The nuclear receptor superfamily: A structural perspective

Protein Science, Journal Year: 2018, Volume and Issue: 27(11), P. 1876 - 1892

Published: Aug. 15, 2018

Abstract Nuclear receptors (NRs) are a family of transcription factors that regulate numerous physiological processes such as metabolism, reproduction, inflammation, well the circadian rhythm. NRs sense changes in lipid metabolite levels to drive differential gene expression, producing distinct physiologic effects. This is an allosteric process whereby binding cognate ligand and specific DNA sequences drives recruitment diverse transcriptional co‐regulators at chromatin ultimately transactivation or transrepression target genes. Dysregulation NR signaling leads various malignances, metabolic disorders, inflammatory disease. Given their important role physiology ability respond small lipophilic ligands, have emerged valuable therapeutic targets. Here, we summarize discuss recent progress on understanding complex mechanism action NRs, primarily from structural perspective. Finally, suggest future studies improve our better design drugs by integrating multiple biophysical approaches.

Language: Английский

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The DNA damage response to transcription stress

Nature Reviews Molecular Cell Biology, Journal Year: 2019, Volume and Issue: 20(12), P. 766 - 784

Published: Sept. 26, 2019

Language: Английский

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Molecular basis and biological function of variability in spatial genome organization

Science, Journal Year: 2019, Volume and Issue: 365(6457)

Published: Sept. 5, 2019

The complex three-dimensional organization of genomes in the cell nucleus arises from a wide range architectural features including DNA loops, chromatin domains, and higher-order compartments. Although these are universally present most types tissues, recent single-cell biochemistry imaging approaches have demonstrated stochasticity transcription high variability architecture individual cells. We review occurrence, mechanistic basis, functional implications genome organization. summarize observations on cell- allele-specific architecture, discuss nature extrinsic intrinsic sources organization, highlight potential structural heterogeneity for function.

Language: Английский

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Structure and mechanism of the RNA polymerase II transcription machinery

Genes & Development, Journal Year: 2020, Volume and Issue: 34(7-8), P. 465 - 488

Published: April 1, 2020

RNA polymerase II (Pol II) transcribes all protein-coding genes and many noncoding RNAs in eukaryotic genomes. Although Pol is a complex, 12-subunit enzyme, it lacks the ability to initiate transcription cannot consistently transcribe through long DNA sequences. To execute these essential functions, an array of proteins protein complexes interact with regulate its activity. In this review, we detail structure mechanism over dozen factors that govern initiation (e.g., TFIID, TFIIH, Mediator), pausing, elongation DSIF, NELF, PAF, P-TEFb). The structural basis for regulation has advanced rapidly past decade, largely due technological innovations cryoelectron microscopy. Here, summarize wealth functional data have enabled deeper understanding mechanisms; also highlight mechanistic questions remain unanswered or controversial.

Language: Английский

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Intrinsic Dynamics of a Human Gene Reveal the Basis of Expression Heterogeneity

Cell, Journal Year: 2018, Volume and Issue: 176(1-2), P. 213 - 226.e18

Published: Dec. 13, 2018

Language: Английский

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Nascent RNA analyses: tracking transcription and its regulation

Nature Reviews Genetics, Journal Year: 2019, Volume and Issue: 20(12), P. 705 - 723

Published: Aug. 9, 2019

Language: Английский

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Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activation

Genes & Development, Journal Year: 2018, Volume and Issue: 32(3-4), P. 202 - 223

Published: Feb. 1, 2018

Enhancers are important genomic regulatory elements directing cell type-specific transcription. They assume a key role during development and disease, their identification functional characterization have long been the focus of scientific interest. The advent next-generation sequencing clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-based genome editing has revolutionized means by which we study enhancer biology. In this review, cover recent developments in prediction enhancers based on chromatin characteristics reporter assays endogenous DNA perturbations. We discuss that two latter approaches provide different complementary insights, especially assessing sufficiency necessity for transcription activation. Furthermore, insights into mechanistic aspects function, including findings about cofactor requirements post-translational histone modifications such as monomethylation H3 Lys4 (H3K4me1). Finally, survey how these advance our understanding regulation with respect to promoter specificity transcriptional bursting an outlook covering open questions promising developments.

Language: Английский

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Time will tell: comparing timescales to gain insight into transcriptional bursting

Trends in Genetics, Journal Year: 2024, Volume and Issue: 40(2), P. 160 - 174

Published: Jan. 12, 2024

Recent imaging studies have captured the dynamics of regulatory events transcription inside living cells. These include factor (TF) DNA binding, chromatin remodeling and modification, enhancer-promoter (E-P) proximity, cluster formation, preinitiation complex (PIC) assembly. Together, these molecular culminate in stochastic bursts RNA synthesis, but their kinetic relationship remains largely unclear. In this review, we compare timescales upstream steps (input) with kinetics transcriptional bursting (output) to generate mechanistic models single We highlight open questions potential technical advances guide future endeavors toward a quantitative understanding regulation.

Language: Английский

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Localized Bicirculating DNAzyme Self-Feedback Amplification Strategy for Ultra-Sensitive Fluorescence Biosensing of MicroRNA

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

DNAzyme-based cascade networks are effective tools to achieve ultrasensitive detection of low-abundance miRNAs. However, their designs complicated and costly, the operation is time-consuming. Herein, a novel simple noncascade DNAzyme network designed its amplification effect comparable or even better than many cascading ones. It nonenzymatic, isothermal, bicirculating consisting two toehold-mediated strand-displacement reactions localized strategy. Taking microRNA-122 as target model, this fluorescence biosensor has limit 84 zmol L–1, which 8-orders magnitude lower that nonamplification one. The ultrasensitivity mainly benefits from exclusive design positive self-feedback mechanism ingenious network. In addition, utilization superparamagnetic Fe3O4@SiO2 particles not only helps for localization DNAzymes but also facilitates rapid separation signal probes (output DNA-CdTe QDs). This fluorescent advantages specificity, speed, thermal stability, low cost. paves new way bioamplification strategy, may be very attractive biosensors, DNA logic gates, computers.

Language: Английский

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What shapes eukaryotic transcriptional bursting?

Molecular BioSystems, Journal Year: 2017, Volume and Issue: 13(7), P. 1280 - 1290

Published: Jan. 1, 2017

Isogenic cells in a common environment present large degree of heterogeneity gene expression. Part this variability is attributed to transcriptional bursting: the stochastic activation and inactivation promoters that leads discontinuous production mRNA. The diversity bursting patterns displayed by different genes suggests existence connection between regulation. Experimental strategies such as single-molecule RNA FISH, MS2-GFP or short-lived protein reporters allow quantification comparison kinetics conditions, allowing therefore identification molecular mechanisms modulating bursting. In review we recapitulate impact on aspects transcription chromatin environment, nucleosome occupancy, histone modifications, number affinity regulatory elements, DNA looping factor availability. More specifically, examine their role tuning burst size frequency. While some involved marks can affect every aspect bursting, others predominantly influence (e.g. cis-regulatory elements) frequency availability).

Language: Английский

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