Stochastic models of nucleosome dynamics reveal regulatory rules of stimulus-induced epigenome remodeling

The genomic positions of nucleosomes are a defining feature of the cell's epigenomic state, but signal-dependent transcription factors (SDTFs), upon activation, bind to specific genomic locations and modify nucleosome positioning. Here we leverage SDTFs as perturbation probes to learn about nucleosome dynamics in living cells. We develop Markov models of nucleosome dynamics and fit them to time course sequencing data of DNA accessibility. We find that (1) the dynamics of DNA unwrapping are significantly slower in cells than reported from cell-free experiments, (2) only models with cooperativity in wrapping and unwrapping fit the available data, (3) SDTF activity produces the highest eviction probability when its binding site is adjacent to but not on the nucleosome dyad, and (4) oscillatory SDTF activity results in high location variability. Our work uncovers the regulatory rules governing SDTF-induced nucleosome dynamics in live cells, which can predict chromatin accessibility alterations during inflammation at single-nucleosome resolution.

Automated summary

By using signal-dependent transcription factors as perturbation probes, the study of nucleosome dynamics in living cells revealed slower unwrapping dynamics, the necessity for cooperativity in wrapping and unwrapping in fitting the data, the highest eviction probability when the binding site of SDTF is adjacent to the nucleosome dyad, and high location variability with oscillatory SDTF activity.