3D genome architecture regulates the traffic of transcription factors throughout human chromosomes.

Abstract

Transcription factors (TFs) are proteins that control the rate of transcription by binding to specific DNA sequences. The time needed for a TF to find its target sites is one of many components contributing to the genetic response mechanism. While TF target site search is a well studied problem, the effect of genome 3D architecture on such process is poorly understood. We use accurate and cell-specific 3D structures of human chromosomes to investigate how the dynamics of TFs is influenced by the spatial organization of binding sites. We use ChIP-Seq data to map the position of binding sites on chromosomal structures and we then simulate the dynamics of individual TF as they move from one binding site to another diffusing throughout chromosomal territories. We find that the distribution of binding sites along chromosomes cooperates with the 3D folding of the chromatin fiber to induce a dynamics in which TF tend to visit sites distributed sequentially along the genome. In this way, genome 3D architecture appears to reduce the time each TF spends in the unbound state while commuting from from one target site to the other. At the same time, genome 3D architecture further reduces the flux of TFs between binding sites that are already well separated along the genome. We compare the TF traffic patterns generated by the 3D structures of human chromosomes with those generated by several alternative structural models characterized by an increasing amount of randomness. Finally, we study the effect of lengthwise compaction and phase separation, known architectural features of the human genome, in TF target search. In short, our analysis demonstrates that genome architecture regulates the traffic of TF within chromosomal territories and reduces the time each TF spends commuting between binding sites.