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

Jinsu Kim; Katherine M Sheu; Quen J Cheng; Alexander Hoffmann; German Enciso

doi:10.1016/j.celrep.2022.111076

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

Cell Rep. 2022 Jul 12;40(2):111076. doi: 10.1016/j.celrep.2022.111076.

Authors

Jinsu Kim¹, Katherine M Sheu², Quen J Cheng³, Alexander Hoffmann⁴, German Enciso⁵

Affiliations

¹ Department of Mathematics, Pohang University of Science and Technology, Pohang, South Korea.
² Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Medicine, Division of Infectious Diseases, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: ahoffmann@ucla.edu.
⁵ Department of Mathematics, University of California, Irvine, Irvine, CA, USA; Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA. Electronic address: enciso@uci.edu.

Abstract

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.

Keywords: ATAC-seq; CP: Molecular biology; NF-κB; cooperativity; histone eviction; nucleosome dynamics; random walk; signal-dependent transcription factor; stochastic model; time-dependent Markov model.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Chromatin Assembly and Disassembly
DNA / metabolism
Epigenome*
Nucleosomes*
Transcription Factors / metabolism

Substances

Nucleosomes
Transcription Factors
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding