Modelling transcription factors diffusion in 3D using Hi-C data

The influence of the transcription factors (TFs) as a result of their interaction with the genetic material made it subject to a lot of studies. From roles of TFs in shaping the DNA landscape, to their functionality and purpose in cell cycle and identity, these DNA binding molecules can upregulate or downregulate the rate at which transcription occurs. Their main mechanism of functioning is described by their ability to interact to DNA, namely, to find their target site and bind to it. In the search mechanism also known as facilitated diffusion, TFs can float freely (Brownian motion) in the nucleoplasm and can bind to non-specific sites performing one- dimensional walks along the DNA strand. Once bound, TFs can slide, hop, or jump across. Recent technological advancements enabled modelling of facilitated diffusion while accounting for the 3D architectural structure of the DNA and parameterization with actual biological data using high-resolution (sub-kilobase) measurements of 3D contacts. In this research, the influence of such environment in the search mechanism performed by the DNA binding molecule is outlined and the model takes in consideration the probability of a TF to rebind on DNA fragment that might be hundreds of base pairs apart but comes in close proximity as a consequence of the DNA’s 3-dimensional structure. DNA fragments that come in contact with each other has been hypothesised to influence the search speed. While other effects like crowding (presence of other non-cognate species of DNA binding proteins) have been shown to influence the speed of the facilitated diffusion mechanisms by covering non- specific binding sites, tests ran on the model with nucleosomes being bound to DNA showed that the intersegmental jumps, being performed by the TFs, are affected by the number of nucleosomes as well as a certain probability of the protein to stay in the microenvironment and to not completely dissociate in the nucleoplasm.