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Formation of Chromosomal Domains in Interphase by Loop Extrusion

Geoffrey Fudenberg, Maxim Imakaev, Carolyn Lu, Anton Goloborodko, Nezar Abdennur, Leonid A. Mirny
doi: https://doi.org/10.1101/024620
Geoffrey Fudenberg
1Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, USA.
2Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Maxim Imakaev
2Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Carolyn Lu
3Program for Research in Mathematics, Engineering and Science for High School Students (PRIMES) and Undergraduate Research Opportunities Program (UROP), MIT, Cambridge Massachusetts, USA.
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Anton Goloborodko
2Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Nezar Abdennur
4Program in Computational and Systems Biology, MIT, Cambridge, Massachusetts, USA.
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Leonid A. Mirny
1Graduate Program in Biophysics, Harvard University, Cambridge, Massachusetts, USA.
2Department of Physics, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA.
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Summary

Topologically Associating Domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes, yet mechanisms of TAD formation remain unknown. Here we propose that loop extrusion underlies TAD formation. In this process, cis-acting loop-extruding factors, likely cohesins, form progressively larger loops, but stall at TAD boundaries due to interactions with boundary proteins, including CTCF. Using polymer simulations, we show that this model can produce TADs as determined by our analyses of Hi-C data. Contrary to typical illustrations, each TAD consists of multiple dynamically formed loops, rather than a single static loop. Our model explains diverse experimental observations, including the preferential orientation of CTCF motifs, enrichments of architectural proteins at TAD boundaries, and boundary deletion experiments, and makes specific predictions for depletion of CTCF versus cohesin. The emerging picture is that TADs arise from actively forming, growing, and dissociating loops, presenting a framework for understanding interphase chromosomal organization.

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  • ↵* Joint first authors listed alphabetically

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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 March 15, 2016.
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Formation of Chromosomal Domains in Interphase by Loop Extrusion
Geoffrey Fudenberg, Maxim Imakaev, Carolyn Lu, Anton Goloborodko, Nezar Abdennur, Leonid A. Mirny
bioRxiv 024620; doi: https://doi.org/10.1101/024620
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Formation of Chromosomal Domains in Interphase by Loop Extrusion
Geoffrey Fudenberg, Maxim Imakaev, Carolyn Lu, Anton Goloborodko, Nezar Abdennur, Leonid A. Mirny
bioRxiv 024620; doi: https://doi.org/10.1101/024620

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