The Energetics and Physiological Impact of Cohesin Extrusion.

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.

Authors

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

Link

https://www.ncbi.nlm.nih.gov/pubmed/29706548