Cohesin extrusion 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 cohesin ATPases. 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-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.
Vian L • Pekowska A • Rao SSP • Kieffer-Kwon KR • Jung S • Baranello L • Huang SC • El Khattabi L • Dose M • Pruett N • Sanborn AL • Canela A • Maman Y • Oksanen A • Resch W • Li X • Lee B • Kovalchuk AL • Tang Z • Nelson S • Di Pierro M • Cheng RR • Machol I • St Hilaire BG • Durand NC • Shamim MS • Stamenova EK • Onuchic JN • Ruan Y • Nussenzweig A • Levens D • Aiden EL • Casellas R
April 26th, 2018