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Chromatin organization by an interplay of loop extrusion and compartmental segregation

Johannes Nuebler, Geoffrey Fudenberg, Maxim Imakaev, Nezar Abdennur, Leonid Mirny
doi: https://doi.org/10.1101/196261
Johannes Nuebler
1Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Geoffrey Fudenberg
2University of California, San Francisco, Gladstone Institutes, San Francisco, CA 94158, USA
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Maxim Imakaev
1Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Nezar Abdennur
1Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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Leonid Mirny
1Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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  • For correspondence: leonid@mit.edu
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Abstract

Mammalian chromatin is organized on length scales ranging from individual nucleosomes to chromosomal territories. At intermediate scales two dominant features emerge in interphase: (i) alternating regions (<5Mb) of active and inactive chromatin that spatially segregate into different compartments, and (ii) domains (<1Mb), i.e. regions that preferentially interact internally, which are also termed 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 compartments are established by a phase separation process according to local chromatin states. Here we use polymer simulations to examine how the two processes, loop extrusion and compartmental segregation, work collectively and potentially interfere in shaping global chromosome organization. Our integrated model faithfully reproduces Hi-C data from previously puzzling experimental observations, where targeting of the TAD-forming machinery led to changes in compartmentalization. Specifically, depletion of chromatin-associated cohesin reduced TADs and revealed hidden, finer compartments, while increased processivity of cohesin led to stronger 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. This also predicts that interference with chromatin epigenetic states or nuclear volume would affect compartments but not TADs. Our results suggest that chromatin organization on the megabase scale emerges from competition of non-equilibrium active loop extrusion and epigenetically defined compartment structure.

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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 October 03, 2017.
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Chromatin organization by an interplay of loop extrusion and compartmental segregation
Johannes Nuebler, Geoffrey Fudenberg, Maxim Imakaev, Nezar Abdennur, Leonid Mirny
bioRxiv 196261; doi: https://doi.org/10.1101/196261
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Chromatin organization by an interplay of loop extrusion and compartmental segregation
Johannes Nuebler, Geoffrey Fudenberg, Maxim Imakaev, Nezar Abdennur, Leonid Mirny
bioRxiv 196261; doi: https://doi.org/10.1101/196261

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