Compaction and segregation of sister chromatids via active loop extrusion

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Abstract

The mechanism by which chromatids and chromosomes are segregated during mitosis and meiosis is a major puzzle of biology and biophysics. Using polymer simulations of chromosome dynamics, we show that a single mechanism of loop extrusion by condensins can robustly compact, segregate and disentangle chromosomes, arriving at individualized chromatids with morphology observed in vivo. Our model resolves the paradox of topological simplification concomitant with chromosome 'condensation', and explains how enzymes a few nanometers in size are able to control chromosome geometry and topology at micron length scales. We suggest that loop extrusion is a universal mechanism of genome folding that mediates functional interactions during interphase and compacts chromosomes during mitosis.

DOI: http://dx.doi.org/10.7554/eLife.14864.001

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Most cited references 56

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Organization of the mitotic chromosome.

Natalia Naumova, Maxim Imakaev, Geoffrey Fudenberg … (2013)

Mitotic chromosomes are among the most recognizable structures in the cell, yet for over a century their internal organization remains largely unsolved. We applied chromosome conformation capture methods, 5C and Hi-C, across the cell cycle and revealed two distinct three-dimensional folding states of the human genome. We show that the highly compartmentalized and cell type-specific organization described previously for nonsynchronous cells is restricted to interphase. In metaphase, we identified a homogenous folding state that is locus-independent, common to all chromosomes, and consistent among cell types, suggesting a general principle of metaphase chromosome organization. Using polymer simulations, we found that metaphase Hi-C data are inconsistent with classic hierarchical models and are instead best described by a linearly organized longitudinally compressed array of consecutive chromatin loops.

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Cohesin: its roles and mechanisms.

Kim Nasmyth, Christian Haering (2009)

The cohesin complex is a major constituent of interphase and mitotic chromosomes. Apart from its role in mediating sister chromatid cohesion, it is also important for DNA double-strand-break repair and transcriptional control. The functions of cohesin are regulated by phosphorylation, acetylation, ATP hydrolysis, and site-specific proteolysis. Recent evidence suggests that cohesin acts as a novel topological device that traps chromosomal DNA within a large tripartite ring formed by its core subunits.

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Self-organization of domain structures by DNA-loop-extruding enzymes

Elnaz Alipour, John Marko (2012)

The long chromosomal DNAs of cells are organized into loop domains much larger in size than individual DNA-binding enzymes, presenting the question of how formation of such structures is controlled. We present a model for generation of defined chromosomal loops, based on molecular machines consisting of two coupled and oppositely directed motile elements which extrude loops from the double helix along which they translocate, while excluding one another sterically. If these machines do not dissociate from DNA (infinite processivity), a disordered, exponential steady-state distribution of small loops is obtained. However, if dissociation and rebinding of the machines occurs at a finite rate (finite processivity), the steady state qualitatively changes to a highly ordered ‘stacked’ configuration with suppressed fluctuations, organizing a single large, stable loop domain anchored by several machines. The size of the resulting domain can be simply regulated by boundary elements, which halt the progress of the extrusion machines. Possible realizations of these types of molecular machines are discussed, with a major focus on structural maintenance of chromosome complexes and also with discussion of type I restriction enzymes. This mechanism could explain the geometrically uniform folding of eukaryote mitotic chromosomes, through extrusion of pre-programmed loops and concomitant chromosome compaction.

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Author and article information

Contributors

Antoine M van Oijen: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 18 May 2016

Publication date Collection: 2016

Volume: 5

Electronic Location Identifier: e14864

Affiliations

[1 ]deptDepartment of Physics , Massachusetts Institute of Technology , Cambridge, United States

[2 ]deptDepartment of Molecular Biosciences , Northwestern University , Evanston, United States

[3 ]deptInstitute for Medical Engineering and Science , Massachusetts Institute of Technology , Cambridge, United States

[4 ]deptDepartment of Physics and Astronomy , Northwestern University , Evanston, United States

[5]University of Groningen , Netherlands

[6]University of Groningen , Netherlands

Author notes

leonid@ 123456mit.edu

Author information

Anton Goloborodko http://orcid.org/0000-0002-2210-8616

Leonid Mirny http://orcid.org/0000-0002-0785-5410

Article

Publisher ID: 14864

DOI: 10.7554/eLife.14864

PMC ID: 4914367

PubMed ID: 27192037

SO-VID: ee8532d5-602d-4f25-a4f4-c741295fd987

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 31 January 2016

Date accepted : 18 May 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: CA193419

Award Recipient : Anton Goloborodko Maxim V Imakaev John F Marko Leonid Mirny

Funded by: FundRef http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;

Award ID: DK107980

Award Recipient : Anton Goloborodko Maxim V Imakaev John F Marko Leonid Mirny

Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;

Award ID: GM114190

Award Recipient : Anton Goloborodko Maxim V Imakaev Leonid Mirny

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: R01HG003143

Award Recipient : Anton Goloborodko Maxim V Imakaev Leonid Mirny

Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;

Award ID: 1504942

Award Recipient : Anton Goloborodko Leonid Mirny

Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;

Award ID: GM105847

Award Recipient : John F Marko

Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;

Award ID: DMR-1206868

Award Recipient : John F Marko

Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;

Award ID: MCB-1022117

Award Recipient : John F Marko

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Custom metadata

elife-xml-version 2.5

Author impact statement Loop extrusion can robustly compact, segregate and disentangle mammalian chromosomes, suggesting it is a universal mechanism of genome folding during cell division.

ScienceOpen disciplines: Life sciences

Keywords: chromosome,compaction,simulations,polymer,molecular dynamics,none

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: chromosome, compaction, simulations, polymer, molecular dynamics, none

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Compaction and segregation of sister chromatids via active loop extrusion

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Abstract

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Higher order chromatin architecture

Most cited references 56

Organization of the mitotic chromosome.

Cohesin: its roles and mechanisms.

Self-organization of domain structures by DNA-loop-extruding enzymes

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