Chromatin organization by an interplay of loop extrusion and compartmental segregation
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Author(s)
Fudenberg, Geoffrey
Nubler, Johannes
Imakaev, Maksim Viktorovich
Abdennur, Nezar Alexander
Mirny, Leonid A
Date Issued
July 2018
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Nuebler, 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 Sciences
Version
Final published version
Abstract
Mammalian 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 matter
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Physics
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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.
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DOI of Published Version
https://doi.org/10.1073/pnas.1717730115
