A phase separation model predicts key features of transcriptional control

By Denes Hnisz, K. Shrinivas, Richard A. Young, Arup K. Chakraborty, Phillip A. Sharp. Cell, 2017

1,477 citations recorded by the source corpus.

Summary Super-enhancers are large clusters of enhancers that control transcription of genes with prominent roles in cell-type specific processes in healthy and diseased states. A model that explains the spectrum of observations regarding super-enhancer formation, function and dissolution is lacking. Phase-separated multi-molecular assemblies provide an essential regulatory mechanism to compartmentalize biochemical reactions within cells. We propose that a phase separation model explains features of transcriptional control, including the formation of super-enhancers, the sensitivity of super-enhancers to perturbation, and their transcriptional bursting patterns. This model provides a conceptual framework to further explore principles of gene control in mammals.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/517687d3f9bdff8a8a0ca99285623023bf53d1d6

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Citations in the corpus

Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells (2018, background): “Together, our observations of chromatin organization in single cells expand upon the emerging view that genome packaging is more complex than pairwise interactions (45).”
Intrinsically disordered regions contribute promiscuous interactions to RNP granule assembly (2017, background): “It is notable that components of all of these assemblies are enriched in IDRs (Banani et al., 2016; Hegde et al., 2010; Hnisz et al., 2017; Iakoucheva et al., 2002; Kai, 2016; Minezaki et al., 2006).”
Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution. (2019, background): “Notably, as proposed for transcriptional control (Hnisz et al., 2017), RNP”
Liquid-Liquid Phase Separation in Disease. (2019, background): “Indeed, a series of recent studies have raised the possibility that condensate formation is critical for regulation of transcription (21, 23, 32, 34, 70, 134).”
Transcription factors activate genes through the phase separation capacity of their activation domains (2018, background): “We recently proposed that transcriptional control may be driven by the formation of phase-separated condensates (Hnisz et al., 2017) and demonstrated that the coactivator proteins MED1 and BRD4 form phase-separated condensates at super-enhancers (SEs) (Sabari et al.”
Sequence-dependent surface condensation of a pioneer transcription factor on DNA (2020, methodology): “Numerical solutions for the time dependence of condensation as well as for the condensation patterns in the steady state show that the model captures key features seen in experiments: (1) the formation of condensates that coexist with regions that are in the adsorbed state (Figs.”
Liquid phase condensation in cell physiology and disease (2017, background): “How highly localized phase separation coupled to local active processes, such as transcription (154), may serve to structure nuclear contents on 10- to 100-nm spatial scales represents a major open question; finite size effects on phase transitions will become increasingly important on these scales ”
Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome. (2018, neutral): “Mechanical Restructuring of Genomic Loci Induced by Droplet Condensation These findings of mechanical chromatin exclusion are surprising, given that enhancer clusters and other nuclear condensates have been hypothesized to bring specifically targeted genomic elements into closer proximity (Hnisz et ”
Cohesin loss eliminates all loop domains (2017, result): “This observation is also compatible with several models: histone modifications might drive the formation of compartments (i.e., “phase separation” (Hnisz et al., 2017; Jost et al., 2014; Di Cell.”
Chromatin Potential Identified by Shared Single-Cell Profiling of RNA and Chromatin (2020, background): “Notably, only 34.4% of DORCs active in hair follicle stem cells (HFSCs) or TACs overlap with super-enhancers identified in these same cell types (Adam et al., 2015), suggesting that DORCs may encompass other mechanisms promoting formation of enhancer clusters (Hnisz et al., 2017; Li et al., 2002).”
Quantitative Proteomics of the Cancer Cell Line Encyclopedia (2020, neutral): “Correlated expression patterns in gene expression data are organized in large part around chromosomal location, driven by mechanisms such as transcription factor activity and chromosomal topology as set up by cellular and tissue identity (Caron et al., 2001; Dixon et al., 2016; Furlong and Levine, 2”