Mesoscale modeling reveals formation of an epigenetically driven HOXC gene hub

Gene expression is orchestrated at the structural level by nucleosome positioning, histone tail acetylation, and linker histone (LH) binding. Here, we integrate available data on nucleosome positioning, nucleosome-free regions (NFRs), acetylation islands, and LH binding sites to "fold" in silico the 55-kb HOXC gene cluster and investigate the role of each feature on the gene's folding. The gene cluster spontaneously forms a dynamic connection hub, characterized by hierarchical loops which accommodate multiple contacts simultaneously and decrease the average distance between promoters by ∼100 nm. Contact probability matrices exhibit "stripes" near promoter regions, a feature associated with transcriptional regulation. Interestingly, while LH proteins alone decrease long-range contacts and acetylation alone increases transient contacts, combined LH and acetylation produce long-range contacts. Thus, our work emphasizes how chromatin architecture is coordinated strongly by epigenetic factors and opens the way for nucleosome resolution models incorporating epigenetic modifications to understand and predict gene activity.