Barriers and silencers: a theoretical toolkit for control and containment of nucleosome-based epigenetic states.
Positive feedback in nucleosome modification has been proposed to allow large chromatin regions to exist stably and heritably in distinct expression states. However, modeling has shown that such epigenetic bistability requires that modifying enzymes recruited by nucleosomes are active on distant nucleosomes, potentially allowing uncontrollable spreading of modification. By modeling the silencing of mating-type loci in Saccharomyces cerevisiae, we show that a modification reaction that combines a long-range component and a locally acting component can provide bistability and can be blocked by simple barriers that interrupt the nucleosome chain. We find that robust containment of the silenced region could be achieved by the presence of a number of weak simple barriers in the surrounding chromatin and a limited capacity of the positive feedback reaction. In addition, we show that the state of the silenced region can be regulated by silencer elements acting only on neighboring nucleosomes. Thus, a relatively simple set of nucleosome-modifying enzymes and recognition domains is all that is needed to make chromatin-based epigenetics useful and safe.
Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen Ø, Denmark. ian.dodd@adelaide.edu.au
Ian B
IB
Dodd
Kim
K
Sneppen
D044127:Epigenesis, Genetic; D025461:Feedback, Physiological; D020868:Gene Silencing; D005800:Genes, Fungal; D009707:Nucleosomes / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D037941:Silencer Elements, Transcriptional; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics
D009707:Nucleosomes; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae