192: At Base-Pair Resolution: Chromatin’s Cis-Regulatory Conversations

️Episode 192: At Base-Pair Resolution: Chromatin’s Cis-Regulatory Conversations In this episode of PaperCast Base by Base, we explore how base-pair resolution maps of chromatin contacts reveal a unified, biophysical model of communication between enhancers, promoters, and other cis-regulatory elements in mammalian cells. Study Highlights:Using Micro Capture-C ultra (MCCu), the authors generate multidimensional chromosome conformation maps with single base-pair pixels, allowing them to resolve contacts between individual transcription factor motifs within cis-regulatory elements in mouse embryonic stem, hematopoietic progenitor, and erythroid cells. They show that nucleosome-depleted regions partition chromatin into nanoscale domains and form highly localized contacts with one another, while surrounding nucleosomes produce distinct patterns of linker spacing that mark inactive regions. By acutely degrading Mediator complex subunits with degron systems, they find that Mediator is critical for fine-scale promoter architecture and transcription complex stabilization but has only minor effects on large-scale enhancer–promoter contacts. Integrating MCCu data with coarse-grained molecular dynamics simulations and super-resolution imaging, they demonstrate that the physicochemical properties of chromatin itself can recapitulate observed contact patterns and help explain how transcription factor binding and nucleosome positioning coordinate cis-regulatory interactions. Conclusion:This work provides a high-resolution framework for linking chromatin biophysics to gene regulation, offering a roadmap for dissecting how specific protein complexes and nucleosome landscapes shape enhancer–promoter communication across the genome. Reference:Li H, Dalgleish JLT, Lister G, et al. Mapping chromatin structure at base-pair resolution unveils a unified model of cis-regulatory element interactions. Cell. 2025;188:1–19. https://doi.org/10.1016/j.cell.2025.10.013 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:If you'd like to support Base by Base, you can make a one-time or monthly donation here: https://basebybase.castos.com/