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Cell. 2018 May 17;173(5):1165-1178.e20. doi: 10.1016/j.cell.2018.03.072. Epub 2018 Apr 26.

The Energetics and Physiological Impact of Cohesin Extrusion.

Author information

1
Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.
2
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Gene Regulation, Laboratory of Pathology, NCI, NIH, Bethesda, MD 20892, USA.
4
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
5
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
6
Laboratory of Genome Integrity, NCI, NIH, Bethesda, MD 20892, USA.
7
The Jackson Laboratory for Genomic Medicine and Department of Genetic and Development Biology, University of Connecticut, Farmington, CT 06030, USA.
8
Laboratory of Immunogenetics, NIAID, NIH, Rockville, MD 20852, USA.
9
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA.
10
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. Electronic address: erez@erez.com.
11
Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA; Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA. Electronic address: rafael.casellas@nih.gov.

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.

KEYWORDS:

CTCF; DNA damage; Nipbl; chromosomal translocations; class switching; cohesin; loop extrusion; nuclear architecture; topoisomerase II

PMID:
29706548
PMCID:
PMC6065110
[Available on 2019-05-17]
DOI:
10.1016/j.cell.2018.03.072

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