Compaction and segregation of sister chromatids via active loop extrusion

  1. Anton Goloborodko
  2. Maxim V Imakaev
  3. John F Marko
  4. Leonid Mirny  Is a corresponding author
  1. Massachusetts Institute of Technology, United States
  2. Northwestern University, United States

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.

Article and author information

Author details

  1. Anton Goloborodko

    Department of Physics, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Maxim V Imakaev

    Department of Physics, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. John F Marko

    Department of Molecular Biosciences, Department of Physics and Astronomy, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Leonid Mirny

    Department of Physics, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    leonid@mit.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Antoine M van Oijen, University of Groningen, Netherlands

Publication history

  1. Received: January 31, 2016
  2. Accepted: May 18, 2016
  3. Accepted Manuscript published: May 18, 2016 (version 1)
  4. Version of Record published: June 20, 2016 (version 2)

Copyright

© 2016, Goloborodko et al.

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

Metrics

  • 6,924
    Page views
  • 1,453
    Downloads
  • 156
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Anton Goloborodko
  2. Maxim V Imakaev
  3. John F Marko
  4. Leonid Mirny
(2016)
Compaction and segregation of sister chromatids via active loop extrusion
eLife 5:e14864.
https://doi.org/10.7554/eLife.14864

Further reading

    1. Structural Biology and Molecular Biophysics
    Christian JG Tessier et al.
    Research Article Updated

    Human adult muscle-type acetylcholine receptors are heteropentameric ion channels formed from two α-subunits, and one each of the β-, δ-, and ε-subunits. To form functional channels, the subunits must assemble with one another in a precise stoichiometry and arrangement. Despite being different, the four subunits share a common ancestor that is presumed to have formed homopentamers. The extent to which the properties of the modern-day receptor result from its subunit complexity is unknown. Here, we discover that a reconstructed ancestral muscle-type β-subunit can form homopentameric ion channels. These homopentamers open spontaneously and display single-channel hallmarks of muscle-type acetylcholine receptor activity. Our findings attest to the homopentameric origin of the muscle-type acetylcholine receptor, and demonstrate that signature features of its function are both independent of agonist and do not necessitate the complex heteropentameric architecture of the modern-day protein.

    1. Chromosomes and Gene Expression
    2. Structural Biology and Molecular Biophysics
    Claudia C Carcamo et al.
    Research Article Updated

    One-dimensional (1D) target search is a well-characterized phenomenon for many DNA-binding proteins but is poorly understood for chromatin remodelers. Herein, we characterize the 1D scanning properties of SWR1, a conserved yeast chromatin remodeler that performs histone exchange on +1 nucleosomes adjacent to a nucleosome-depleted region (NDR) at gene promoters. We demonstrate that SWR1 has a kinetic binding preference for DNA of NDR length as opposed to gene-body linker length DNA. Using single and dual color single-particle tracking on DNA stretched with optical tweezers, we directly observe SWR1 diffusion on DNA. We found that various factors impact SWR1 scanning, including ATP which promotes diffusion through nucleotide binding rather than ATP hydrolysis. A DNA-binding subunit, Swc2, plays an important role in the overall diffusive behavior of the complex, as the subunit in isolation retains similar, although faster, scanning properties as the whole remodeler. ATP-bound SWR1 slides until it encounters a protein roadblock, of which we tested dCas9 and nucleosomes. The median diffusion coefficient, 0.024 μm2/s, in the regime of helical sliding, would mediate rapid encounter of NDR-flanking nucleosomes at length scales found in cellular chromatin.