrial transcriptional condensates

Feric

Sarfallah

Dar

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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In live cells, phase separation is thought to organize macromolecules into membraneless structures known as biomolecular condensates. Here, we reconstituted transcription in condensates from purified mitochondrial components using optimized in vitro reaction conditions to probe the structure–function relationships of biomolecular condensates. We find that the core components of the mt-transcription machinery form multiphasic, viscoelastic condensates in vitro. Strikingly, the rates of condensate-mediated transcription are substantially lower than in solution. The condensate-mediated decrease in transcriptional rates is associated with the formation of vesicle-like structures that are driven by the production and accumulation of RNA during transcription. The generation of RNA alters the global phase behavior and organization of transcription components within condensates. Coarse-grained simulations of mesoscale structures at equilibrium show that the components stably assemble into multiphasic condensates and that the vesicles formed in vitro are the result of dynamical arrest. Overall, our findings illustrate the complex phase behavior of transcribing, multicomponent condensates, and they highlight the intimate, bidirectional interplay of structure and function in transcriptional condensates.

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Structure-function relationships in mitochondrial transcriptional condensates

Cited by 3 publications

References 77 publications

Function moves biomolecular condensates in phase space

Function moves biomolecular condensates in phase space

May the force be with you: Nuclear condensates function beyond transcription control

Mesoscale structure–function relationships in mitochondrial transcriptional condensates

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