Investigating the epigenetic code through data-driven chromosome structure modeling.

The three-dimensional organization of chromatin plays a major role in pathways of gene regulation and disease. Increasing evidence indicates that features of the three-dimensional structure control the physical readout of genetic information and may ultimately establish programs of gene expression. Advances in experimental probes of chromatin organization (Hi-C) provide unprecedented insight into pairwise contact frequencies, but the three-dimensional structure is not furnished by these methods. Computational models have been advanced to predict chromatin structures consistent with these experiments, but have thus-far been limited to a resolution no finer than the resolution of state-of-the-art Hi-C experiments (~5 kbp). However, models of this type are unable to investigate the structure interior to individual genes which are crucial to regulatory pathways. We present a model for chromosome architecture at nucleosome resolution, using maximum entropy methods to recapitulate experimental Hi-C contact maps. We explore how models at this resolution can connect length scales from nucleosome interactions all the way to whole-chromosome organization. We expect that models of this resolution are necessary to investigate important features of epigenetic regulation that require information at multiple length scales.