Following the tracks: How transcription factor binding dynamics control transcription

Jonge, Wim J. de; Patel, Heta; Meeussen, Joseph V.W.; Lenstra, Tineke L.

doi:10.1016/j.bpj.2022.03.026

Cited by 29 publications

(18 citation statements)

References 102 publications

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“…Since a cluster located near a promoter locally increases the concentration of Gal4 molecules, we can imagine that, once a Gal4 molecule is released from the DNA, quick rebinding of another Gal4 from the nearby cluster to the DNA may increase the overall time that the promoter is occupied. In addition, self-interactions between the cluster and the bound Gal4 molecules could increase the dwell time of the bound molecule 12,21 . It will be interesting in the future to examine how self-interactions and clustering influence Gal4 binding kinetics at different genes and at the single-molecule level.…”

Section: Self-interactions Facilitate Target Searchmentioning

confidence: 99%

“…Moreover, an important open question is how clustering influences TFs during the different steps of transcription activation 13,[21][22][23] . Clustering and IDR-mediated interactions have been reported to enhance target search (increasing the DNA binding rate) [24][25][26][27][28] , to increase the local concentration of TFs at the promoter (increasing the DNA binding rate), to stabilize TF binding to DNA (decreasing the rate of TF unbinding) 12 , to enable 3D genomic interactions between target genes 29 and to boost transcription activation through enhanced recruitment of cofactors and polymerase molecules 30,20,16,31,32 .…”

Section: Introductionmentioning

confidence: 99%

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Transcription factor clusters enable target search but do not contribute to target gene activation

Meeussen

Pomp

Brouwer

et al. 2022

Preprint

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Many transcription factors (TFs) localize in nuclear clusters of locally increased concentrations, but how TF clustering is regulated and how it influences gene expression is not well understood. Here, we use quantitative microscopy in living cells to study the regulation and function of clustering of the budding yeast TF Gal4 in its endogenous context. Our results show that Gal4 cluster formation is facilitated by, but does not completely depend on DNA binding and intrinsically disordered regions. Gal4 cluster properties are regulated by the Gal4-inhibitor Gal80 and Gal4 concentration. Moreover, we discover that clustering acts as a double-edged sword: self-interactions aid TF recruitment to target genes, but recruited Gal4 molecules that are not DNA-bound do not contribute to, and may even inhibit, transcription activation. We propose that cells need to balance the different effects of TF clustering on target search and transcription activation to facilitate proper gene expression.

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Section: Self-interactions Facilitate Target Searchmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcription factor clusters enable target search but do not contribute to target gene activation

Meeussen

Pomp

Brouwer

et al. 2022

Preprint

Self Cite

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“…Global systematic analyses are usually focused on direct targets and secondary interactions are ignored, and thus implication of the off-target actions seems to be underestimated. Moreover, TF/DNA interactions depend on multiple cellular parameters, such as the nucleoid environment, and in particular, the cooperativity with other DNA-binding proteins within the regulatory networks ( 62 , 63 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular basis for lethal cross-talk between two unrelated bacterial transcription factors - the regulatory protein of a restriction-modification system and the repressor of a defective prophage

Wiśniewska

Wons

Potrykus

et al. 2022

Nucleic Acids Research

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Bacterial gene expression depends on the efficient functioning of global transcriptional networks, however their interconnectivity and orchestration rely mainly on the action of individual DNA binding proteins called transcription factors (TFs). TFs interact not only with their specific target sites, but also with secondary (off-target) sites, and vary in their promiscuity. It is not clear yet what mechanisms govern the interactions with secondary sites, and how such rewiring affects the overall regulatory network, but this could clearly constrain horizontal gene transfer. Here, we show the molecular mechanism of one such off-target interaction between two unrelated TFs in Escherichia coli: the C regulatory protein of a Type II restriction-modification system, and the RacR repressor of a defective prophage. We reveal that the C protein interferes with RacR repressor expression, resulting in derepression of the toxic YdaT protein. These results also provide novel insights into regulation of the racR-ydaST operon. We mapped the C regulator interaction to a specific off-target site, and also visualized C protein dynamics, revealing intriguing differences in single molecule dynamics in different genetic contexts. Our results demonstrate an apparent example of horizontal gene transfer leading to adventitious TF cross-talk with negative effects on the recipient's viability. More broadly, this study represents an experimentally-accessible model of a regulatory constraint on horizontal gene transfer.

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“…Long-lasting sequence-specific interactions are established between residues in the DNA-binding domain (DBD) and DNA bases within consensus sequence recognition motifs. In addition, TFs engage in non-specific interactions with chromatin, mediated primarily by electrostatic forces that do not rely on specific DNA sequences [13][14][15]. These interactions are thought to facilitate the search for sequencespecific sites.…”

Section: Distinct Forces Mediate Binding Of Tfs To Chromatinmentioning

confidence: 99%

Function and regulation of transcription factors during mitosis-to-G1 transition

2022

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During cell division, drastic cellular changes characteristic of mitosis result in the inactivation of the transcriptional machinery, and global downregulation of transcription. Sequence-specific transcription factors (TFs) have thus been considered mere bystanders, devoid of any regulatory function during mitosis. This view changed significantly in recent years, upon the conclusion that many TFs associate with condensed chromosomes during cell division, even occupying a fraction of their genomic target sites in mitotic chromatin. This finding was at the origin of the concept of mitotic bookmarking by TFs, proposed as a mechanism to propagate gene regulatory information across cell divisions, by facilitating the reactivation of specific bookmarked genes. While the underlying mechanisms and biological significance of this model remain elusive, recent developments in this fast-moving field have cast new light into TF activity during mitosis, beyond a bookmarking role. Here, we start by reviewing the most recent findings on the complex nature of TF–chromatin interactions during mitosis, and on mechanisms that may regulate them. Next, and in light of recent reports describing how transcription is reinitiated in temporally distinct waves during mitosis-to-G1 transition, we explore how TFs may contribute to defining this hierarchical gene expression process. Finally, we discuss how TF activity during mitotic exit may impact the acquisition of cell identity upon cell division, and propose a model that integrates dynamic changes in TF–chromatin interactions during this cell-cycle period, with the execution of cell-fate decisions.

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Following the tracks: How transcription factor binding dynamics control transcription

Cited by 29 publications

References 102 publications

Transcription factor clusters enable target search but do not contribute to target gene activation

Transcription factor clusters enable target search but do not contribute to target gene activation

Molecular basis for lethal cross-talk between two unrelated bacterial transcription factors - the regulatory protein of a restriction-modification system and the repressor of a defective prophage

Function and regulation of transcription factors during mitosis-to-G1 transition

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