Modelling chromosome-wide target search

TL;DR

This study introduces a cross-scale computational model integrating DNA diffusion and chromosome-wide interactions to understand how 3D genome structure influences transcription factor target search efficiency.

Contribution

We developed a novel multi-scale model combining facilitated diffusion and chromosome-wide network analysis, revealing the impact of 3D genome architecture on search times.

Findings

Median search times depend on network metrics combining node strength and dissociation rates.

Certain 3D configurations significantly accelerate or slow down target search compared to random models.

Chromosome structure influences transcription factor targeting efficiency.

Abstract

The most common gene regulation mechanism is when a transcription factor protein binds to a regulatory sequence to increase or decrease RNA transcription. However, transcription factors face two main challenges when searching for these sequences. First, they are vanishingly short relative to the genome length. Second, many nearly identical sequences are 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 transcription factors. 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 transcription factors to relevant DNA regions.