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 language | English |
|---|---|
| Pages (from-to) | 1165-1178.e20 |
| Journal | Cell |
| Volume | 173 |
| Issue number | 5 |
| DOIs | |
| State | Published - 17 May 2018 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2018 Elsevier Inc.
Funding
We thank Kim Nasmyth, who independently noticed stripes in Hi-C data, for his valuable input on the manuscript. We thank Megan Laycock for proofreading the manuscript and Gustavo Gutierrez for technical assistance. This work was supported by NIAMS, NCI, and NIAID funding and NIH Helix Systems (https://helix.nih.gov). This work was also supported by a Paul and Daisy Soros Fellowship, a Fannie and John Hertz Foundation Fellowship, a Cornelia de Lange Syndrome Foundation grant (to S.S.P.R.), an NIH New Innovator Award (1DP2OD008540-01), an NSF Physics Frontiers Center Award (PHY-1427654), the NHGRI Center for Excellence for Genomic Sciences (HG006193), the Welch Foundation (Q-1866), an NVIDIA Research Center Award, an IBM University Challenge Award, a Google Research Award, a Cancer Prevention Research Institute of Texas Scholar Award (R1304), a USDA Agriculture and Food Research Initiative Grant (2017-05741), a McNair Medical Institute Scholar Award, an NIH Encyclopedia of DNA Elements Mapping Center Award (UM1HG009375), and the President's Early Career Award in Science and Engineering (to E.L.A.). Work at CTBP was supported by NSF (PHY-1427654, CHE-1614101) and Welch Foundation (C-1792). We thank Kim Nasmyth, who independently noticed stripes in Hi-C data, for his valuable input on the manuscript. We thank Megan Laycock for proofreading the manuscript and Gustavo Gutierrez for technical assistance. This work was supported by NIAMS , NCI , and NIAID funding and NIH Helix Systems ( https://helix.nih.gov ). This work was also supported by a Paul and Daisy Soros Fellowship , a Fannie and John Hertz Foundation Fellowship , a Cornelia de Lange Syndrome Foundation grant (to S.S.P.R.), an NIH New Innovator Award ( 1DP2OD008540-01 ), an NSF Physics Frontiers Center Award ( PHY-1427654 ), the NHGRI Center for Excellence for Genomic Sciences ( HG006193 ), the Welch Foundation ( Q-1866 ), an NVIDIA Research Center Award , an IBM University Challenge Award , a Google Research Award , a Cancer Prevention Research Institute of Texas Scholar Award ( R1304 ), a USDA Agriculture and Food Research Initiative Grant ( 2017-05741 ), a McNair Medical Institute Scholar Award , an NIH Encyclopedia of DNA Elements Mapping Center Award ( UM1HG009375 ), and the President’s Early Career Award in Science and Engineering (to E.L.A.). Work at CTBP was supported by NSF ( PHY-1427654 , CHE-1614101 ) and Welch Foundation ( C-1792 ).
| Funders | Funder number |
|---|---|
| IBM University | |
| McNair Medical Institute | CHE-1614101, UM1HG009375 |
| NHGRI Center for Excellence for Genomic Sciences | HG006193 |
| National Science Foundation | PHY-1427654 |
| National Institutes of Health | 1DP2OD008540-01 |
| National Cancer Institute | ZIABC011011 |
| National Institute of Allergy and Infectious Diseases | |
| National Institute of Arthritis and Musculoskeletal and Skin Diseases | |
| U.S. Department of Agriculture | 2017-05741 |
| Welch Foundation | Q-1866, C-1792 |
| Cornelia de Lange Syndrome Foundation | |
| Hertz Foundation | |
| R1304 | |
| NVIDIA | |
| National Computational Infrastructure | |
| National Stroke Foundation | |
| National Cancer Institute, Cairo University |
Keywords
- CTCF
- DNA damage
- Nipbl
- chromosomal translocations
- class switching
- cohesin
- loop extrusion
- nuclear architecture
- topoisomerase II
