Physical Constraints and Functional Characteristics of Transcription Factor-DNA Interaction

Gene expression is controlled primarily by interactions between transcription factor proteins (TFs) and the regulatory DNA sequence, a process that can be captured well by thermodynamic models of regulation. These models, however, neglect regulatory crosstalk: the possibility that non-cognate TFs could initiate transcription, with potentially disastrous effects for the cell. Here we estimate the importance of crosstalk, suggest that its avoidance strongly constrains equilibri...

Hidden Markov Models (HMMs) are a commonly used tool for inference of transcription factor (TF) binding sites from DNA sequence data. We exploit the mathematical equivalence between HMMs for TF binding and the "inverse" statistical mechanics of hard rods in a one-dimensional disordered potential to investigate learning in HMMs. We derive analytic expressions for the Fisher information, a commonly employed measure of confidence in learned parameters, in the biologically releva...

Site-specific transcription factors (TFs) bind to their target sites on the DNA, where they regulate the rate at which genes are transcribed. Bacterial TFs undergo facilitated diffusion (a combination of 3D diffusion around and 1D random walk on the DNA) when searching for their target sites. Using computer simulations of this search process, we show that the organisation of the binding sites, in conjunction with TF copy number and binding site affinity, plays an important ro...

Evolutionary trajectories and phenotypic states available to cell populations are ultimately dictated by intermolecular interactions between DNA, RNA, proteins, and other molecular species. Here we study how evolution of gene regulation in a single-cell eukaryote S. cerevisiae is affected by the interactions between transcription factors (TFs) and their cognate genomic sites. Our study is informed by high-throughput in vitro measurements of TF-DNA binding interactions and by ...

We develop a theoretical framework on the mechanism of combinatorial binding of transcription factors (TFs) with their specific binding sites on DNA. We consider three possible mechanisms viz. monomer, hetero-oligomer and coordinated recruitment pathways. In the monomer pathway, combinatorial TFs search for their targets in an independent manner and the protein-protein interactions among them will be insignificant. The protein-protein interactions are very strong so that the ...

Transcription factors (TFs) are regulatory proteins that bind DNA in promoter regions of the genome and either promote or repress gene expression. Here we predict analytically that enhanced homo-oligonucleotide sequence correlations, such as poly(dA:dT) and poly(dC:dG) tracts, statistically enhance non-specific TF-DNA binding affinity. This prediction is generic and qualitatively independent of microscopic parameters of the model. We show that non-specific TF binding affinity...

The speed of site-specific binding of transcription factor (TFs) proteins with genomic DNA seems to be strongly retarded by the randomly occurring sequence traps. Traps are those DNA sequences sharing significant similarity with the original specific binding sites. It is an intriguing question how the naturally occurring TFs and their specific binding sites are designed to manage the retarding effects of such randomly occurring traps. We develop a simple random walk model on ...

Specific binding of proteins to DNA is one of the most common ways in which gene expression is controlled. Although general rules for the DNA-protein recognition can be derived, the ambiguous and complex nature of this mechanism precludes a simple recognition code, therefore the prediction of DNA target sequences is not straightforward. DNA-protein interactions can be studied using computational methods which can complement the current experimental methods and offer some adva...

The mutation and selection of regulatory DNA sequences is presented as an ideal model system of molecular evolution where genotype, phenotype, and fitness can be explicitly and independently characterized. In this theoretical study, we construct an explicit model for the evolution of regulatory sequences, making use of the known biophysics of the binding of regulatory proteins to DNA sequences, under the assumption that fitness of a sequence depends only on its binding affini...

We develop revised theoretical ideas on the mechanism by which the transcription factor proteins locate their specific binding sites on DNA faster than the three-dimensional (3D) diffusion controlled rate limit. We demonstrate that the 3D-diffusion controlled rate limit can be enhanced when the protein molecule reads several possible binding stretches of the template DNA via one-dimensional (1D) diffusion upon each 3D-diffusion mediated collision or nonspecific binding event....