Enhancers are critical genetic elements controlling transcription from promoters, yet how they convey regulatory information across large genomic distances remains unclear. In this study, we engineered pluripotent stem cells in which cohesin loop extrusion can be inducibly disrupted without confounding cell cycle defects. Transcriptional dysregulation is cell type specific, and not all loci with distal enhancers depend equally on cohesin extrusion. Using comparative genome editing, we demonstrated that enhancer-promoter communication over just 20 kb can require cohesin. However, promoter-proximal elements can support long-range, cohesin-independent enhancer action-even across strong CCCTC-binding factor (CTCF) insulators. Lastly, transcriptional dynamics and the emergence of embryonic cell types remain largely robust despite disrupted extrusion. Beyond establishing strategies to study cohesin in enhancer biology, our work provides mechanistic insight into cell type specificity and genomic context specificity.
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