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Cohesin loss eliminates all loop domains, leading to links among superenhancers and downregulation of nearby genes

Suhas S. P. Rao, Su-Chen Huang, Brian Glenn St Hilair, Jesse M. Engreitz, Elizabeth M. Perez, Kyong-Rim Kieffer-Kwon, Adrian L. Sanborn, Sarah E. Johnstone, Ivan D. Bochkov, Xingfan Huang, Muhammad S. Shamim, Arina D. Omer, Bradley E. Bernstein, Rafael Casellas, Eric S. Lander, Erez Lieberman Aiden
doi: https://doi.org/10.1101/139782
Suhas S. P. Rao
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,TX 77030, USA.
3Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Su-Chen Huang
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,TX 77030, USA.
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Brian Glenn St Hilair
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,TX 77030, USA.
4Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA.
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Jesse M. Engreitz
5Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
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Elizabeth M. Perez
5Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
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Kyong-Rim Kieffer-Kwon
6Genomics & Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
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Adrian L. Sanborn
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
4Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA.
7Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
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Sarah E. Johnstone
5Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
8Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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Ivan D. Bochkov
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,TX 77030, USA.
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Xingfan Huang
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
9Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA.
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Muhammad S. Shamim
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,TX 77030, USA.
9Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA.
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Arina D. Omer
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,TX 77030, USA.
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Bradley E. Bernstein
5Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
8Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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Rafael Casellas
6Genomics & Immunity, NIAMS, NIH, Bethesda, MD 20892, USA.
10Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
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Eric S. Lander
5Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
11Department of Biology, MIT, Cambridge, MA 02139, USA.
12Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
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Erez Lieberman Aiden
1The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,TX 77030, USA.
4Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA.
5Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
9Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA.
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  • For correspondence: erez@erez.com
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SUMMARY

The human genome folds to create thousands of intervals, called “contact domains,” that exhibit enhanced contact frequency within themselves. “Loop domains” form because of tethering between two loci - almost always bound by CTCF and cohesin – lying on the same chromosome. “Compartment domains” form when genomic intervals with similar histone marks co-segregate. Here, we explore the effects of degrading cohesin. All loop domains are eliminated, but neither compartment domains nor histone marks are affected. Loci in different compartments that had been in the same loop domain become more segregated. Loss of loop domains does not lead to widespread ectopic gene activation, but does affect a significant minority of active genes. In particular, cohesin loss causes superenhancers to co-localize, forming hundreds of links within and across chromosomes, and affecting the regulation of nearby genes. Cohesin restoration quickly reverses these effects, consistent with a model where loop extrusion is rapid.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 18, 2017.
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Cohesin loss eliminates all loop domains, leading to links among superenhancers and downregulation of nearby genes
Suhas S. P. Rao, Su-Chen Huang, Brian Glenn St Hilair, Jesse M. Engreitz, Elizabeth M. Perez, Kyong-Rim Kieffer-Kwon, Adrian L. Sanborn, Sarah E. Johnstone, Ivan D. Bochkov, Xingfan Huang, Muhammad S. Shamim, Arina D. Omer, Bradley E. Bernstein, Rafael Casellas, Eric S. Lander, Erez Lieberman Aiden
bioRxiv 139782; doi: https://doi.org/10.1101/139782
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Cohesin loss eliminates all loop domains, leading to links among superenhancers and downregulation of nearby genes
Suhas S. P. Rao, Su-Chen Huang, Brian Glenn St Hilair, Jesse M. Engreitz, Elizabeth M. Perez, Kyong-Rim Kieffer-Kwon, Adrian L. Sanborn, Sarah E. Johnstone, Ivan D. Bochkov, Xingfan Huang, Muhammad S. Shamim, Arina D. Omer, Bradley E. Bernstein, Rafael Casellas, Eric S. Lander, Erez Lieberman Aiden
bioRxiv 139782; doi: https://doi.org/10.1101/139782

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