Biomolecular condensates as arbiters of biochemical reactions inside the nucleus

Laflamme, Guillaume; Mekhail, Karim

doi:10.1038/s42003-020-01517-9

Cited by 79 publications

(60 citation statements)

References 98 publications

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“…Recently, biomolecular condensates between proteins and nucleic acids formed via LLPS have been proposed to be associated not only with the regulation of gene transcription ( Hnisz et al, 2017 ), DNA replication ( Parker et al, 2019 ), and DNA damage repair ( Laflamme and Mekhail, 2020 ), but also with the organization of specific chromatin domains ( Erdel and Rippe, 2018 ; Larson and Narlikar, 2018 ; Gibson et al, 2019 ). Although the major factor in the formation of these condensates is the LLPS-prone proteins, the DNA itself is also critical in this event.…”

Section: Introductionmentioning

confidence: 99%

Uncharged Components of Single-Stranded DNA Modulate Liquid–Liquid Phase Separation With Cationic Linker Histone H1

Mimura

Tomita

Sugai

et al. 2021

Front. Cell Dev. Biol.

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Liquid–liquid phase separation (LLPS) of proteins and DNAs has been recognized as a fundamental mechanism for the formation of intracellular biomolecular condensates. Here, we show the role of the constituent DNA components, i.e., the phosphate groups, deoxyribose sugars, and nucleobases, in LLPS with a polycationic peptide, linker histone H1, a known key regulator of chromatin condensation. A comparison of the phase behavior of mixtures of H1 and single-stranded DNA-based oligomers in which one or more of the constituent moieties of DNA were removed demonstrated that not only the electrostatic interactions between the anionic phosphate groups of the oligomers and the cationic residues of H1, but also the interactions involving nucleobases and deoxyriboses (i) promoted the generation of spherical liquid droplets via LLPS as well as (ii) increased the density of DNA and decreased its fluidity within the droplets under low-salt conditions. Furthermore, we found the formation of non-spherical assemblies with both mobile and immobile fractions at relatively higher concentrations of H1 for all the oligomers. The roles of the DNA components that promote phase separation and modulate droplet characteristics revealed in this study will facilitate our understanding of the formation processes of the various biomolecular condensates containing nucleic acids, such as chromatin organization.

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Section: Introductionmentioning

confidence: 99%

Uncharged Components of Single-Stranded DNA Modulate Liquid–Liquid Phase Separation With Cationic Linker Histone H1

Mimura

Tomita

Sugai

et al. 2021

Front. Cell Dev. Biol.

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“…Biomolecular condensates represent a class of dynamic membrane-less bodies that are central in compartmentalizing subcellular biochemical processes in viruses 1 , bacteria 2,3 , yeast 4,5 , and human 6 . Past studies have reported a variety of biomolecular condensates with a broad range of physiological functions including stress response 7,8 , mRNA processing 9 , transcriptional activity control [10][11][12] , and genome organization 13 .…”

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confidence: 99%

Programmable Viscoelasticity in Protein-RNA Condensates with Disordered Sticker-Spacer Polypeptides

Alshareedah

Moosa

Banerjee

2021

Preprint

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The rheological properties of biological matters play a fundamental role in many cell processes. At the organelle level, liquid-liquid phase separation of multivalent proteins and RNAs drives the formation of biomolecular condensates that facilitate dynamic compartmentalization of cellular biochemistry1. With recent advances, it is becoming increasingly clear that the structure and rheological properties of these condensates are critical to their cellular functions2,3. Meanwhile, aberrant liquid-to-solid transitions in some cellular condensates are implicated in neurodegenerative disorders4. Within the limits of two extreme material states, viz., viscous liquid and amorphous or fibrillar solid, there lies a spectrum of materials known as viscoelastic fluids. Viscoelastic fluids behave as an elastic solid at time-scales shorter than their network reconfiguration time but as a viscous fluid at longer time-scales. Viscoelasticity of biomolecular condensates may constitute an adaptive mechanism for sensing mechanical stress and regulating biochemical processes5. From an engineering standpoint, viscoelastic fluids hold great potential for designing soft biomaterials with programmable mechanosensitivity6,7. Here, employing microrheology with optical tweezers, we demonstrate how multivalent disordered sticker-spacer8,9 polypeptides undergoing associative phase separation with RNA can be designed to control the frequency-dependent viscoelastic behavior of their condensates. Utilizing linear repeat polypeptides inspired by natural RNA-binding sequences, we show that polypeptide-RNA condensates behave as Maxwell fluids, with viscoelastic behavior that can be fine-tuned by the identity of the sticker and spacer residues. The sequence heuristics that we uncovered allowed us to create biomolecular condensates spanning two orders of magnitude in their viscous and elastic responses to the applied mechanical stress. This sequence-encoded regulation of viscoelasticity in disordered polypeptide-RNA condensates establishes a link between the molecular architecture of the polypeptide chains and the rheological properties of the resulting condensates at the mesoscale, enabling a route to engineer soft biomaterials with programmable mechanics.

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“…However, the role of LLPS in A compartment organization is currently an active area of research. Histone acetylation disrupted compacted chromatin droplets, and multi-bromodomain proteins, such as BRD4, induced LLPS of acetylated histones, forming liquid droplets (30,31). Growing evidence suggests that phase separation is one of the critical mechanisms of chromatin compartmentalization in 3D genome organization, although further efforts are needed to decipher the dynamics and mechanisms of regulation involving phase separation in chromosome compartmentalization.…”

Section: Chromosome Territories and A/b Compartmentsmentioning

confidence: 99%

Advances in higher-order chromatin architecture: the move towards 4D genome

Jung

Kim

2021

BMB Rep

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In eukaryotes, the genome is hierarchically packed inside the nucleus, which facilitates physical contact between cis-regulatory elements (CREs), such as enhancers and promoters. Accumulating evidence highlights the critical role of higherorder chromatin structure in precise regulation of spatiotemporal gene expression under diverse biological contexts including lineage commitment and cell activation by external stimulus. Genomics and imaging-based technologies, such as Hi-C and DNA fluorescence in situ hybridization (FISH), have revealed the key principles of genome folding, while newly developed tools focus on improvement in resolution, throughput and modality at single-cell and population levels, and challenge the knowledge obtained through conventional approaches. In this review, we discuss recent advances in our understanding of principles of higher-order chromosome conformation and technologies to investigate 4D chromatin interactions. [BMB Reports 2021; 54(5): 233-245]

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Biomolecular condensates as arbiters of biochemical reactions inside the nucleus

Cited by 79 publications

References 98 publications

Uncharged Components of Single-Stranded DNA Modulate Liquid–Liquid Phase Separation With Cationic Linker Histone H1

Uncharged Components of Single-Stranded DNA Modulate Liquid–Liquid Phase Separation With Cationic Linker Histone H1

Programmable Viscoelasticity in Protein-RNA Condensates with Disordered Sticker-Spacer Polypeptides

Advances in higher-order chromatin architecture: the move towards 4D genome

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