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Mitotic chromosome compaction via active loop extrusion

Anton Goloborodko, John F. Marko, Leonid A. Mirny
doi: https://doi.org/10.1101/021642
Anton Goloborodko
1Department of Physics, Massachusetts Institute of Technology, Cambridge MA 02139
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John F. Marko
2Department of Molecular Biosciences and Department of Physics and Astronomy, Northwestern University, Evanston IL 60208
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Leonid A. Mirny
1Department of Physics, Massachusetts Institute of Technology, Cambridge MA 02139
3Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge MA 02139
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Abstract

During cell division chromosomes are compacted in length by more than a hundred-fold. A wide range of experiments demonstrated that in their compacted state, mammalian chromosomes form arrays of closely stacked consecutive ∼100Kb loops. The mechanism underlying the active process of chromosome compaction into a stack of loops is unknown. Here we test the hypothesis that chromosomes are compacted by enzymatic machines that actively extrude chromatin loops. When such loop-extruding factors (LEF) bind to chromosomes, they progressively bridge sites that are further away along the chromosome, thus extruding a loop. We demonstrate that collective action of LEFs leads to formation of a dynamic array of consecutive loops. Simulations and an analytically solved model identify two distinct steady states: a sparse state where loops are highly dynamic but provide little compaction, and a dense state with more stable loops and dramatic chromosome compaction. We find that human chromosomes operate at the border of the dense steady state. Our analysis also shows how the macroscopic characteristics of the loop array are determined by the microscopic properties of LEFs and their abundance. When number of LEFs are used that match experimentally based estimates, the model can quantitatively reproduce the average loop length, the degree of compaction, and the general loop-array morphology of compact human chromosomes. Our study demonstrates that efficient chromosome compaction can be achieved solely by an active loop-extrusion process.

Significance Statement During cell division chromosomes are compacted in length more than a hundred-fold and are folded in arrays of loops. The mechanism underlying this essential biological process is unknown. Here we test whether chromosome compaction can be performed by molecular machines that actively extrude chromatin loops. These machines bind to DNA and progressively bridge sites that are further and further away along the chromosome. We demonstrate that the collective action of loop-extruding machines can fold a chromosome into a dynamic array of loops. Simulated chromosome agrees with compact human chromosomes in its degree of compaction, loop size and the general loop-array morphology. Our study demonstrates that efficient chromosome compaction can be achieved solely by such active loop-extrusion process.

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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 June 29, 2015.
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Mitotic chromosome compaction via active loop extrusion
Anton Goloborodko, John F. Marko, Leonid A. Mirny
bioRxiv 021642; doi: https://doi.org/10.1101/021642
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Mitotic chromosome compaction via active loop extrusion
Anton Goloborodko, John F. Marko, Leonid A. Mirny
bioRxiv 021642; doi: https://doi.org/10.1101/021642

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