Transcription factor binding kinetics and transcriptional bursting: What do we really know?

Mazzocca, Matteo; Colombo, Emanuele; Callegari, A.; Mazza, Davide

doi:10.1016/j.sbi.2021.08.002

Cited by 36 publications

(30 citation statements)

References 78 publications

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“…We would note here that the fast value of the diffusion coefficient observed with FCS is not experimentally accessible with our FRAP device. A possible interpretation of these two kinetic timescales observed with FRAP experiments would be that the fast residence time corresponds to GAF non-specific binding as observed previously 7 , while the long-lived residence time would correspond to sequence-specific binding to its consensus binding sites. Interestingly, similar GAF kinetics were very recently observed in larval hemocytes 44 .…”

Section: Resultsmentioning

confidence: 58%

“…We propose that the function of GAF as a mitotic bookmarker is possible because GAF has the intrinsic property to remain bound to chromatin for long periods (residence time in the order of minute). This long engagement of GAF to DNA is in sharp contrast with the binding kinetics of many other TF, such as Zelda or Bicoid in Drosophila embryos 31 , 45 or pluripotency TF in mouse ES cells 7 , 69 . Another particularity of GAF binding, contrasting with other TF, resides in the multimerization of its DNA-binding sites as GAGAG repeats in a subset of its targets (76% of mitotically retained peaks display four or more repetitions of GAGAG motifs).…”

Section: Discussionmentioning

confidence: 77%

“…Based on live imaging studies and genome-wide profiling experiments on drug-synchronized mitotic cells, it is now well established that a subset of transcription factors (TF), chromatin regulators, and histone modifications are retained on their targets during mitosis 2 , 4 , 5 . These TFs can be retained via specific DNA binding, non-specific DNA binding, or a combination of both 5 – 7 .…”

Section: Introductionmentioning

confidence: 99%

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The control of transcriptional memory by stable mitotic bookmarking

et al. 2022

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To maintain cellular identities during development, gene expression profiles must be faithfully propagated through cell generations. The reestablishment of gene expression patterns upon mitotic exit is mediated, in part, by transcription factors (TF) mitotic bookmarking. However, the mechanisms and functions of TF mitotic bookmarking during early embryogenesis remain poorly understood. In this study, taking advantage of the naturally synchronized mitoses of Drosophila early embryos, we provide evidence that GAGA pioneer factor (GAF) acts as a stable mitotic bookmarker during zygotic genome activation. We show that, during mitosis, GAF remains associated to a large fraction of its interphase targets, including at cis-regulatory sequences of key developmental genes with both active and repressive chromatin signatures. GAF mitotic targets are globally accessible during mitosis and are bookmarked via histone acetylation (H4K8ac). By monitoring the kinetics of transcriptional activation in living embryos, we report that GAF binding establishes competence for rapid activation upon mitotic exit.

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Section: Resultsmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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The control of transcriptional memory by stable mitotic bookmarking

et al. 2022

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“…The observed differences in protein accessibility to DNA dense nuclear regions did not appear to be caused by size-exclusion effects, as no correlation between protein molecular weight and enrichment in higher DNA classes was observed ( Figure 1E ). Rather, the tendency of NFs to localize in DNA dense region is correlated to their ability to bind chromatin, as measured by the fraction of bound molecules (Mazzocca et al, 2021b). This suggests that the different localization of the tested NFs might be driven by interactions with scaffolds, such as chromatin itself ( Figure 1F ).…”

Section: Resultsmentioning

confidence: 99%

Chromatin organization drives the exploration strategy of nuclear factors

Mazzocca

Loffreda

Colombo

et al. 2022

Preprint

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Nuclear Factors (NFs) rapidly scan the genome for their targets, but the role of nuclear organization in such search is unexplored. To address this, we combined live-cell single-molecule tracking of NFs with multifocal structured illumination of DNA density and characterized the exploration strategy of multiple NFs, including the tumor suppressor p53. p53 alternates between rapid diffusion in the interchromatin compartment (IC) and compact sampling of chromatin dense regions (CDs). This slowed down diffusion - mediated by p53 intrinsically disordered regions (IDRs) - directs p53 to its binding sites in CDs surrounded by IC channels. Efficient targeting requires balanced IDR/chromatin interactions: strong IDRs potentiate target gene activation, but excessive IDR/IDR interactions lead to p53 condensates, derailing its search and downregulating transcription. Our findings highlight the role of NF IDRs on their search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus and dissect how nuclear organization guides NFs action.

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“…For example, the availability and activities of transcription factors influence the recruitment of RNA polymerases to promoters, affecting the initiation of transcription (Mazzocca et al, 2021;Mejia-Almonte et al, 2020). The interactions between RNA polymerases queuing along the DNA template also contribute to "bursty" transcription (Fujita et al, 2016;Tripathi et al, 2022).…”

Section: Tr An Scrip Ti On Is Not Always a S Mooth Pro Ce Ssmentioning

confidence: 99%

VariableDNAtopology is an epigenetic generator of physiological heterogeneity in bacterial populations

Dorman

2022

Molecular Microbiology

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In 1902, Almroth Wright, an Irish-Swedish bacteriologist who had trained in medicine at Trinity College Dublin (TCD), founded the Bacteriology Department at St. Mary's Hospital in London. In 1912, Wright's department provided training in bacteriology for Adrian Stokes, another medical student from TCD, who would become that university's first Professor of Bacteriology and Preventive Medicine in 1919in (Coakley, 1992. Stokes' successor in the TCD chair was Joseph Warwick Bigger, the person who described the phenomenon of "persisters" in bacterial populations (Bigger, 1944). It is believed that Alexander Fleming, working in Wright's department at St. Mary's, was attempting to repeat Bigger's experiments on small colony variants of Staphylococcus aureus (Bigger et al., 1927), when he made the breakthrough in 1928 that led to the discovery of penicillin (Greenwood, 2008). These events illustrate the interconnectedness of institutions, individuals, and ideas in the development of scientific thought.Persisters are bacterial cells that have become non-susceptible to antimicrobial treatment without becoming resistant (Balaban et al., 2019;Bigger, 1944). They are phenotypic outliers with an environment-specific enhanced survival trait, and they arise stochastically in a population of otherwise antimicrobial-susceptible

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Transcription factor binding kinetics and transcriptional bursting: What do we really know?

Cited by 36 publications

References 78 publications

The control of transcriptional memory by stable mitotic bookmarking

The control of transcriptional memory by stable mitotic bookmarking

Chromatin organization drives the exploration strategy of nuclear factors

VariableDNAtopology is an epigenetic generator of physiological heterogeneity in bacterial populations

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