Modelling chromosome-wide target search

Abstract

The most common gene regulation mechanism is when a transcription factor (TF) protein binds to a regulatory sequence to increase or decrease RNA transcription. However, TFs face two main challenges when searching for these sequences. First, the sequences are vanishingly short relative to the genome length. Second, there are many nearly identical sequences scattered across the genome, causing proteins to suspend the search. But as pointed out in a computational study of LacI regulation in Escherichia coli, such almost-targets may lower search times if considering DNA looping. In this paper, we explore if this also occurs over chromosome-wide distances. To this end, we developed a cross-scale computational framework that combines established facilitated-diffusion models for basepair-level search and a network model capturing chromosome-wide leaps. To make our model realistic, we used Hi-C data sets as a proxy for 3D proximity between long-ranged DNA segments and binding profiles for more than 100 TFs. Using our cross-scale model, we found that median search times to individual targets critically depend on a network metric combining node strength (sum of link weights) and local dissociation rates. Also, by randomizing these rates, we found that some actual 3D target configurations stand out as considerably faster or slower than their random counterparts. This finding hints that chromosomes’ 3D structure funnels essential TFs to relevant DNA regions.