Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes

We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian genomes. Here, we combine these maps with new Hi-C, microscopy, and genome-editing experiments to study the physical structure of chromatin fibers, domains, and loops. We find that the observed contact domains are incon...

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Main Authors: Sanborn, Adrian L., Rao, Suhas S. P., Huang, Su-Chen, Durand, Neva C., Huntley, Miriam H., Jewett, Andrew I., Bochkov, Ivan D., Chinnappan, Dharmaraj, Cutkosky, Ashok, Li, Jian, Geeting, Kristopher P., Gnirke, Andreas, Melnikov, Alexandre, McKenna, Doug, Stamenova, Elena K., Aiden, Erez Lieberman, Lander, Eric Steven
Other Authors: Massachusetts Institute of Technology. Department of Biology
Format: Article
Language:en_US
Published: National Academy of Sciences (U.S.) 2017
Online Access:http://hdl.handle.net/1721.1/108680
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author Sanborn, Adrian L.
Rao, Suhas S. P.
Huang, Su-Chen
Durand, Neva C.
Huntley, Miriam H.
Jewett, Andrew I.
Bochkov, Ivan D.
Chinnappan, Dharmaraj
Cutkosky, Ashok
Li, Jian
Geeting, Kristopher P.
Gnirke, Andreas
Melnikov, Alexandre
McKenna, Doug
Stamenova, Elena K.
Aiden, Erez Lieberman
Lander, Eric Steven
author2 Massachusetts Institute of Technology. Department of Biology
author_facet Massachusetts Institute of Technology. Department of Biology
Sanborn, Adrian L.
Rao, Suhas S. P.
Huang, Su-Chen
Durand, Neva C.
Huntley, Miriam H.
Jewett, Andrew I.
Bochkov, Ivan D.
Chinnappan, Dharmaraj
Cutkosky, Ashok
Li, Jian
Geeting, Kristopher P.
Gnirke, Andreas
Melnikov, Alexandre
McKenna, Doug
Stamenova, Elena K.
Aiden, Erez Lieberman
Lander, Eric Steven
author_sort Sanborn, Adrian L.
collection MIT
description We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian genomes. Here, we combine these maps with new Hi-C, microscopy, and genome-editing experiments to study the physical structure of chromatin fibers, domains, and loops. We find that the observed contact domains are inconsistent with the equilibrium state for an ordinary condensed polymer. Combining Hi-C data and novel mathematical theorems, we show that contact domains are also not consistent with a fractal globule. Instead, we use physical simulations to study two models of genome folding. In one, intermonomer attraction during polymer condensation leads to formation of an anisotropic “tension globule.” In the other, CCCTC-binding factor (CTCF) and cohesin act together to extrude unknotted loops during interphase. Both models are consistent with the observed contact domains and with the observation that contact domains tend to form inside loops. However, the extrusion model explains a far wider array of observations, such as why loops tend not to overlap and why the CTCF-binding motifs at pairs of loop anchors lie in the convergent orientation. Finally, we perform 13 genome-editing experiments examining the effect of altering CTCF-binding sites on chromatin folding. The convergent rule correctly predicts the affected loops in every case. Moreover, the extrusion model accurately predicts in silico the 3D maps resulting from each experiment using only the location of CTCF-binding sites in the WT. Thus, we show that it is possible to disrupt, restore, and move loops and domains using targeted mutations as small as a single base pair.
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spelling mit-1721.1/1086802022-09-30T18:54:58Z Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes Sanborn, Adrian L. Rao, Suhas S. P. Huang, Su-Chen Durand, Neva C. Huntley, Miriam H. Jewett, Andrew I. Bochkov, Ivan D. Chinnappan, Dharmaraj Cutkosky, Ashok Li, Jian Geeting, Kristopher P. Gnirke, Andreas Melnikov, Alexandre McKenna, Doug Stamenova, Elena K. Aiden, Erez Lieberman Lander, Eric Steven Massachusetts Institute of Technology. Department of Biology Lander, Eric Steven We recently used in situ Hi-C to create kilobase-resolution 3D maps of mammalian genomes. Here, we combine these maps with new Hi-C, microscopy, and genome-editing experiments to study the physical structure of chromatin fibers, domains, and loops. We find that the observed contact domains are inconsistent with the equilibrium state for an ordinary condensed polymer. Combining Hi-C data and novel mathematical theorems, we show that contact domains are also not consistent with a fractal globule. Instead, we use physical simulations to study two models of genome folding. In one, intermonomer attraction during polymer condensation leads to formation of an anisotropic “tension globule.” In the other, CCCTC-binding factor (CTCF) and cohesin act together to extrude unknotted loops during interphase. Both models are consistent with the observed contact domains and with the observation that contact domains tend to form inside loops. However, the extrusion model explains a far wider array of observations, such as why loops tend not to overlap and why the CTCF-binding motifs at pairs of loop anchors lie in the convergent orientation. Finally, we perform 13 genome-editing experiments examining the effect of altering CTCF-binding sites on chromatin folding. The convergent rule correctly predicts the affected loops in every case. Moreover, the extrusion model accurately predicts in silico the 3D maps resulting from each experiment using only the location of CTCF-binding sites in the WT. Thus, we show that it is possible to disrupt, restore, and move loops and domains using targeted mutations as small as a single base pair. National Science Foundation (U.S.) (Grant PHY-1427654) National Institutes of Health (U.S.) (New Innovator Award 1DP2OD008540-01) Cancer Prevention and Research Institute of Texas (Scholar Award R1304) Baylor College of Medicine (McNair Medical Institute Scholar Award) Presidential Early Career Award for Scientists and Engineers 2017-05-04T23:04:05Z 2017-05-04T23:04:05Z 2015-10 2015-07 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/108680 Sanborn, Adrian L. et al. “Chromatin Extrusion Explains Key Features of Loop and Domain Formation in Wild-Type and Engineered Genomes.” Proceedings of the National Academy of Sciences 112.47 (2015): E6456–E6465. © 2015 National Academy of Sciences en_US http://dx.doi.org/10.1073/pnas.1518552112 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) National Academy of Sciences (U.S.)
spellingShingle Sanborn, Adrian L.
Rao, Suhas S. P.
Huang, Su-Chen
Durand, Neva C.
Huntley, Miriam H.
Jewett, Andrew I.
Bochkov, Ivan D.
Chinnappan, Dharmaraj
Cutkosky, Ashok
Li, Jian
Geeting, Kristopher P.
Gnirke, Andreas
Melnikov, Alexandre
McKenna, Doug
Stamenova, Elena K.
Aiden, Erez Lieberman
Lander, Eric Steven
Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes
title Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes
title_full Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes
title_fullStr Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes
title_full_unstemmed Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes
title_short Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes
title_sort chromatin extrusion explains key features of loop and domain formation in wild type and engineered genomes
url http://hdl.handle.net/1721.1/108680
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