Chromatin structure shapes the search process of transcription factors

Abstract

The diffusion of regulatory proteins within the nucleus plays a crucial role in the dynamics of transcriptional regulation. The standard model assumes a 3D plus ID diffusion process: regulatory proteins either move freely in solution or slide on DNA. This model however does not considered the 3D structure of chromatin. Here we proposed a multi-scale stochastic model that integrates, for the first time, high-resolution information on chromatin structure as well as DNA-protein interactions. The dynamics of transcription factors was modeled as a slide plus jump diffusion process on a chromatin network based on pair-wise contact maps obtained from high-resolution Hi-C experiments. Our model allowed us to uncover the effects of chromatin structure on transcription factor occupancy profiles and target search times. Finally, we showed that binding sites clustered on few topological associated domains leading to a higher local concentration of transcription factors which could reflect an optimal strategy to efficiently use limited transcriptional resources.