[13] Mapping the evolving landscape of super-enhancers during cell differentiation

Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive high-level expression of genes defining cell identity. While SEs have been cataloged in many static cell types, understanding how they evolve during dynamic processes like differentiation is critical.

In this study, we performed a comprehensive mapping of SEs during hematopoietic differentiation. We developed computational approaches to track “SE constellations”—groups of enhancer constituents that merge, split, or shift during development.

Our findings shed light on:

• Dynamic Remodeling: SEs are highly dynamic, with components being decommissioned or engaging new partners to shift gene expression programs.
• Hierarchical Regulation: We identified “hub” enhancers within SEs that are essential for the integrity of the entire regulatory domain.
• Disease Variants: Many disease-associated genetic variants (GWAS hits) cluster within these dynamic SE regions, suggesting a mechanism by which they perturb developmental trajectories.

This landscape provides a resource for understanding the regulatory logic governing cell fate decisions.