Spatiotemporal coordination of transcription preinitiation complex assembly in live cells

Nguyen, Vu Q.; Ranjan, Anand; Liu, Sheng; Tang, Xiaona; Ling, Yick Hin; Wiśniewski, Jan; Mizuguchi, Gaku; Li, Kai Yu; Jou, Vivian; Zheng, Qinsi; Lavis, Luke D.; Lionnet, Timothée; Wu, Carl

doi:10.1016/j.molcel.2021.07.022

Cited by 77 publications

(81 citation statements)

References 104 publications

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“…4c, d ). Regulatory processes at the interface between enhancers and promoters have been estimated to occur in the order of tens of seconds 41 , 43 , 46 , consistent with the condition that intermediate regulatory steps should be faster than bursting kinetics (Fig. 3f ).…”

Section: Mechanistic Model Of Enhancer Regulationsupporting

confidence: 63%

“…Enhancer–promoter contacts are stochastic 32 , 37 , 38 and probably dynamic 39 in single cells. Molecular processes that are thought to transmit regulatory information from enhancers to promoters (such as recruitment of transcription factors and coactivators, assembly of the Mediator complex 40 ), as well as those that are associated with promoter operation itself (such as pre-initiation complex assembly, RNA polymerase II pausing and release 41 , 42 ) are also stochastic and dynamic 43 . We reasoned that the interplay between the timescales of these processes might generate nonlinear effects, as was recently hypothesized to explain promoter bursting 44 .…”

Section: Mechanistic Model Of Enhancer Regulationmentioning

confidence: 99%

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Nonlinear control of transcription through enhancer–promoter interactions

Zuin

Roth

Zhan

et al. 2022

Nature

247

166

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Chromosome structure in mammals is thought to regulate transcription by modulating three-dimensional interactions between enhancers and promoters, notably through CTCF-mediated loops and topologically associating domains (TADs)1–4. However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. Here, to address this question, we use an assay to position an enhancer at large numbers of densely spaced chromosomal locations relative to a fixed promoter, and measure promoter output and interactions within a genomic region with minimal regulatory and structural complexity. A quantitative analysis of hundreds of cell lines reveals that the transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship. Mathematical modelling suggests that nonlinearity might arise from transient enhancer–promoter interactions being translated into slower promoter bursting dynamics in individual cells, therefore uncoupling the temporal dynamics of interactions from those of transcription. This uncovers a potential mechanism of how distal enhancers act from large genomic distances, and of how topologically associating domain boundaries block distal enhancers. Finally, we show that enhancer strength also determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation. Our measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation.

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Section: Mechanistic Model Of Enhancer Regulationsupporting

confidence: 63%

Section: Mechanistic Model Of Enhancer Regulationmentioning

confidence: 99%

Nonlinear control of transcription through enhancer–promoter interactions

Zuin

Roth

Zhan

et al. 2022

Nature

247

166

View full text Add to dashboard Cite

show abstract

“…However, activator proteins at most distal enhancers do not stably recruit Mediator, even though they are able to recruit multiple chromatin-modifying activities. In contrast, yeast activators can efficiently recruit Mediator to enhancers even when PIC formation and transcription is blocked ( Knoll et al, 2018 ; Nguyen et al, 2021 ). These considerations suggest that most mammalian enhancer regions lack an efficient promoter that permits a stable PIC containing Mediator.…”

Section: Discussionmentioning

confidence: 99%

Comparison of transcriptional initiation by RNA polymerase II across eukaryotic species

Petrenko

Struhl

2021

eLife

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The preinitation complex (PIC) for transcriptional initiation by RNA polymerase (Pol) II is composed of general transcription factors that are highly conserved. However, analysis of ChIP-seq datasets reveals kinetic and compositional differences in the transcriptional initiation process among eukaryotic species. In yeast, Mediator associates strongly with activator proteins bound to enhancers, but it transiently associates with promoters in a form that lacks the kinase module. In contrast, in human, mouse, and fly cells, Mediator with its kinase module stably associates with promoters, but not with activator-binding sites. This suggests that yeast and metazoans differ in the nature of the dynamic bridge of Mediator between activators and Pol II and the composition of a stable inactive PIC-like entity. As in yeast, occupancies of TBP and associated factors (Tafs) at mammalian promoters are not strictly correlated. This suggests that within PICs, TFIID is not a monolithic entity, and multiple forms of TBP affect initiation at different classes of genes. TFIID in flies, but not yeast and mammals, interacts strongly at regions downstream of the initiation site, consistent with the importance of downstream promoter elements in that species. Lastly, Taf7 and the mammalian-specific Med26 subunit of Mediator also interact near the Pol II pause region downstream of the PIC, but only in subsets of genes and often not together. Species-specific differences in PIC structure and function are likely to affect how activators and repressors affect transcriptional activity.

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“…To determine rs, we considered two scenarios underlying detection of binding events during slow tracking 72 . Blinking-limited ( r s,bl .…”

Section: Methodsmentioning

confidence: 99%

“…The steady-state open chromatin landscape at promoters and enhancers featuring nucleosomedepleted regions genome-wide 45,65,66 belies highly dynamic interactions with transcription and chromatin factors [67][68][69][70][71][72] . The establishment and maintenance of chromatin accessibility, i.e.…”

Section: Constitutively High Temporal Occupancy Defines Pioneering Activitymentioning

confidence: 99%

Kinetic principles underlying pioneer function of GAGA transcription factor in live cells

Tang

et al. 2021

Preprint

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How pioneer factors interface with chromatin to promote accessibility for transcription control is poorly understood in vivo. Here, we directly visualize chromatin association by the prototypical GAGA pioneer factor (GAF) in live Drosophila hemocytes. Single-particle tracking reveals that the majority of GAF is chromatin-bound, with a stable-binding fraction showing nucleosome-like confinement residing on chromatin for over 2 minutes, far longer than the dynamic range of most transcription factors. These kinetic properties require the full complement of GAF's DNA-binding, multimerization and intrinsically disordered domains, and are autonomous from recruited chromatin remodelers NURF and PBAP, whose activities primarily benefit GAF's neighbors such as HSF. Evaluation of GAF kinetics together with its endogenous abundance indicates that despite on-off dynamics, GAF constitutively and fully occupies chromatin targets, thereby providing a temporal mechanism that sustains open chromatin for transcriptional responses to homeostatic, environmental, and developmental signals.

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Spatiotemporal coordination of transcription preinitiation complex assembly in live cells

Cited by 77 publications

References 104 publications

Nonlinear control of transcription through enhancer–promoter interactions

Nonlinear control of transcription through enhancer–promoter interactions

Comparison of transcriptional initiation by RNA polymerase II across eukaryotic species

Kinetic principles underlying pioneer function of GAGA transcription factor in live cells

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