Modeling heterochromatin dynamics in S. pombe across diverse timescales.

Abstract

From bread yeast to human cancer cells, histone regulation underpins the epigenetics of almost all eukaryotic genes. While it is possible to experimentally isolate the behavior of single elements of histone regulation, using that data to generate a full mechanistic understanding of regulation is nontrivial. To isolate the machinery involved, we have chosen to model the elements of gene silencing in S. pombe on several spatial and temporal scales. These models were based on many single molecule experiments done in vivo on the dynamics of evolutionarily conserved parts of the regulation machinery, such as Swi6, Clr4, and the SHREC complex. Using the Lattice Microbes software package, we synthesized these independent experimental results to model an interacting network of gene regulation. We began by modeling the chemical behavior of the individual regulators: we used single molecule experimental results where possible, and generated several plausible mechanisms of chemical action for chemical behaviors that were not precisely known. Different mechanisms on the chemical level suggested different timescales and spatial behaviors for small scale histone modification to affect larger scale transcription. We were able to compare these theoretical timescales to timescales in S. pombe adaptive epigenetic silencing experiments, allowing us to identify the likeliest chemical interaction mechanisms. With these, we were able to construct models on the timescale of gene regulation which captured the spatial and temporal dynamics of the chemical mechanisms while remaining computationally efficient. Because we can now efficiently model chemically accurate epigenetic mechanisms, we can now model epigenetic decision making, allowing us to probe how eukaryotic cells might thrive even under novel stresses or subvert apoptotic triggers.