The Energetics and Physiological Impact of Cohesin Extrusion

Summary Cohesinextrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo , and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesinATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancersto cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocationsand cancer. In plasmacytomas, stripes can deregulate Igh -translocated oncogenes. We propose that higher organisms have coopted cohesinextrusion to enhance transcription and recombination, with implications for tumor development.