title: Mechanistic stochastic model of histone modification pattern formation.
abstract: BACKGROUND
  The activity of a single gene is influenced by the composition of the chromatin in which it is embedded. Nucleosome turnover, conformational dynamics, and covalent histone modifications each induce changes in the structure of chromatin and its affinity for regulatory proteins. The dynamics of histone modifications and the persistence of modification patterns for long periods are still largely unknown.
  
  
  RESULTS
  In this study, we present a stochastic mathematical model that describes the molecular mechanisms of histone modification pattern formation along a single gene, with non-phenomenological, physical parameters. We find that diffusion and recruitment properties of histone modifying enzymes together with chromatin connectivity allow for a rich repertoire of stochastic histone modification dynamics and pattern formation. We demonstrate that histone modification patterns at a single gene can be established or removed within a few minutes through diffusion and weak recruitment mechanisms of histone modification spreading. Moreover, we show that strong synergism between diffusion and weak recruitment mechanisms leads to nearly irreversible transitions in histone modification patterns providing stable patterns. In the absence of chromatin connectivity spontaneous and dynamic histone modification boundaries can be formed that are highly unstable, and spontaneous fluctuations cause them to diffuse randomly. Chromatin connectivity destabilizes this synergistic system and introduces bistability, illustrating state switching between opposing modification states of the model gene. The observed bistable long-range and localized pattern formation are critical effectors of gene expression regulation.
  
  
  CONCLUSIONS
  This study illustrates how the cooperative interactions between regulatory proteins and the chromatin state generate complex stochastic dynamics of gene expression regulation.
authors.affiliation: Swammerdam Institute for Life Science (SILS), University of Amsterdam, Science Park 904, P.O. Box 94215, 1098 GE Amsterdam, The Netherlands.
authors.forename: Lisette C M
authors.initials: LC
authors.lastname: Anink-Groenen
authors.affiliation: Systems Bioinformatics, Amsterdam Institute for Molecules Medicines and Systems, VU University Amsterdam, Amsterdam, The Netherlands ; Life Sciences, Centrum Wiskunde & Informatica, Amsterdam, The Netherlands ; BioSolar Cells, Wageningen, The Netherlands.
authors.forename: Timo R
authors.initials: TR
authors.lastname: Maarleveld
authors.affiliation: Swammerdam Institute for Life Science (SILS), University of Amsterdam, Science Park 904, P.O. Box 94215, 1098 GE Amsterdam, The Netherlands.
authors.forename: Pernette J
authors.initials: PJ
authors.lastname: Verschure
authors.affiliation: Systems Bioinformatics, Amsterdam Institute for Molecules Medicines and Systems, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Bruggeman
keywords: Bistable dynamics; Boundary formation; Chromatin structure; Cooperative interactions; Epigenetics; Histone modification patterns; Stochastic mathematical model