A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers

Khattabi, Laïla El; Zhao, Haiyan; Kalchschmidt, Jens; Young, Natalie; Jung, Seolkyoung; Blerkom, Peter Van; Kieffer-Kwon, Philippe; Kieffer-Kwon, Kyong-Rim; Park, Solji; Wang, Xiang; Krebs, Jordan; Tripathi, Subhash; Sakabe, Noboru Jo; Sobreira, Débora R.; Huang, Shaoming; Rao, Suhas S.P.; Pruett, Nathanael; Chauss, Daniel; Sadler, Erica; López, Andrea; Nóbrega, Marcelo A.; Aiden, E; Asturias, Francisco J.; Casellas, Rafael

doi:10.1016/j.cell.2019.07.011

Cited by 198 publications

(267 citation statements)

References 99 publications

(102 reference statements)

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“…Our data demonstrate that these low affinity interactions are not necessary for the maintenance of enhancerpromoter contacts, as reduction of BRD4 chromatin binding had no effect on promoter interaction profiles. A similar lack of effects was recently observed, albeit at lower resolution by Hi-C, in Mediator mutant mouse embryonic stem cells (mESCs) 21 . Importantly, the high resolution and sensitivity of Capture-C confirms the lack of even subtle changes in enhancer-promoter contacts in our experiments, for example localized to BRD4 binding sites.…”

Section: Discussionsupporting

confidence: 78%

“…Whilst the loop extrusion model is widely accepted in the maintenance of higher order domain structure, a function at enhancers is less clear 67 . Depletion of cohesin or its loader NIPBL disrupts interactions between promoters and distal enhancers 21,72,73 , although this may be an indirect effect through loss of TAD boundaries rather than physical contact with enhancers. As has been reported 23 , in our analysis we observed an enrichment for CTCF/RAD21 binding at promoter-interacting loci, consistent with a direct role for loop extrusion in mediating enhancer-promoter interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Whilst loop extrusion mediated by CTCF and cohesin is the most common explanation for controlling large scale chromatin structure, less is known about what stabilizes more localized enhancer-promoter loops. Possible models include CTCF/cohesin-stabilized enhancer-promoter interactions [21][22][23] and protein/RNA complexes bound to both the enhancer and promoter that interact with one another [24][25][26] . Binding of these complexes is likely initiated by key sequencespecific TFs.…”

Section: Next Generationmentioning

confidence: 99%

“…In SEM cells, CTCF and RAD21 show a strong positive correlation at ATAC peaks (Fig 1b), suggesting that all or most of these CTCF binding sites are competent to enrich or stabilize RAD21 association with chromatin. It is unclear whether loop extrusion may contribute to the increased local interactions between promoters and enhancers, although recent work has suggested this possibility 21,22 . In support of this idea, CTCF and RAD21…”

Section: Cohesin/ctcf Binding Patterns Support a Role In Mediating A mentioning

confidence: 99%

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BET inhibition disrupts transcription but retains enhancer-promoter contact

Crump

Ballabio

Godfrey

et al. 2019

Preprint

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In higher eukaryotes, enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. The formation of phase condensates is thought to be an essential component of enhancer function. Here, we show that pharmacological targeting of cells with inhibitors of BET (Bromodomain and Extra-Terminal domain) proteins can have a strong impact on transcription but very little impact on enhancer-promoter interactions. Treatment with 1,6-hexanediol, which dissolves phase condensate structures and reduces BET and Mediator protein binding at enhancers, can also have a strong effect on gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancerpromoter interactions are separable events. Our findings further suggest that enhancer-promoter interactions are not dependent on high levels of BRD4 (Bromodomain-containing protein 4) and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and loop extrusion by CTCF/cohesin.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Next Generationmentioning

confidence: 99%

Section: Cohesin/ctcf Binding Patterns Support a Role In Mediating A mentioning

confidence: 99%

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BET inhibition disrupts transcription but retains enhancer-promoter contact

Crump

Ballabio

Godfrey

et al. 2019

Preprint

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“…The unchanged phenotype after transcription inhibition in mammalian cells is usually based on aggregate analyses of all chromatin loops [17,18,[21][22][23]. It is hard to evaluate the contribution of transcription, as CTCF and Cohesin play a predominant role in the 3D chromatin landscape, and they occupy most of the loops in mammalian cells [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide analyses of chromatin interactions after the loss of Pol I, Pol II and Pol III

Jiang

Huang

lun

et al. 2020

Preprint

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Background:The relationship between transcription and the 3D genome organization is one of the most important questions in molecular biology, but the roles of transcription in 3D chromatin remain controversial. Multiple groups showed that transcription affects global Cohesin binding and genome 3D structures. At the same time, several studies have indicated that transcription inhibition does not affect global chromatin interactions.Results: Here, we provide the most comprehensive evidence to date to demonstrate that transcription plays a marginal role in organizing the 3D genome in mammalian cells: 1) degraded Pol I, Pol II and Pol III proteins in mESCs, and showed their loss results in little or no changes of global 3D chromatin structures for the first time; 2) selected RNA polymerases high abundance binding sitesassociated interactions and found they still persist after the degradation; 3) generated higher resolution chromatin interaction maps and revealed that transcription inhibition mildly alters small loop domains; 4) identified Pol II bound but CTCF and Cohesin unbound loops and disclosed that they are largely resistant to transcription inhibition. Interestingly, Pol II depletion for a longer time significantly affects the chromatin accessibility and Cohesin occupancy, suggesting RNA polymerases are capable of affecting the 3D genome indirectly.So, the direct and indirect effects of transcription inhibition explain the previous confusing effects on the 3D genome. Conclusions:We conclude that Pol I, Pol II, and Pol III loss only mildly alter chromatin interactions in mammalian cells, suggesting the 3D chromatin structures are pre-established and relatively stable.

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MED12 interacts with the heat‐shock transcription factor HSF1 and recruits CDK8 to promote the heat‐shock response in mammalian cells

et al. 2021

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Activated and promoter-bound heat-shock transcription factor 1 (HSF1) induces RNA polymerase II recruitment upon heat shock, and this is facilitated by the core Mediator in Drosophila and yeast. Another Mediator module, CDK8 kinase module (CKM), consisting of four subunits including MED12 and CDK8, plays a negative or positive role in the regulation of transcription; however, its involvement in HSF1-mediated transcription remains unclear. We herein demonstrated that HSF1 interacted with MED12 and recruited MED12 and CDK8 to the HSP70 promoter during heat shock in mammalian cells. The kinase activity of CDK8 (and its paralog CDK19) promoted HSP70 expression partly by phosphorylating HSF1-S326 and maintained proteostasis capacity. These results indicate an important role for CKM in the protection of cells against proteotoxic stress.

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A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers

Cited by 198 publications

References 99 publications

BET inhibition disrupts transcription but retains enhancer-promoter contact

BET inhibition disrupts transcription but retains enhancer-promoter contact

Genome-wide analyses of chromatin interactions after the loss of Pol I, Pol II and Pol III

MED12 interacts with the heat‐shock transcription factor HSF1 and recruits CDK8 to promote the heat‐shock response in mammalian cells

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