Enhancer Cis Elements Instruct Promoter-Enhancer Interaction, Promoter-Enhancer Insulation and Compartmental Segregation

Enhancers harbor instructions encoded for the interactions between cis-elements and transcription factors to orchestrate lineage specific gene programs. Here we developed a modified method for chromosome conformation capture (3C), named MID Hi-C, to reveal how in mouse embryonic stem cells differential cooperation of enhancers and the chromatin remodeler BAF, as instructed by the underlying transcription factor motifs, modulate enhancer-promoter communication. We show that BAF-dependent enhancers permit genomic interactions beyond enhancer boundaries. BAF-dependent enhancers do not dictate genomic interactions within enhancer-promoter loop domains but rather act to instruct remote enhancer-promoter communication. In contrast, BAF-independent enhancers interact with promoter regions within tightly insulated enhancer-promoter loop domains that are marked by promoter and enhancer boundary elements. In addition, enhancer activeness modulated by BAF enforces compartment segregation. Based on these observations, we propose that enhancer cis elements instruct with great precision BAF-induced enhancer-promoter communication and compartmental segregation. We benchmarked the qualities of MID Hi-C data against published in situ Hi-C and Micro-C data on mouse embryonic stem cells (mESCs). Then, using ATAC-seq and our newly-developed MID Hi-C, we investigated changes in chromatin accessibilities and chromatin interactions during BRG1 degradation in mESCs.