Long-Range Enhancer Interactions Are Prevalent in Mouse Embryonic Stem Cells and Are Reorganized upon Pluripotent State Transition

Summary: Transcriptional enhancers, including super-enhancers (SEs), form physical interactions with promoters to regulate cell-type-specific gene expression. SEs are characterized by high transcription factor occupancy and large domains of active chromatin, and they are commonly assigned to target promoters using computational predictions. How promoter-SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, have not been reported. Here, we used promoter-capture Hi-C to identify promoters that interact with SEs in mouse embryonic stem cells (ESCs). We found that SEs form complex, spatial networks in which individual SEs contact multiple promoters, and a rewiring of promoter-SE interactions occurs between pluripotent states. We also show that long-range promoter-SE interactions are more prevalent in ESCs than in epiblast stem cells (EpiSCs) or Nanog-deficient ESCs. We conclude that SEs form cell-type-specific interaction networks that are partly dependent on core transcription factors, thereby providing insights into the gene regulatory organization of pluripotent cells. : Novo et al. use promoter-capture Hi-C to map the target promoters of super-enhancers (SEs) in mouse pluripotent cells. SEs form complex networks, and a subset of promoter-SE interactions was rewired between ESCs and EpiSCs. In ESCs, many SEs form long-range contacts that are not detected in EpiSC or Nanog-deficient ESCs. Keywords: epigenetics, genome organization, chromatin looping, gene regulation, pluripotency, differentiation, promoter capture Hi-