A Model for de-novo Epigenetic Knock-Outs and the Histone Code

The three-dimensional structure of chromatin is increasingly understood to be a major player in gene

regulation and genome function. There is interest in the prospect of developing therapeutic strategies

conceived to tailor the functional role of chromatin by modulating its 3D structure. However, while some

new biochemical methods are available to precisely edit epigenetic marks in vivo, little is known about

the downstream effects of these edits on the physical organization of chromatin. In this work, we present

a physical model for genome organization that represents epigenetic marks explicitly, providing a first

step toward de novo epigenetic engineering. The underlying model consists of a polymeric molecule that

represents an entire chromosome, with interactions between segments described at the level of Flory-Huggins

theory and monomer identities defined according to epigenetic mark occupancies taken from ChIP-seq

experiments. Following structural optimization, we demonstrate good agreement with the experimentally

determined chromatin organization as determined from Hi-C contact maps and FISH experiments. In the

process, we determine the Flory-Huggins χ interaction parameters between each pair of epigenetic marks,

which encompass the net effect of all regulatory proteins that bind to epigenetic marks, leading to the

folding of chromatin. Through selective mutations of the χ parameters and the location of epigenetic

marks, we explore the design space of chromatin interactions in silico and predict the modulated chromatin

conformations that would result from epigenetic engineering.