Phase Separation and Transcription Regulation: Are Super‐Enhancers and Locus Control Regions Primary Sites of Transcription Complex Assembly?

Gurumurthy, Aishwarya; Shen, Yong; Gunn, Eliot M.; Bungert, Jörg

doi:10.1002/bies.201800164

Cited by 42 publications

(38 citation statements)

References 86 publications

(167 reference statements)

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“…It is important to emphasize that compared to a diffusion model, loop extrusion effectively turns a 3D search into 1D scanning (Bulger and Groudine, 2011). Furthermore, the diffusion model hypothesizes that promoter-enhancer interactions within a TAD are mediated by high local concentration of diffusible activators (Gurumurthy et al, 2019), such as transcription factors and the Mediator complex. Although, the transcription factor and Mediator binding is largely unchanged in the context of WAPL and RAD21 depletion, the contact frequency between promoters and enhancers is strongly diminished, emphasizing the importance of cohesin over diffusion mediated interactions.…”

Section: A Role For Loop Extrusion In Gene Regulation?mentioning

confidence: 99%

WAPL maintains dynamic cohesin to preserve lineage specific distal gene regulation

Liu

Maresca

Brand

et al. 2019

Preprint

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HIGHLIGHTS 1. The cohesin release factor WAPL is crucial for maintaining a pluripotency-specific phenotype.2. Dynamic cohesin is enriched at lineage specific loci and overlaps with binding sites of pluripotency transcription factors.3. Expression of lineage specific genes is maintained by dynamic cohesin binding through the formation of promoter-enhancer associated self-interaction domains.4. CTCF-independent cohesin binding to chromatin is controlled by the pioneer factor OCT4. SUMMARYThe cohesin complex plays essential roles in sister chromatin cohesin, chromosome organization and gene expression. The role of cohesin in gene regulation is incompletely understood. Here, we report that the cohesin release factor WAPL is crucial for maintaining a pool of dynamic cohesin bound to regions that are associated with lineage specific genes in mouse embryonic stem cells. These regulatory regions are enriched for active enhancer marks and transcription factor binding sites, but largely devoid of CTCF binding sites. Stabilization of cohesin, which leads to a loss of dynamic cohesin from these regions, does not affect transcription factor binding or active enhancer marks, but does result in changes in promoter-enhancer interactions and downregulation of genes.Acute cohesin depletion can phenocopy the effect of WAPL depletion, showing that cohesin plays a crucial role in maintaining expression of lineage specific genes. The binding of dynamic cohesin to chromatin is dependent on the pluripotency transcription factor OCT4, but not NANOG. Finally, dynamic cohesin binding sites are also found in differentiated cells, suggesting that they represent a general regulatory principle. We propose that cohesin dynamically binding to regulatory sites creates a favorable spatial environment in which promoters and enhancers can communicate to ensure proper gene expression.

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Section: A Role For Loop Extrusion In Gene Regulation?mentioning

confidence: 99%

WAPL maintains dynamic cohesin to preserve lineage specific distal gene regulation

Liu

Maresca

Brand

et al. 2019

Preprint

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“…This topology is dependent on the level of transcription with highly expressed entities (entire community or specific gene within a community) located in the core of the hierarchical 3D organisation and low expressed entities found at the periphery. We hypothesise that the observed communities could represent cell-type specific transcription factories [24, 55-57] or phase-separated foci [58-60] organised following a gradient of transcription with high concentration of nascent transcripts and transcription machinery in the core of the assemblies that create a “sticky” environment to the less expressed peripheral loci. This hierarchical organisation is only marginally present in nCD4 and Mon, suggesting that it also contributes to the cell-type specific 3D signature characterising the β-globin region in cb-Ery.…”

Section: Discussionmentioning

confidence: 99%

3D reconstruction of genomic regions from sparse interaction data

Mendieta-Esteban

Stefano

Castillo

et al. 2020

Preprint

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Chromosome Conformation Capture (3C) technologies measure the interaction frequency between pairs of chromatin regions within the nucleus in a cell or a population of cells. Some of these 3C technologies retrieve interactions involving non-contiguous sets of loci, resulting in sparse interaction matrices. One of such 3C technologies is Promoter Capture Hi-C (pcHi-C) that is tailored to probe only interactions involving gene promoters. As such, pcHi-C provides sparse interaction matrices that are suitable to characterise short- and long-range enhancer-promoter interactions. Here, we introduce a new method to reconstruct the chromatin structural (3D) organisation from sparse 3C-based datasets such as pcHi-C. Our method allows for data normalisation, detection of significant interactions, and reconstruction of the full 3D organisation of the genomic region despite of the data sparseness. Specifically, it produces reliable reconstructions, in line with the ones obtained from dense interaction matrices, with as low as the 2-3% of the data from the matrix. Furthermore, the method is sensitive enough to detect cell-type-specific 3D organisational features such as the formation of different networks of active gene communities.

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“…Being brought to spatial proximity, liquid compartments associated with an enhancer and a promoter fuse, giving rise to a common compartment rich in proteins necessary for effective transcription initiation ( Figure 3 ) [ 107 , 116 ]. Of note, this system allows for the assembly of various multicomponent complexes containing several enhancers and promoters.…”

Section: Regulation Of Gene Expressionmentioning

confidence: 99%

Divide and Rule: Phase Separation in Eukaryotic Genome Functioning

Razin

Ulianov

2020

Cells

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The functioning of a cell at various organizational levels is determined by the interactions between macromolecules that promote cellular organelle formation and orchestrate metabolic pathways via the control of enzymatic activities. Although highly specific and relatively stable protein-protein, protein-DNA, and protein-RNA interactions are traditionally suggested as the drivers for cellular function realization, recent advances in the discovery of weak multivalent interactions have uncovered the role of so-called macromolecule condensates. These structures, which are highly divergent in size, composition, function, and cellular localization are predominantly formed by liquid-liquid phase separation (LLPS): a physical-chemical process where an initially homogenous solution turns into two distinct phases, one of which contains the major portion of the dissolved macromolecules and the other one containing the solvent. In a living cell, LLPS drives the formation of membrane-less organelles such as the nucleolus, nuclear bodies, and viral replication factories and facilitates the assembly of complex macromolecule aggregates possessing regulatory, structural, and enzymatic functions. Here, we discuss the role of LLPS in the spatial organization of eukaryotic chromatin and regulation of gene expression in normal and pathological conditions.

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Phase Separation and Transcription Regulation: Are Super‐Enhancers and Locus Control Regions Primary Sites of Transcription Complex Assembly?

Cited by 42 publications

References 86 publications

WAPL maintains dynamic cohesin to preserve lineage specific distal gene regulation

WAPL maintains dynamic cohesin to preserve lineage specific distal gene regulation

3D reconstruction of genomic regions from sparse interaction data

Divide and Rule: Phase Separation in Eukaryotic Genome Functioning

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