Polymer Simulations of Heteromorphic Chromatin Predict the 3-D Folding of Complex Genomic Loci

Chromatin folded into 3-D macromolecular structures is often analysed by 3C and FISH techniques, but frequently provide contradictory results. Instead, chromatin can be modelled as a simple polymer comprised of a connected chain of units. By embedding data for epigenetic marks (H3K27ac), genomic disruptions (ATAC-seq) and structural anchors (CTCF) we developed a highly predictive heteromorphic polymer (HiP-HoP) model, where the chromatin fibre varied along its length; combined with diffusing protein bridges and loop extrusion this model predicted the 3-D organisation of genomic loci at a population and single cell level. The model was validated at several gene loci, including the complex Pax6 gene, and was able to determine locus conformations across cell types with varying levels of transcriptional activity and explain different mechanisms of enhancer use. Minimal a priori knowledge of epigenetic marks is sufficient to recapitulate complex genomic loci in 3-D and enable predictions of chromatin folding paths.

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