Cohesin Loss Eliminates All Loop Domains

Suhas S P Rao; Su-Chen Huang; Brian Glenn St Hilaire; Jesse M Engreitz; Elizabeth M Perez; Kyong-Rim Kieffer-Kwon; Adrian L Sanborn; Sarah E Johnstone; Gavin D Bascom; Ivan D Bochkov; Xingfan Huang; Muhammad S Shamim; Jaeweon Shin; Douglass Turner; Ziyi Ye; Arina D Omer; James T Robinson; Tamar Schlick; Bradley E Bernstein; Rafael Casellas; Eric S Lander; Erez Lieberman Aiden

doi:10.1016/j.cell.2017.09.026

Cohesin Loss Eliminates All Loop Domains

Cell. 2017 Oct 5;171(2):305-320.e24. doi: 10.1016/j.cell.2017.09.026.

Authors

Suhas S P Rao¹, Su-Chen Huang², Brian Glenn St Hilaire³, Jesse M Engreitz⁴, Elizabeth M Perez⁴, Kyong-Rim Kieffer-Kwon⁵, Adrian L Sanborn⁶, Sarah E Johnstone⁷, Gavin D Bascom⁸, Ivan D Bochkov², Xingfan Huang⁹, Muhammad S Shamim¹⁰, Jaeweon Shin⁹, Douglass Turner¹¹, Ziyi Ye⁹, Arina D Omer², James T Robinson¹², Tamar Schlick¹³, Bradley E Bernstein⁷, Rafael Casellas¹⁴, Eric S Lander¹⁵, Erez Lieberman Aiden¹⁶

Affiliations

¹ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁵ Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.
⁶ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁸ Department of Chemistry, New York University, New York, NY 10003, USA.
⁹ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA.
¹⁰ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
¹¹ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
¹² The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
¹³ Department of Chemistry, New York University, New York, NY 10003, USA; Courant Institute of Mathematical Sciences, New York University, New York, NY 10012, USA; NYU-ECNU Center for Computational Chemistry, NYU Shanghai, Shanghai 200062, China.
¹⁴ Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA; Center of Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
¹⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
¹⁶ The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA; Departments of Computer Science and Computational and Applied Mathematics, Rice University, Houston, TX 77030, USA. Electronic address: erez@erez.com.

Abstract

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. 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. We then restore cohesin and monitor the re-formation of each loop. Although re-formation rates vary greatly, many megabase-sized loops recovered in under an hour, consistent with a model where loop extrusion is rapid.

Keywords: 4D Nucleome; CTCF; Hi-C; chromatin loops; cohesion; gene regulation; genome architecture; loop extrusion; nuclear compartments; superenhancers.

MeSH terms

CCCTC-Binding Factor
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cell Nucleus / genetics*
Chromosomal Proteins, Non-Histone / metabolism*
Chromosomes / metabolism*
Cohesins
DNA-Binding Proteins
Enhancer Elements, Genetic
Genome, Human*
Histone Code
Humans
Nuclear Proteins / metabolism
Nucleosomes / metabolism
Phosphoproteins / metabolism
Repressor Proteins / metabolism*

Substances

CCCTC-Binding Factor
CTCF protein, human
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Nuclear Proteins
Nucleosomes
Phosphoproteins
RAD21 protein, human
Repressor Proteins

Abstract

MeSH terms

Substances

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