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Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation.

ABSTRACT: RNA Polymerase II (Pol II) and transcription factors form concentrated hubs in cells via multivalent protein-protein interactions, often mediated by proteins with intrinsically disordered regions. During Herpes Simplex Virus infection, viral replication compartments (RCs) efficiently enrich host Pol II into membraneless domains, reminiscent of liquid-liquid phase separation. Despite sharing several properties with phase-separated condensates, we show that RCs operate via a distinct mechanism wherein unrestricted nonspecific protein-DNA interactions efficiently outcompete host chromatin, profoundly influencing the way DNA-binding proteins explore RCs. We find that the viral genome remains largely nucleosome-free, and this increase in accessibility allows Pol II and other DNA-binding proteins to repeatedly visit nearby DNA binding sites. This anisotropic behavior creates local accumulations of protein factors despite their unrestricted diffusion across RC boundaries. Our results reveal underappreciated consequences of nonspecific DNA binding in shaping gene activity, and suggest additional roles for chromatin in modulating nuclear function and organization.

SUBMITTER: McSwiggen DT

PROVIDER: S-EPMC6522219 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation.

McSwiggen David Trombley DT Hansen Anders S AS Teves Sheila S SS Marie-Nelly Hervé H Hao Yvonne Y Heckert Alec Basil AB Umemoto Kayla K KK Dugast-Darzacq Claire C Tjian Robert R Darzacq Xavier X

eLife 20190507

RNA Polymerase II (Pol II) and transcription factors form concentrated hubs in cells via multivalent protein-protein interactions, often mediated by proteins with intrinsically disordered regions. During Herpes Simplex Virus infection, viral replication compartments (RCs) efficiently enrich host Pol II into membraneless domains, reminiscent of liquid-liquid phase separation. Despite sharing several properties with phase-separated condensates, we show that RCs operate via a distinct mechanism whe ...[more]

PMID: 31038454

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Project description:How could the incredible complexity of modern cells evolve from something simple enough to have appeared in a primordial soup? This enduring question has sparked the interest of researchers since Darwin first considered his theory of natural selection. Organic molecules, even potentially functional molecules including peptides and nucleotides, can be produced abiotically. Amphiphiles such as surfactants and lipids display remarkable self-assembly processes including the spontaneous formation of vesicles resembling the membranes of living cells. Nonetheless, numerous questions remain. Given the presumably dilute concentrations of macromolecules in the prebiotic pools where the earliest cells are thought to have appeared, how could the necessary components become concentrated and encapsulated within a semipermeable membrane? What would drive the further structural complexity that is a hallmark of modern living systems? The interior of modern cells is subdivided into microcompartments such as the nucleoid of bacteria or the organelles of eukaryotic cells. Even within what at first appears to be a single compartment, for example, the cytoplasm or nucleus, chemical composition is often nonuniform, containing gradients, macromolecular assemblies, and/or liquid droplets. What might the internal structure of intermediate evolutionary forms have looked like? The nonideal aqueous solution chemistry of macromolecules offers an attractive possible answer to these questions. Aqueous polymer solutions will form multiple coexisting thermodynamic phases under a variety of readily accessible conditions. In this Account, we describe aqueous phase separation as a model system for biological compartmentalization in both early and modern cells, with an emphasis on systems that have been encapsulated within a lipid bilayer. We begin with an introduction to aqueous phase separation and discuss how this phenomenon can lead to microcompartmentalization and could facilitate biopolymer encapsulation by partitioning of solutes between the phases. We then describe primitive model cells based on phase separation inside lipid vesicles, which mimic several basic properties of biological cells: microcompartmentation, protein relocalization in response to stimulus, loss of symmetry, and asymmetric vesicle division. We observe these seemingly complex phenomena in the absence of genetic molecules, enzymes, or cellular machinery, and as a result these processes could provide clues to possible intermediates in the early evolution of cell-like assemblies.

Dataset Information

Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation.

Publications

Evidence for DNA-mediated nuclear compartmentalization distinct from phase separation.

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