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

Many eukaryotic transcription factors (TFs) contain intrinsically disordered low-complexity sequence domains (LCDs), but how these LCDs drive transactivation remains unclear. We used live-cell single-molecule imaging to reveal that TF LCDs form local high-concentration interaction hubs at synthetic...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2018-07, Vol.361 (6400)
Main Authors: Chong, Shasha, Dugast-Darzacq, Claire, Liu, Zhe, Dong, Peng, Dailey, Gina M, Cattoglio, Claudia, Heckert, Alec, Banala, Sambashiva, Lavis, Luke, Darzacq, Xavier, Tjian, Robert
Format: Article
Language:English
Subjects:
Amino acid sequence
Binding
Cell activation
Cell Line, Tumor
Cofactors
Complexity
Condensates
CRISPR
Deoxyribonucleic acid
DNA
DNA-Binding Proteins - chemistry
DNA-directed RNA polymerase
Drug delivery
Elongation
Enhancers
Fluorescence
Fluorescence in situ hybridization
Fluorescence recovery after photobleaching
Fluorescence spectroscopy
Gene expression
Gene loci
Gene regulation
Genes, Synthetic
Genetic transformation
Genetics
Genome editing
Genomes
Hubs
Humans
Image resolution
In vivo methods and tests
Microscopy
Molecular chains
Mutagenesis
Operator Regions, Genetic
Operators (mathematics)
Particle tracking
Phase separation
Photobleaching
Physiology
Protein Binding
Protein interaction
Protein Interaction Domains and Motifs
Proteins
Ribonucleic acid
RNA
RNA polymerase
RNA polymerase II
RNA Polymerase II - chemistry
Sarcoma
Single Molecule Imaging - methods
Sp1 protein
Transcription activation
Transcription elongation
Transcription factors
Transcription Factors - chemistry
Transcription, Genetic
Transcriptional Activation
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Description
Summary:Many eukaryotic transcription factors (TFs) contain intrinsically disordered low-complexity sequence domains (LCDs), but how these LCDs drive transactivation remains unclear. We used live-cell single-molecule imaging to reveal that TF LCDs form local high-concentration interaction hubs at synthetic and endogenous genomic loci. TF LCD hubs stabilize DNA binding, recruit RNA polymerase II (RNA Pol II), and activate transcription. LCD-LCD interactions within hubs are highly dynamic, display selectivity with binding partners, and are differentially sensitive to disruption by hexanediols. Under physiological conditions, rapid and reversible LCD-LCD interactions occur between TFs and the RNA Pol II machinery without detectable phase separation. Our findings reveal fundamental mechanisms underpinning transcriptional control and suggest a framework for developing single-molecule imaging screens for drugs targeting gene regulatory interactions implicated in disease.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aar2555