Dynamic rewiring of super-enhancers shapes condition-specific genome regulation

Abstract

Enhancers and promoters communicate through three-dimensional chromatin contacts to control cell13 type-specific gene expression. While chromosome conformation capture has enabled genome-wide mapping of these contacts, and graph-based analyses of the resulting interaction networks have shown that super enhancers occupy highly connected positions. However, how the network positions of super enhancers and typical enhancers changes as cells transition between states remains unclear. In this study, enhancer-promoter networks from high-resolution Hi-C data were constructed, and network18 based approaches were applied to characterize the regulatory architecture and its remodeling during differentiation, using Hi-C and HiChIP datasets from three differentiation systems: PMA-induced K562 differentiation, cardiomyocyte differentiation of h9 cells, and differentiation of primary foreskin keratinocytes. The networks are modular, with the largest clusters consisting of promoters and both enhancer types. Super-enhancer constituents and typical enhancers occupy distinct topological positions. During differentiation, network structure is mainly reshaped by enhancer turnover rather than by enhancer reorganization. Among the persistent enhancers, super-enhancer constituents rewire more extensively than typical enhancers. Functionally, remodeled super-enhancers connect to promoters controlling cell type's identity-defining programs, whereas typical enhancers connect to promoters involved in general metabolic and stress-response loci. These results provide evidence that super-enhancers act as a sensitive, identity-focused layer of chromatin communication. The present study also providesquantitative, network-level evidence for how super-enhancers shape the architecture of chromatin communication.