Abstract
Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Such epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of the states are thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. We developed a simplified stochastic model for dynamic nucleosome modification based on the silent mating-type region of the yeast Schizosaccharomyces pombe. We show that the mechanism can give strong bi-stability that is resistant both to high noise due to random gain or loss of nucleosome modifications and to random partitioning upon DNA replication. However, robust bi-stability required: (1) cooperativity, and (2) that nucleosomes occasionally stimulate modification beyond their neighbor nucleosomes. We finally discuss discuss how these findings can be merged with the fact that silenced regions can be localized within certain boundaries on the chromosome.
Kim Sneppen, Professor/Head of Center
Center for Models of Life
Niels Bohr Institute
University of Copenhagen
References:
IB. Dodd, MA. Micheelsen, K. Sneppen and G. Thon
Theoretical Analysis of Epigenetic Cell Memory by Nucleosome Modification
Cell 129:813-822 (2007)
K. Sneppen, MA Micheelsen & IB Dodd
Ultrasensitive gene regulation by positive feedback loops in nucleosome
modification
Molecular Systems Biology 4:182 (2008)
Ian B. Dodd and Kim Sneppen
Barriers and Silencers: A Theoretical Toolkit for Control and
Containment of Nucleosome-Based Epigenetic States
Journal of Molecular Biology (2011)