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The Energetics and Physiological Impact of Cohesin Extrusion

Vian, Laura, Pękowska, Aleksandra, Rao, Suhas S.P., Kieffer-Kwon, Kyong-Rim, Jung, Seolkyoung, Baranello, Laura, Huang, Su-Chen, El Khattabi, Laila, Dose, Marei, Pruett, Nathanael, Sanborn, Adrian L., Canela, Andres, Maman, Yaakov, Oksanen, Anna, Resch, Wolfgang, Li, Xingwang, Lee, Byoungkoo, Kovalchuk, Alexander L., Tang, Zhonghui, Nelson, Steevenson, Di Pierro, Michele, Cheng, Ryan R., Machol, Ido, St Hilaire, Brian Glenn, Durand, Neva C., Shamim, Muhammad S., Stamenova, Elena K., Onuchic, José N., Ruan, Yijun, Nussenzweig, Andre, Levens, David, Aiden, Erez Lieberman, Casellas, Rafael
Cell 2018 v.173 no.5 pp. 1165-1178.e20
B-lymphocytes, DNA, adenosine triphosphate, adenosinetriphosphatase, chromosome translocation, energy, extrusion, mammals, neoplasms, oncogenes, transcription (genetics)
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.