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dc.contributor.authorFudenberg, Geoffrey
dc.contributor.authorNubler, Johannes
dc.contributor.authorImakaev, Maksim Viktorovich
dc.contributor.authorAbdennur, Nezar Alexander
dc.contributor.authorMirny, Leonid A
dc.date.accessioned2019-03-01T16:58:18Z
dc.date.available2019-03-01T16:58:18Z
dc.date.issued2018-07
dc.date.submitted2017-10
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/120590
dc.description.abstractMammalian chromatin is spatially organized at many scales showing two prominent features in interphase: (i) alternating regions (1–10 Mb) of active and inactive chromatin that spatially segregate into different compartments, and (II) domains (<1 Mb), that is, regions that preferentially interact internally [topologically associating domains (TADs)] and are central to gene regulation. There is growing evidence that TADs are formed by active extrusion of chromatin loops by cohesin, whereas compartmentalization is established according to local chromatin states. Here, we use polymer simulations to examine how loop extrusion and compartmental segregation work collectively and potentially interfere in shaping global chromosome organization. A model with differential attraction between euchromatin and heterochromatin leads to phase separation and reproduces compartmentalization as observed in Hi-C. Loop extrusion, essential for TAD formation, in turn, interferes with compartmentalization. Our integrated model faithfully reproduces Hi-C data from puzzling experimental observations where altering loop extrusion also led to changes in compartmentalization. Specifically, depletion of chromatin-associated cohesin reduced TADs and revealed finer compartments, while increased processivity of cohesin strengthened large TADs and reduced compartmentalization; and depletion of the TAD boundary protein CTCF weakened TADs while leaving compartments unaffected. We reveal that these experimental perturbations are special cases of a general polymer phenomenon of active mixing by loop extrusion. Our results suggest that chromatin organization on the megabase scale emerges from competition of nonequilibrium active loop extrusion and epigenetically defined compartment structure. Keywords: chromatin; genome architecture; Hi-C; polymer physics; active matteren_US
dc.description.sponsorshipNational Science Foundation (U.S.) (Grant 1504942)en_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1717730115en_US
dc.rightsArticle 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.en_US
dc.sourcePNASen_US
dc.titleChromatin organization by an interplay of loop extrusion and compartmental segregationen_US
dc.typeArticleen_US
dc.identifier.citationNuebler, Johannes et al. “Chromatin Organization by an Interplay of Loop Extrusion and Compartmental Segregation.” Proceedings of the National Academy of Sciences 115, 29 (July 2018): E6697–E6706 © 2018 National Academy of Sciencesen_US
dc.contributor.departmentMassachusetts Institute of Technology. Institute for Medical Engineering & Scienceen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Physicsen_US
dc.contributor.mitauthorNubler, Johannes
dc.contributor.mitauthorImakaev, Maksim Viktorovich
dc.contributor.mitauthorAbdennur, Nezar Alexander
dc.contributor.mitauthorMirny, Leonid A
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2019-02-08T18:28:42Z
dspace.orderedauthorsNuebler, Johannes; Fudenberg, Geoffrey; Imakaev, Maxim; Abdennur, Nezar; Mirny, Leonid A.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0002-5320-2728
dc.identifier.orcidhttps://orcid.org/0000-0001-5814-0864
dc.identifier.orcidhttps://orcid.org/0000-0002-0785-5410
mit.licensePUBLISHER_POLICYen_US


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