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. [Display omitted] •Markov models of nucleosome-SDTF interactions fit stimulus response ATAC-seq data•In cells, unwrapping may occur in minutes, rather than seconds, as in in vitro•Models reveal cooperativity and estimate an SDTF effect range of 30–40 bp•SDTF sites close to but not on the dyad evict nucleosomes with greatest likelihood Kim et al. examine regulatory principles governing transcription factor-induced nucleosome eviction by analyzing Markov models fit to genome-wide chromatin accessibility measurements. Fitted models reveal nucleosome unwrapping rates, cooperativity of unwrapping steps, and why nucleosome eviction probability is highest when transcription factor binding sites are adjacent to the nucleosome dyad.