An integrated model of transcription factor diffusion shows the importance of intersegmental transfer and quaternary protein structure for target site finding.

Hugo G Schmidt,Sven Sewitz,Karen Lipkow,Steven S Andrews,Attila Csikász-Nagy

doi:10.1371/journal.pone.0108575

Hugo G Schmidt, Sven Sewitz + Show 3 more

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https://doi.org/10.1371/journal.pone.0108575

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Abstract

We present a computational model of transcription factor motion that explains both the observed rapid target finding of transcription factors, and how this motion influences protein and genome structure. Using the Smoldyn software, we modelled transcription factor motion arising from a combination of unrestricted 3D diffusion in the nucleoplasm, sliding along the DNA filament, and transferring directly between filament sections by intersegmental transfer. This presents a fine-grain picture of the way in which transcription factors find their targets two orders of magnitude faster than 3D diffusion alone allows. Eukaryotic genomes contain sections of nucleosome free regions (NFRs) around the promoters; our model shows that the presence and size of these NFRs can be explained as their acting as antennas on which transcription factors slide to reach their targets. Additionally, our model shows that intersegmental transfer may have shaped the quaternary structure of transcription factors: sequence specific DNA binding proteins are unusually enriched in dimers and tetramers, perhaps because these allow intersegmental transfer, which accelerates target site finding. Finally, our model shows that a ‘hopping’ motion can emerge from 3D diffusion on small scales. This explains the apparently long sliding lengths that have been observed for some DNA binding proteins observed in vitro. Together, these results suggest that transcription factor diffusion dynamics help drive the evolution of protein and genome structure.

Highlights

Control of gene regulation and cellular development relies on the ability of transcription factors (TFs), a subset of the sequencespecific DNA binding proteins, to activate or repress selected genes in response to internal cues or changes in the environment
We investigated this effect by placing 20 target gene (TG) at the centres of 20 DNA segments and starting 50 TFs at random locations in the 3D nuclear volume (Figure 3A)
Longer antennas conferred minimal additional advantage toward forming TG-TF complexes, which arose from the increasing likelihood of TF dissociation from the DNA

Summary

Introduction

Control of gene regulation and cellular development relies on the ability of transcription factors (TFs), a subset of the sequencespecific DNA binding proteins (ssDBP), to activate or repress selected genes in response to internal cues or changes in the environment. To perform their function, TFs must first reach relatively small regulatory sequences within much larger genomes. Recent DNA-DNA contact maps show that chromatin is segregated into territories, in which DNA loci mainly contact regions on the same chromosome Examples of such organisation are a fractal globular arrangement [3] and multiple solenoidal structures [2] within the nucleus, depending on the species

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