Chromatin remodeling in silico: A stochastic model for SWI/SNF

摘要

Beside their contribution in DNA packaging, histone-core particles modulate the transcription machinery access to the DNA through dynamic chromatin structure. Chromatin remodeling complexes perturb such modulations through diverse mechanisms. SWI/SNF is a well-studied highly conserved chromatin remodeling complex that is ubiquitous across eukaryotes. Rigorous study of experimental observations suggests randomness in dynamics of SWI/SNF in cis chromatin remodeling process. In this work we propose a stochastic computational model that captures such fluctuations. We incorporate the physiological properties of the process through parametric microevents. Each microevent is then associated with a stochastic model that couples its random temporal and spatial dynamics with the energy landscape of the remodeling process. We further show that DNA sequence stacks and friction force have negligible effect on chromatin remodeling. Our approach shows a promising approximation to the force impinged on the DNA by the SWI/SNF complex. We validate our model predictions with several experimental data sets. The proposed model suggest that the in cis translocation rate of histone-core particle follows a Gamma distribution. By carefully analyzing the simulation results we conjecture that SWI/SNF chromatin remodeling has low energy efficiency (<0.30). We use our model to recapitulate the dynamics of the parallel remodeling processes that occur in close proximity across a typical eukaryotic genome. Our results suggest that the orchestrated chromatin remodeling makes few kilobase-pairs of the DNA accessible to the transcription machinery in a timely manner.