The Energetics and Physiological Impact of Cohesin Extrusion

Laura Vian, Aleksandra Pękowska, Suhas S.P. Rao, Kyong Rim Kieffer-Kwon, Seolkyoung Jung, Laura Baranello, Su Chen Huang, Laila El Khattabi, Marei Dose, Nathanael Pruett, Adrian L. Sanborn, Andres Canela, Yaakov Maman, Anna Oksanen, Wolfgang Resch, Xingwang Li, Byoungkoo Lee, Alexander L. Kovalchuk, Zhonghui Tang, Steevenson NelsonMichele Di Pierro, Ryan R. Cheng, Ido Machol, Brian Glenn St Hilaire, Neva C. Durand, Muhammad S. Shamim, Elena K. Stamenova, José N. Onuchic, Yijun Ruan, Andre Nussenzweig, David Levens, Erez Lieberman Aiden, Rafael Casellas

Research output: Contribution to journalArticlepeer-review

279 Citations (Scopus)

Abstract

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. Cohesin continually extrudes loops of chromatin in vivo, relying on ATP to fuel the process.

Original languageEnglish
Pages (from-to)1165-1178.e20
JournalCell
Volume173
Issue number5
DOIs
Publication statusPublished - 17 May 2018

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