This guest post is by Radu Zabet on his papers “The effects of transcription factor competition on gene regulation” and “The influence of transcription factor competition on the relationship between occupancy and affinity”
Transcription factors (TFs) find their genomic target sites by a combination of three-dimensional diffusion and one-dimensional translocation on the DNA. We previously developed the stochastic simulation framework GRiP (http://logic.sysbiol.cam.ac.uk/grip/) that allows the realistic representation of the target finding process. The following two papers show our application of GRiP to address a few interesting phenomena:
The effects of transcription factor competition on gene regulation
The binding of site-specific TFs to their genomic target sites controls the transcription rate of the target genes. In this manuscript, we discuss the influence of TF abundance on the arrival time of TFs on their target sites as well as the time they stay bound to the DNA. We investigate the TF search process using stochastic simulations and found that molecular crowding on the DNA always leads to longer times required by TF molecules to locate their target sites as well as to lower occupancy. There is also an “emergent property” in cases where many molecules compete in some sort of molecular traffic jam on the DNA. This newly identified noise component may be a contributor to transcriptional noise, by affecting both the size of the fluctuations and the distribution of the arrival times (unimodal or bimodal).
The influence of transcription factor competition on the relationship between occupancy and affinity
This manuscript deals with the discrepancy between “predicted occupancy” of a TF to a binding site on the basis of, say, a PWM, in contrast to a “measured occupancy” when we simulate the system with our GRiP framework. Again, we can show that absolute TF abundances play an important role in gene expression, and also provide a compelling case where selecting “the highest peaks” from a ChIP experiment may not necessarily identify the most affine binding sites. Our results showed that for medium and high affinity sites, TF competition does not play a significant role for genomic occupancy except in cases when the abundance of the TF is significantly increased, or when the PWM displays relatively low information content. Nevertheless, for medium and low affinity sites, an increase in TF abundance (for both cognate and non-cognate molecules) leads to an increase in occupancy at several sites.