Allostery through DNA drives phenotype switching

Rosenblum, Gabriel; Elad, Nadav; Rozenberg, Haim; Wiggers, Felix; Hofmann, Hagen

doi:10.1101/2020.07.04.187450

Cited by 7 publications

(11 citation statements)

References 48 publications

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“…A more common phenomenon is that of proximal allostery, which involves the binding of small molecules in the DNA minor groove altering the corresponding major groove binding site affinity for a protein (see for example the discussion in [48] and [49]). Our analysis indicates that, within linear elasticity, distal allostery is rather modest as compared to the distal effects seen in these experiments [46,47]. This short perturbation range was obtained from the average elastic behavior of the considered sequences.…”

Section: Local Perturbationsmentioning

confidence: 48%

“…For the analyzed models we find that the effect is rather modest, with the perturbation involving just three flanking sites. Experiments analyzing DNA-proteins interactions have highlighted a few cases of distal allosteric effects [46,47], where the binding of a protein at a given site increases the binding affinity to a second protein. This distance is of about 15−20 nucleotides.…”

Section: Local Perturbationsmentioning

confidence: 99%

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Length-scale-dependent elasticity in DNA from coarse-grained and all-atom models

et al. 2021

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We investigate the influence of non-local couplings on the torsional and bending elasticities of DNA. Such couplings have been observed in the past by several simulation studies. Here, we use a description of DNA conformations based on the variables tilt, roll and twist. Our analysis of both coarse-grained (oxDNA) and all-atom models indicates that these share strikingly similar features: there are strong off-site couplings for tilt-tilt and twist-twist, while they are much weaker in the roll-roll case. By developing an analytical framework to estimate bending and torsional persistence lengths in non-local DNA models, we show how off-site interactions generate a length scale dependent elasticity. Based on the simulation generated elasticity data the theory predicts a significant length scale dependent effect on torsional fluctuations, but only a modest effect on bending fluctuations. These results are in agreement with experiments probing DNA mechanics from single base pair to kilobase pair scales.

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Section: Local Perturbationsmentioning

confidence: 48%

Section: Local Perturbationsmentioning

confidence: 99%

Length-scale-dependent elasticity in DNA from coarse-grained and all-atom models

et al. 2021

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“…The ability to distinguish and quantify the different modes of regulation (stabilization and acceleration) and characterize TFs based on them is important for developing general theories of regulation that include multiple TFs that act on different kinetic steps of the transcription process ( Scholes et al, 2017 ; Martinez-Corral et al, 2020 ; Wong and Gunawardena, 2020 ); predictions for the combined regulatory effect of two stabilizing TFs should be different than predictions for a stabilizing TF acting together with an accelerating TF ( Scholes et al, 2017 ). With each characterized TF, we can develop an empirical baseline or null hypothesis for what a TF should do on a gene; departures from this expectation, because of emergence of complex regulatory phenomenon brought about by TF-TF interactions ( Weingarten-Gabbay and Segal, 2014 ), allosteric interactions ( Rosenblum et al, 2020 ; Kim et al, 2013 ), or other effects indicate surprises that warrant testing in these expanded models.…”

Section: Discussionmentioning

confidence: 99%

Quantifying the regulatory role of individual transcription factors in Escherichia coli

et al. 2021

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SUMMARY Gene regulation often results from the action of multiple transcription factors (TFs) acting at a promoter, obscuring the individual regulatory effect of each TF on RNA polymerase (RNAP). Here we measure the fundamental regulatory interactions of TFs in E. coli by designing synthetic target genes that isolate individual TFs’ regulatory effects. Using a thermodynamic model, each TF’s regulatory interactions are decoupled from TF occupancy and interpreted as acting through (de)stabilization of RNAP and (de)acceleration of transcription initiation. We find that the contribution of each mechanism depends on TF identity and binding location; regulation immediately downstream of the promoter is insensitive to TF identity, but the same TFs regulate by distinct mechanisms upstream of the promoter. These two mechanisms are uncoupled and can act coherently, to reinforce the observed regulatory role (activation/repression), or incoherently, wherein the TF regulates two distinct steps with opposing effects.

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“…denotes the adjoint matrix. Combining (42) and (43) and performing the inverse Fourier transform we obtain…”

Section: Local Perturbationsmentioning

confidence: 99%

Length scale dependent elasticity in DNA from coarse-grained and all-atom models

Skoruppa,

Voorspoels,

Vreede

et al. 2020

Preprint

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The mechanical properties of DNA are typically described by elastic theories with purely local couplings (on-site models). We discuss and analyze coarse-grained (oxDNA) and all-atom simulations, which indicate that in DNA distal sites are coupled. Hence, off-site models provide a more realistic description of the mechanics of the double helix. We show that off-site interactions are responsible for a length scale dependence of the elasticity, and we develop an analytical framework to estimate bending and torsional persistence lengths in models including these interactions. Our simulations indicate that off-site couplings are particularly strong for certain degrees of freedom, while they are very weak for others. If stiffness parameters obtained from DNA data are used, the theory predicts large length scale dependent effects for torsional fluctuations and a modest effect in bending fluctuations, which is in agreement with experiments.

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Allostery through DNA drives phenotype switching

Cited by 7 publications

References 48 publications

Length-scale-dependent elasticity in DNA from coarse-grained and all-atom models

Length-scale-dependent elasticity in DNA from coarse-grained and all-atom models

Quantifying the regulatory role of individual transcription factors in Escherichia coli

Length scale dependent elasticity in DNA from coarse-grained and all-atom models

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