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Register a new userBubble lifetimes in DNA gene promoters and their mutations affecting transcription
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Relative lifetimes of inherent double stranded DNA openings with lengths up to ten base pairs are presented for different gene promoters and corresponding mutants that either increase or decrease transcriptional activity, in the framework of the Peyrard-Bishop-Dauxois model. Extensive microcanonical simulations are used, with energies corresponding to physiological temperature. The bubble lifetime profiles along the DNA sequences demonstrate a significant reduction of the average lifetime at the mutation sites when the mutated promoter decreases transcription, while a corresponding enhancement of the bubble lifetime is observed in the case of mutations leading to increased transcription. The relative difference of bubble lifetimes between the mutated and the wild type promoters at the position of mutation varies from 20% to more than 30% as the bubble length is decreasing
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We investigate the distribution of bubble lifetimes and bubble lengths in DNA at physiological temperature, by performing extensive molecular dynamics simulations with the Peyrard-Bishop-Dauxois (PBD) model, as well as an extended version (ePBD) having a sequence-dependent stacking interaction, emphasizing the effect of the sequences guanine-cytosine (GC)/adenine-thymine (AT) content on these distributions. For both models we find that base pair-dependent (GC vs AT) thresholds for considering complementary nucleotides to be separated are able to reproduce the observed dependence of the melting temperature on the GC content of the DNA sequence. Using these thresholds for base pair openings, we obtain bubble lifetime distributions for bubbles of lengths up to ten base pairs as the GC content of the sequences is varied, which are accurately fitted with stretched exponential functions. We find that for both models the average bubble lifetime decreases with increasing either the bubble length or the GC content. In addition, the obtained bubble length distributions are also fitted by appropriate stretched exponential functions and our results show that short bubbles have similar likelihoods for any GC content, but longer ones are substantially more likely to occur in AT-rich sequences. We also show that the ePBD model permits more, longer-lived, bubbles than the PBD system.
Much of the complexity observed in gene regulation originates from cooperative protein-DNA binding. While studies of the target search of proteins for their specific binding sites on the DNA have revealed design principles for the quantitative characteristics of protein-DNA interactions, no such principles are known for the cooperative interactions between DNA-binding proteins. We consider a simple theoretical model for two interacting transcription factor (TF) species, searching for and binding to two adjacent target sites hidden in the genomic background. We study the kinetic competition of a dimer search pathway and a monomer search pathway, as well as the steady-state regulation function mediated by the two TFs over a broad range of TF-TF interaction strengths. Using a transcriptional AND-logic as exemplary functional context, we identify the functionally desirable regime for the interaction. We find that both weak and very strong TF-TF interactions are favorable, albeit with different characteristics. However, there is also an unfavorable regime of intermediate interactions where the genetic response is prohibitively slow.
Gene transcription is a stochastic process mostly occurring in bursts. Regulation of transcription arises from the interaction of transcription factors (TFs) with the promoter of the gene. The TFs, such as activators and repressors can interact with the promoter in a competitive or non-competitive way. Some experimental observations suggest that the mean expression and noise strength can be regulated at the transcription level. A Few theories are developed based on these experimental observations. Here we re-establish that experimental results with the help of our exact analytical calculations for a stochastic model with non-competitive transcriptional regulatory architecture and find out some properties of Noise strength (like sub-Poissonian fano factor) and mean expression as we found in a two state model earlier. Along with those aforesaid properties we also observe some anomalous characteristics in noise strength of mRNA and in variance of protein at lower activator concentrations.
There is growing appreciation that gene function is connected to the dynamic structure of the chromosome. Here we explore the interplay between three-dimensional structure and transcriptional activity at the single cell level. We show that inactive loci are spatially more compact than active ones, and that within active loci the enhancer driving transcription is closest to the promoter. On the other hand, even this shortest distance is too long to support direct physical contact between the enhancer-promoter pair when the locus is transcriptionally active. Artificial manipulation of genomic separations between enhancers and the promoter produces changes in physical distance and transcriptional activity, recapitulating the correlation seen in wild-type embryos, but disruption of topological domain boundaries has no effect. Our results suggest a complex interdependence between transcription and the spatial organization of cis-regulatory elements.
The effective DNA-DNA interaction force is calculated by computer simulations with explicit tetravalent counterions and monovalent salt. For overcharged DNA molecules, the interaction force shows a double-minimum structure. The positions and depths of these minima are regulated by the counterion density in the bulk. Using two-dimensional lattice sum and free energy perturbation theories, the coexisting phases for DNA bundles are calculated. A DNA-condensation and redissolution transition and a stable mesocrystal with an intermediate lattice constant for high counterion concentration are obtained.
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