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Molecular basis of CTCF binding polarity in genome folding

Elphège P. Nora, Laura Caccianini, Geoffrey Fudenberg, Vasumathi Kameswaran, Abigail Nagle, Alec Uebersohn, Kevin So, Bassam Hajj, Agnès Le Saux, Antoine Coulon, Leonid A. Mirny, Katherine S. Pollard, Maxime Dahan, Benoit G. Bruneau
doi: https://doi.org/10.1101/2019.12.13.876177
Elphège P. Nora
1Gladstone Institutes, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
3Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA
4Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143, USA
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  • For correspondence: elphege.nora@ucsf.edu benoit.bruneau@gladstone.ucsf.edu
Laura Caccianini
5Laboratoire Physico-Chimie, Institut Curie, PSL Research University, Sorbonne Université, Université Pierre et Marie Curie-Paris, CNRS UMR168, 26, Rue D’Ulm, 75005, Paris, France
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Geoffrey Fudenberg
1Gladstone Institutes, San Francisco, CA 94158, USA
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Vasumathi Kameswaran
1Gladstone Institutes, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
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Abigail Nagle
1Gladstone Institutes, San Francisco, CA 94158, USA
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Alec Uebersohn
1Gladstone Institutes, San Francisco, CA 94158, USA
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Kevin So
1Gladstone Institutes, San Francisco, CA 94158, USA
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Bassam Hajj
5Laboratoire Physico-Chimie, Institut Curie, PSL Research University, Sorbonne Université, Université Pierre et Marie Curie-Paris, CNRS UMR168, 26, Rue D’Ulm, 75005, Paris, France
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Agnès Le Saux
6Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Mammalian Developmental Epigenetics group, F-75005 Paris, France; Sorbonne Université, F-75005 Paris, France
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Antoine Coulon
5Laboratoire Physico-Chimie, Institut Curie, PSL Research University, Sorbonne Université, Université Pierre et Marie Curie-Paris, CNRS UMR168, 26, Rue D’Ulm, 75005, Paris, France
7Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR3664, Nuclear Dynamics unit, F-75005 Paris, France
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Leonid A. Mirny
8Institute for Medical Engineering and Science and Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Katherine S. Pollard
1Gladstone Institutes, San Francisco, CA 94158, USA
9Department of Epidemiology & Biostatistics, Institute for Human Genetics, Quantitative Biology Institute, and Institute for Computational Health Sciences, University of California San Francisco, San Francisco, CA, USA
10Chan Zuckerberg Biohub, San Francisco, California, USA
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Maxime Dahan
5Laboratoire Physico-Chimie, Institut Curie, PSL Research University, Sorbonne Université, Université Pierre et Marie Curie-Paris, CNRS UMR168, 26, Rue D’Ulm, 75005, Paris, France
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Benoit G. Bruneau
1Gladstone Institutes, San Francisco, CA 94158, USA
2Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA
3Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA
11Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA
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  • For correspondence: elphege.nora@ucsf.edu benoit.bruneau@gladstone.ucsf.edu
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Summary

Current models propose that boundaries of mammalian topologically associating domains (TADs) arise from the ability of the CTCF protein to stop extrusion of chromatin loops by cohesin proteins (Merkenschlager & Nora, 2016; Fudenberg, Abdennur, Imakaev, Goloborodko, & Mirny, 2017). While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially stabilize DNA loops (de Wit et al., 2015; Guo et al., 2015; Rao et al., 2014; Vietri Rudan et al., 2015), the molecular basis of this polarity remains mysterious. Here we report that CTCF positions cohesin but does not control its overall binding or dynamics on chromatin by single molecule live imaging. Using an inducible complementation system, we found that CTCF mutants lacking the N-terminus cannot insulate TADs properly, despite normal binding. Cohesin remained at CTCF sites in this mutant, albeit with reduced enrichment. Given that the orientation of the CTCF motif presents the CTCF N-terminus towards cohesin as it translocates from the interior of TADs, these observations provide a molecular explanation for how the polarity of CTCF binding sites determines the genomic distribution of chromatin loops.

Footnotes

  • ↵* co-first authors

  • ↵† deceased

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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 4.0 International license.
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Posted December 14, 2019.
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Molecular basis of CTCF binding polarity in genome folding
Elphège P. Nora, Laura Caccianini, Geoffrey Fudenberg, Vasumathi Kameswaran, Abigail Nagle, Alec Uebersohn, Kevin So, Bassam Hajj, Agnès Le Saux, Antoine Coulon, Leonid A. Mirny, Katherine S. Pollard, Maxime Dahan, Benoit G. Bruneau
bioRxiv 2019.12.13.876177; doi: https://doi.org/10.1101/2019.12.13.876177
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Molecular basis of CTCF binding polarity in genome folding
Elphège P. Nora, Laura Caccianini, Geoffrey Fudenberg, Vasumathi Kameswaran, Abigail Nagle, Alec Uebersohn, Kevin So, Bassam Hajj, Agnès Le Saux, Antoine Coulon, Leonid A. Mirny, Katherine S. Pollard, Maxime Dahan, Benoit G. Bruneau
bioRxiv 2019.12.13.876177; doi: https://doi.org/10.1101/2019.12.13.876177

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