Fig. 1: Enhancer-promoter hubs are systematically identified by divisive hierarchical spectral clustering of an undirected interactivity graph of enhancers and promoters.
From: Enhancer-promoter hubs organize transcriptional networks promoting oncogenesis and drug resistance
a Process of detecting enhancer-promoter hubs from raw chromatin conformation capture data. First, the interactivity graph of enhancer and promoter elements is created from regulatory element nodes connected by pairwise Hi-C or SMC1 HiChIP spatial interactions. Next, an efficient matrix-free divisive hierarchical spectral clustering algorithm is used to partition the enhancer-promoter interactivity graph into spatial clusters. Clusters are then characterized by their contiguous linear genomic intervals from their most upstream spatially interacting regulatory element to their most downstream spatially interacting regulatory element to form enhancer-promoter hubs. These hubs can be ranked based on their interaction count, enhancer/promoter number, and the expressed genes contained within their linear genomic intervals. Input interaction data depicted is for illustrative purposes only. Created with BioRender.com. b Procedure for identifying differential enhancer-promoter hubs between two conditions based on within-hub total interactivity. Top: enhancer-promoter hubs separately identified in each condition are combined into a union set of hubs based on their linear genomic coordinates. The input interaction data depicted is for illustrative purposes only. Spatial enhancer hubs with markedly differential interactivity are identified based on log2 fold change of interaction count between the two conditions. Bottom: diagram of an illustrative differential hub. Bottom left depicts this hub on the linear genome where Hi-C valid interactions (arcs) connect enhancers and promoters (circle nodes) in condition 1 (upper) and condition 2 (lower). Bottom right illustrates a simplified, potential 3D rendering of this hub in each condition, demonstrating that cells in condition 2 gain more than two-fold interactivity at this locus to form a (differential) spatial hub. Created with BioRender.com.
