1. Chromosomes and Gene Expression
  2. Physics of Living Systems

Chromosome organization by one-sided and two-sided loop extrusion

  1. Edward J Banigan
  2. Aafke A van den Berg
  3. Hugo B Brandão
  4. John F Marko
  5. Leonid A Mirny  Is a corresponding author
  1. Massachusetts Institute of Technology, United States
  2. Harvard University, United States
  3. Northwestern University, United States
https://doi.org/10.7554/eLife.53558
Share this article
Cite this article
  1. Edward J Banigan
  2. Aafke A van den Berg
  3. Hugo B Brandão
  4. John F Marko
  5. Leonid A Mirny
(2020)
Chromosome organization by one-sided and two-sided loop extrusion
eLife 9:e53558.
https://doi.org/10.7554/eLife.53558
  2. Download BibTeX
  3. Download .RIS

Abstract

SMC complexes, such as condensin or cohesin, organize chromatin throughout the cell cycle by a process known as loop extrusion. SMC complexes reel in DNA, extruding and progressively growing DNA loops. Modeling assuming two-sided loop extrusion reproduces key features of chromatin organization across different organisms. In vitro single-molecule experiments confirmed that yeast condensins extrude loops, however, they remain anchored to their loading sites and extrude loops in a 'one-sided' manner. We therefore simulate one-sided loop extrusion to investigate whether 'one-sided' complexes can compact mitotic chromosomes, organize interphase domains, and juxtapose bacterial chromosomal arms, as can be done by 'two-sided' loop extruders. While one-sided loop extrusion cannot reproduce these phenomena, variants can recapitulate in vivo observations. We predict that SMC complexes in vivo constitute effectively two-sided motors or exhibit biased loading and propose relevant experiments. Our work suggests that loop extrusion is a viable general mechanism of chromatin organization.

Data availability

Simulation and analysis code used to produce and analyze data has been made publicly available on GitHub. Methods and code documentation explains usage. In Figure 3, we show Hi-C data from another publication with GEO accession number GSE96107. In Figure 3 - figure supplement 8, we show Hi-C data from another publication with Bioproject accession number PRJNA427106. In Figure 4, we show Hi-C data from another publication with GEO accession number GSE68418.

The following previously published data sets were used

Article and author information

Author details

  1. Edward J Banigan

    Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5478-7425

  2. Aafke A van den Berg

    Department of Physics and Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Hugo B Brandão

    Graduate Program in Biophysics, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5496-0638

  4. 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.

  5. Leonid A Mirny

    Institute for Medical Engineering and Science and Department of Physics, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    lmirny@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0785-5410

Funding

National Institutes of Health (U54DK107980)

  • Edward J Banigan
  • Aafke A van den Berg
  • Hugo B Brandão
  • John F Marko
  • Leonid A Mirny

National Institutes of Health (U54CA193419)

  • Edward J Banigan
  • Aafke A van den Berg
  • Hugo B Brandão
  • John F Marko
  • Leonid A Mirny

National Institutes of Health (GM114190)

  • Edward J Banigan
  • Aafke A van den Berg
  • Hugo B Brandão
  • Leonid A Mirny

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

Copyright

© 2020, Banigan 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

  • 5,800
    views
  • 892
    downloads
  • 96
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Edward J Banigan
  2. Aafke A van den Berg
  3. Hugo B Brandão
  4. John F Marko
  5. Leonid A Mirny
(2020)
Chromosome organization by one-sided and two-sided loop extrusion
eLife 9:e53558.
https://doi.org/10.7554/eLife.53558

Share this article

https://doi.org/10.7554/eLife.53558

Categories and tags

Research organisms

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression

    TPR is required for cytoplasmic chromatin fragment formation during senescence

    Bethany M Bartlett, Yatendra Kumar ... Wendy A Bickmore
    Research Article Updated

    During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme – the senescence-associated secretory phenotype (SASP) – driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.

    1. Chromosomes and Gene Expression
    2. Evolutionary Biology

    The emergence and evolution of gene expression in genome regions replete with regulatory motifs

    Timothy Fuqua, Yiqiao Sun, Andreas Wagner
    Research Article

    Gene regulation is essential for life and controlled by regulatory DNA. Mutations can modify the activity of regulatory DNA, and also create new regulatory DNA, a process called regulatory emergence. Non-regulatory and regulatory DNA contain motifs to which transcription factors may bind. In prokaryotes, gene expression requires a stretch of DNA called a promoter, which contains two motifs called –10 and –35 boxes. However, these motifs may occur in both promoters and non-promoter DNA in multiple copies. They have been implicated in some studies to improve promoter activity, and in others to repress it. Here, we ask whether the presence of such motifs in different genetic sequences influences promoter evolution and emergence. To understand whether and how promoter motifs influence promoter emergence and evolution, we start from 50 ‘promoter islands’, DNA sequences enriched with –10 and –35 boxes. We mutagenize these starting ‘parent’ sequences, and measure gene expression driven by 240,000 of the resulting mutants. We find that the probability that mutations create an active promoter varies more than 200-fold, and is not correlated with the number of promoter motifs. For parent sequences without promoter activity, mutations created over 1500 new –10 and –35 boxes at unique positions in the library, but only ~0.3% of these resulted in de-novo promoter activity. Only ~13% of all –10 and –35 boxes contribute to de-novo promoter activity. For parent sequences with promoter activity, mutations created new –10 and –35 boxes in 11 specific positions that partially overlap with preexisting ones to modulate expression. We also find that –10 and –35 boxes do not repress promoter activity. Overall, our work demonstrates how promoter motifs influence promoter emergence and evolution. It has implications for predicting and understanding regulatory evolution, de novo genes, and phenotypic evolution.

    1. Chromosomes and Gene Expression
    2. Developmental Biology

    N-terminus of Drosophila melanogaster MSL1 is critical for dosage compensation

    Valentin Babosha, Natalia Klimenko ... Oksana Maksimenko
    Research Article

    The male-specific lethal complex (MSL), which consists of five proteins and two non-coding roX RNAs, is involved in the transcriptional enhancement of X-linked genes to compensate for the sex chromosome monosomy in Drosophila XY males compared with XX females. The MSL1 and MSL2 proteins form the heterotetrameric core of the MSL complex and are critical for the specific recruitment of the complex to the high-affinity ‘entry’ sites (HAS) on the X chromosome. In this study, we demonstrated that the N-terminal region of MSL1 is critical for stability and functions of MSL1. Amino acid deletions and substitutions in the N-terminal region of MSL1 strongly affect both the interaction with roX2 RNA and the MSL complex binding to HAS on the X chromosome. In particular, substitution of the conserved N-terminal amino-acids 3–7 in MSL1 (MSL1GS) affects male viability similar to the inactivation of genes encoding roX RNAs. In addition, MSL1GS binds to promoters such as MSL1WT but does not co-bind with MSL2 and MSL3 to X chromosomal HAS. However, overexpression of MSL2 partially restores the dosage compensation. Thus, the interaction of MSL1 with roX RNA is critical for the efficient assembly of the MSL complex on HAS of the male X chromosome.