Imaging dynamic and selective low-complexity domain interactions that control gene transcription

Chong, Shasha; Dugast-Darzacq, Claire; Liu, Zhe; Dong, Peng; Dailey, Gina M; Cattoglio, Claudia; Heckert, Alec; Banala, Sambashiva; Lavis, Luke D.; Darzacq, Xavier; Tjian, Robert

doi:10.1126/science.aar2555

Cited by 828 publications

(934 citation statements)

References 55 publications

(71 reference statements)

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“…The biomimetic construction of liquid organelle‐like materials in vitro provides a simplified alternative to understand the pathological phase transition of diseased organelles, thus shedding lights on the understanding of mechanism of neurodegenerative diseases and cancers. Besides, microfluidic preparation of organelle‐like materials also provides a platform to the preliminary screening and rapid testing of small molecular drugs targeting for specific organelle diseases . The membraneless organelles inspired biomaterials therefore are of great clinical importance in both disease study and treatment.…”

Section: Conclusion and Outlooksmentioning

confidence: 99%

Cell‐Inspired All‐Aqueous Microfluidics: From Intracellular Liquid–Liquid Phase Separation toward Advanced Biomaterials

et al. 2020

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Living cells have evolved over billions of years to develop structural and functional complexity with numerous intracellular compartments that are formed due to liquid–liquid phase separation (LLPS). Discovery of the amazing and vital roles of cells in life has sparked tremendous efforts to investigate and replicate the intracellular LLPS. Among them, all‐aqueous emulsions are a minimalistic liquid model that recapitulates the structural and functional features of membraneless organelles and protocells. Here, an emerging all‐aqueous microfluidic technology derived from micrometer‐scaled manipulation of LLPS is presented; the technology enables the state‐of‐art design of advanced biomaterials with exquisite structural proficiency and diversified biological functions. Moreover, a variety of emerging biomedical applications, including encapsulation and delivery of bioactive gradients, fabrication of artificial membraneless organelles, as well as printing and assembly of predesigned cell patterns and living tissues, are inspired by their cellular counterparts. Finally, the challenges and perspectives for further advancing the cell‐inspired all‐aqueous microfluidics toward a more powerful and versatile platform are discussed, particularly regarding new opportunities in multidisciplinary fundamental research and biomedical applications.

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Section: Conclusion and Outlooksmentioning

confidence: 99%

Cell‐Inspired All‐Aqueous Microfluidics: From Intracellular Liquid–Liquid Phase Separation toward Advanced Biomaterials

et al. 2020

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“…Hnisz et al have suggested a phase separation model of enhancer assembly and function. Direct tracking of enhancer binding factors by different live cell microscopic approaches revealed formation of interaction hubs and a highly dynamic binding behavior of these factors with often very short dwelling times (< seconds) (for review, see References 46 and 97). Notably, these studies record the dynamics of binding factors and not potential movements of enhancer sequences per se.…”

Section: Accessibility Of Tres By Tfs May Depend On the Active Or Silmentioning

confidence: 99%

Nuclear compartmentalization, dynamics, and function of regulatory DNA sequences

Cremer

2019

Genes Chromosomes & Cancer

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Transcription regulatory elements (TREs) have been extensively studied on the biochemical level with respect to their interactions with transcription factors (TFs), other DNA segments, and larger protein complexes. In this review, we describe concepts and preliminary experimental evidence for positional changes of TREs within a dynamic, functional nuclear architecture. We suggest a multilayered shell‐like chromatin organization of chromatin domain clusters with increasing chromatin compaction levels from the periphery toward the interior with a decondensed transcriptionally active peripheral layer and compact repressed chromatin typically located in the interior. This model organization of nuclear architecture implies a differential accessibility of TFs to targets located in co‐aligned active and inactive nuclear compartments (ANC and INC). It is based on evidence that active, easily accessible chromatin (perichromatin region, PR) lines a network of channels (interchromatin compartment, IC) involved in nuclear import–export functions. The IC and PR constitute the ANC, whereas transcriptionally noncompetent chromatin with higher compactness is part of the likely less accessible INC. Preliminary experimental evidence shows an enrichment of active TREs in the ANC and of inactive TREs in the INC suggesting positional changes of TREs between the ANC and INC depending on changes in their functional state.

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“…The modular nature of the phase transition‐promoting segment also helps with phenotypic diversity and the manifestation of new phenotypes during evolution, since such segments can evolve independently of the biochemical function mediated by the rest of the polypeptide (Bornberg‐Bauer & Alba, ; Boke et al , ; Lees et al , ). This may possibly explain why many regulators such as transcription factors (e.g., Snf5) contain phase separation‐promoting segments (e.g., Q/N‐rich segments) independently of structured domains that perform specific biochemical function such as DNA binding (Chavali et al , 2017a; Chong et al , ; Sabari et al , ). It is known that cell‐to‐cell variation in protein abundance of such regulators can lead to differential activation of downstream regulatory networks and drive the phenotypic differences in an isogenic population (Jothi et al , ; Halfmann et al , ; Holmes et al , ; Gemayel et al , ).…”

Section: Discussionmentioning

confidence: 99%

The fitness cost and benefit of phase‐separated protein deposits

Groot

Torrent

Ravarani

et al. 2019

Molecular Systems Biology

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Phase separation of soluble proteins into insoluble deposits is associated with numerous diseases. However, protein deposits can also function as membrane‐less compartments for many cellular processes. What are the fitness costs and benefits of forming such deposits in different conditions? Using a model protein that phase‐separates into deposits, we distinguish and quantify the fitness contribution due to the loss or gain of protein function and deposit formation in yeast. The environmental condition and the cellular demand for the protein function emerge as key determinants of fitness. Protein deposit formation can influence cell‐to‐cell variation in free protein abundance between individuals of a cell population (i.e., gene expression noise). This results in variable manifestation of protein function and a continuous range of phenotypes in a cell population, favoring survival of some individuals in certain environments. Thus, protein deposit formation by phase separation might be a mechanism to sense protein concentration in cells and to generate phenotypic variability. The selectable phenotypic variability, previously described for prions, could be a general property of proteins that can form phase‐separated assemblies and may influence cell fitness.

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Imaging dynamic and selective low-complexity domain interactions that control gene transcription

Cited by 828 publications

References 55 publications

Cell‐Inspired All‐Aqueous Microfluidics: From Intracellular Liquid–Liquid Phase Separation toward Advanced Biomaterials

Cell‐Inspired All‐Aqueous Microfluidics: From Intracellular Liquid–Liquid Phase Separation toward Advanced Biomaterials

Nuclear compartmentalization, dynamics, and function of regulatory DNA sequences

The fitness cost and benefit of phase‐separated protein deposits

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