Polymer Simulations of Heteromorphic Chromatin Predict the 3D Folding of Complex Genomic Loci.
Chromatin folded into 3D macromolecular structures is often analyzed by chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH) techniques, but these frequently provide contradictory results. Chromatin can be modeled as a simple polymer composed of a connected chain of units. By embedding data for epigenetic marks (H3K27ac), chromatin accessibility (assay for transposase-accessible chromatin using sequencing [ATAC-seq]), and structural anchors (CCCTC-binding factor [CTCF]), we developed a highly predictive heteromorphic polymer (HiP-HoP) model, where the chromatin fiber varied along its length; combined with diffusing protein bridges and loop extrusion, this model predicted the 3D organization 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 3D and enable predictions of chromatin folding paths.
['Buckle|Adam|A|', 'Brackley|Chris A|CA|', 'Boyle|Shelagh|S|', 'Marenduzzo|Davide|D|', 'Gilbert|Nick|N|']
D000818:Animals D000076246:CCCTC-Binding Factor D002460:Cell Line D002843:Chromatin D002875:Chromosomes D003198:Computer Simulation D004268:DNA-Binding Proteins D016678:Genome D023281:Genomics D006801:Humans D017404:In Situ Hybridization, Fluorescence D051379:Mice D008968:Molecular Conformation D011108:Polymers D012045:Regulatory Sequences, Nucleic Acid
chromatin 3C FISH transcription enhancer Capture-C genome organization histone modifications polymer modeling