Cohesin is required for long-range enhancer action

Summary The mammalian genome is organised into topologically associating domains (TADs) that are formed through the process of cohesin-driven loop extrusion1–3 and whose extent is constrained at TAD boundaries by orientation-dependent CTCF binding4–7. The large regulatory landscapes of developmental genes frequently correspond to TADs, leading to the hypothesis that TADs and/or loop extrusion are important for enhancers to act on their cognate gene8,9. However, it has proven hard to interpret the consequences of experimental disruption of TADs or loop-extrusion on gene regulation3,6,10, in part because of the difficulty in distinguishing direct from indirect effects on enhancer-driven gene expression. By coupling acute protein degradation with synthetic activation by targeted transcription factor recruitment in mouse embryonic stem cells, here we show that cohesin, but not CTCF, is required for activation of a target gene by distant distal regulatory elements. Cohesin is not required for activation directly at the promoter or activation from an enhancer located closer to the gene. Our findings support the hypothesis that chromatin compaction mediated by cohesin-mediated loop extrusion allows for genes to be activated by regulatory elements that are located many hundreds of kilobases away in the linear genome but suggests that cohesin is dispensable for more genomically close enhancers.