Transcription factor search for a DNA promoter in a three-states model

TL;DR

This paper models the facilitated diffusion process of transcription factors searching for DNA promoters, revealing a three-state mechanism that enhances search efficiency and regulatory control.

Contribution

It introduces a new three-state model for TF search dynamics, deriving a formula for mean search time and showing improved speed and regulation potential.

Findings

Search time is faster and less sensitive to binding energy fluctuations.

Optimal search involves longer DNA binding times than 3D diffusion.

Modifying switching states can regulate transcription efficiently.

Abstract

To ensure fast gene activation, Transcription Factors (TF) use a mechanism known as facilitated diffusion to find their DNA promoter site. Here we analyze such a process where a TF alternates between 3D and 1D diffusion. In the latter (TF bound to the DNA), the TF further switches between a fast translocation state dominated by interaction with the DNA backbone, and a slow examination state where interaction with DNA base pairs is predominant. We derive a new formula for the mean search time, and show that it is faster and less sensitive to the binding energy fluctuations compared to the case of a single sliding state. We find that for an optimal search, the time spent bound to the DNA is larger compared to the 3D time in the nucleus, in agreement with recent experimental data. Our results further suggest that modifying switching via phosphorylation or methylation of the TF or the DNA can efficiently regulate transcription.