Transcription factors perform a 2-step search of the nucleus

Staller, Max V.

doi:10.1093/genetics/iyac111

Cited by 22 publications

(18 citation statements)

References 84 publications

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“…Moreover, FRI associates with many regulators of the FLC -locus, including TFs and chromatin modification factors, to control the transcription of FLC ( Choi et al., 2011 ). In addition to chromatin-modification, the association of FRI with TFs also supports the above-mentioned two-step model of TF-interaction and subsequent DNA-target-binding ( Staller, 2022 ), indicating that several processes could overlap and synergize. Furthermore, cell-type-specific chromatin-modeling on a submegabase scale regulates the cell fate of mammalian SCs ( Phillips-Cremins et al., 2013 ), and could similarly influence plant SC fate, e.g., PLT3-dependently in distal root SCs.…”

Section: Discussionsupporting

confidence: 64%

“…The target-promoter will be found by a two-step-process where the IDR first localizes the TF to a broad DNA-region and then the DNA-binding domain finds the precise binding site. This two-step model was further adapted suggesting that the IDRs mediate protein-protein interaction, bringing together several factors that search and bind the target-sites specifically ( Staller, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

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Come together now: Dynamic body-formation of key regulators integrates environmental cues in plant development

2022

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Plants as sessile organisms are constantly exposed to changing environmental conditions, challenging their growth and development. Indeed, not only above-ground organs but also the underground root system must adapt accordingly. Consequently, plants respond to these constraints at a gene-regulatory level to ensure their survival and well-being through key transcriptional regulators involved in different developmental processes. Recently, intrinsically disordered domains within these regulators are emerging as central nodes necessary not only for interactions with other factors but also for their partitioning into biomolecular condensates, so-called bodies, possibly driven by phase separation. Here, we summarize the current knowledge about body-forming transcriptional regulators important for plant development and highlight their functions in a possible environmental context. In this perspective article, we discuss potential mechanisms for the formation of membrane-less bodies as an efficient and dynamic program needed for the adaptation to external cues with a particular focus on the Arabidopsis root. Hereby, we aim to provide a perspective for future research on transcriptional regulators to investigate body formation as an expeditious mechanism of plant-environment interactions.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Come together now: Dynamic body-formation of key regulators integrates environmental cues in plant development

2022

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“…We note that IDR-mediated chromatin engagement could happen either before and after DNA binding. It is possible that these IDR-mediated interactions first locate the TF to a few highly concentrated protein hubs in the vicinity of selected genomic binding sites, and then the TF performs a more localized target search with the DBD to find its motif, as it has been recently proposed ( Jana et al, 2021 ; Darzacq and Tjian, 2022 ; Staller, 2022 ). In this case, whether the TF explores the nucleus alone to join the hubs or explores it as a larger complex containing other TFs/coactivators, IDRs both determine the TF dynamics and significantly improves the TF on-rate.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms governing target search and binding dynamics of hypoxia-inducible factors

Chen

Cattoglio

Dailey

et al. 2022

eLife

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Transcription factors (TFs) are classically attributed a modular construction, containing well-structured sequence specific DNA-binding domains (DBDs) paired with disordered activation domains (ADs) responsible for protein-protein interactions targeting cofactors or the core transcription initiation machinery. However, this simple division of labor model struggles to explain why TFs with identical DNA binding sequence specificity determined in vitro exhibit distinct binding profiles in vivo. The family of Hypoxia-Inducible Factors (HIFs) offer a stark example: aberrantly expressed in several cancer types, HIF-1α and HIF-2α subunit isoforms recognize the same DNA motif in vitro - the hypoxia response element (HRE) - but only share a subset of their target genes in vivo, while eliciting contrasting effects on cancer development and progression under certain circumstances. To probe the mechanisms mediating isoform-specific gene regulation, we used live cell single particle tracking (SPT) to investigate HIF nuclear dynamics and how they change upon genetic perturbation or drug treatment. We found that HIF-α subunits and their dimerization partner HIF-1β exhibit distinct diffusion and binding characteristics that are exquisitely sensitive to concentration and subunit stoichiometry. Using domain-swap variants, mutations, and a HIF-2α specific inhibitor, we found that although the DBD and dimerization domains are important, another main determinant of chromatin binding and diffusion behavior is the AD-containing intrinsically disordered region (IDR). Using Cut&Run and RNA-seq as orthogonal genomic approaches we also confirmed IDR-dependent binding and activation of a specific subset of HIF-target genes. These findings reveal a previously unappreciated role of IDRs in regulating the TF search and binding process that contribute to functional target site selectivity on chromatin.

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“…We envision that once Gal4 molecules are bound to the DNA, their exposed IDRs allow for interaction with additional unbound Gal4 molecules, thereby creating a larger effective target size. Such a mechanism may ensure that the DBD of each Gal4 molecule does not need to probe all DNA sequences to find its binding site, and reduces the search space to areas where other Gal4 molecules have already found their target 13,76 .…”

Section: Self-interactions Facilitate Target Searchmentioning

confidence: 99%

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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Transcription factors perform a 2-step search of the nucleus

Cited by 22 publications

References 84 publications

Come together now: Dynamic body-formation of key regulators integrates environmental cues in plant development

Come together now: Dynamic body-formation of key regulators integrates environmental cues in plant development

Mechanisms governing target search and binding dynamics of hypoxia-inducible factors

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

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