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, The Jackson Laboratory
Byoungkoo Lee, The Jackson Laboratory
Alexander L Kovalchuk
Zhonghui Tang, The Jackson Laboratory
Steevenson Nelson
Michele 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, The Jackson Laboratory
Andre Nussenzweig
David Levens
Erez Lieberman Aiden
Rafael Casellas


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. Cell 2018 Apr 24 [Epub ahead of print]