Molecular basis of CTCF binding polarity in genome folding

© 2020, The Author(s). 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. While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially sta...

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Main Authors: Nora, Elphège P, Caccianini, Laura, Fudenberg, Geoffrey, So, Kevin, Kameswaran, Vasumathi, Nagle, Abigail, Uebersohn, Alec, Hajj, Bassam, Saux, Agnès Le, Coulon, Antoine, Mirny, Leonid A, Pollard, Katherine S, Dahan, Maxime, Bruneau, Benoit G
Other Authors: Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Format: Article
Language:English
Published: Springer Science and Business Media LLC 2021
Online Access:https://hdl.handle.net/1721.1/138402
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author Nora, Elphège P
Caccianini, Laura
Fudenberg, Geoffrey
So, Kevin
Kameswaran, Vasumathi
Nagle, Abigail
Uebersohn, Alec
Hajj, Bassam
Saux, Agnès Le
Coulon, Antoine
Mirny, Leonid A
Pollard, Katherine S
Dahan, Maxime
Bruneau, Benoit G
author2 Massachusetts Institute of Technology. Institute for Medical Engineering & Science
author_facet Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Nora, Elphège P
Caccianini, Laura
Fudenberg, Geoffrey
So, Kevin
Kameswaran, Vasumathi
Nagle, Abigail
Uebersohn, Alec
Hajj, Bassam
Saux, Agnès Le
Coulon, Antoine
Mirny, Leonid A
Pollard, Katherine S
Dahan, Maxime
Bruneau, Benoit G
author_sort Nora, Elphège P
collection MIT
description © 2020, The Author(s). 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. While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially stabilize loops, the molecular basis of this polarity remains unclear. By combining ChIP-seq and single molecule live imaging we report that CTCF positions cohesin, but does not control its overall binding dynamics on chromatin. Using an inducible complementation system, we find that CTCF mutants lacking the N-terminus cannot insulate TADs properly. Cohesin remains at CTCF sites in this mutant, albeit with reduced enrichment. Given the orientation of CTCF motifs presents the N-terminus towards cohesin as it translocates from the interior of TADs, these observations explain how the orientation of CTCF binding sites translates into genome folding patterns.
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spelling mit-1721.1/1384022024-03-19T14:09:31Z Molecular basis of CTCF binding polarity in genome folding Nora, Elphège P Caccianini, Laura Fudenberg, Geoffrey So, Kevin Kameswaran, Vasumathi Nagle, Abigail Uebersohn, Alec Hajj, Bassam Saux, Agnès Le Coulon, Antoine Mirny, Leonid A Pollard, Katherine S Dahan, Maxime Bruneau, Benoit G Massachusetts Institute of Technology. Institute for Medical Engineering & Science Massachusetts Institute of Technology. Department of Physics © 2020, The Author(s). 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. While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially stabilize loops, the molecular basis of this polarity remains unclear. By combining ChIP-seq and single molecule live imaging we report that CTCF positions cohesin, but does not control its overall binding dynamics on chromatin. Using an inducible complementation system, we find that CTCF mutants lacking the N-terminus cannot insulate TADs properly. Cohesin remains at CTCF sites in this mutant, albeit with reduced enrichment. Given the orientation of CTCF motifs presents the N-terminus towards cohesin as it translocates from the interior of TADs, these observations explain how the orientation of CTCF binding sites translates into genome folding patterns. 2021-12-09T13:18:22Z 2021-12-09T13:18:22Z 2020 2021-12-09T13:15:19Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/138402 Nora, Elphège P, Caccianini, Laura, Fudenberg, Geoffrey, So, Kevin, Kameswaran, Vasumathi et al. 2020. "Molecular basis of CTCF binding polarity in genome folding." Nature Communications, 11 (1). en 10.1038/S41467-020-19283-X Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature
spellingShingle Nora, Elphège P
Caccianini, Laura
Fudenberg, Geoffrey
So, Kevin
Kameswaran, Vasumathi
Nagle, Abigail
Uebersohn, Alec
Hajj, Bassam
Saux, Agnès Le
Coulon, Antoine
Mirny, Leonid A
Pollard, Katherine S
Dahan, Maxime
Bruneau, Benoit G
Molecular basis of CTCF binding polarity in genome folding
title Molecular basis of CTCF binding polarity in genome folding
title_full Molecular basis of CTCF binding polarity in genome folding
title_fullStr Molecular basis of CTCF binding polarity in genome folding
title_full_unstemmed Molecular basis of CTCF binding polarity in genome folding
title_short Molecular basis of CTCF binding polarity in genome folding
title_sort molecular basis of ctcf binding polarity in genome folding
url https://hdl.handle.net/1721.1/138402
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