Large domains of heterochromatin direct the formation of short mitotic chromosome loops

  1. Maximilian H. Fitz-James
  2. Pin Tong
  3. Alison L Pidoux
  4. Hakan Ozadam
  5. Liyan Yang
  6. Sharon A. White
  7. Job Dekker  Is a corresponding author
  8. Robin Allshire  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. Wellcome Trust Centre for Cell Biology, United Kingdom
  3. University of Massachusetts Medical School, United States

Abstract

During mitosis chromosomes reorganise into highly compact, rod-shaped forms, thought to consist of consecutive chromatin loops around a central protein scaffold. Condensin complexes are involved in chromatin compaction, but the contribution of other chromatin proteins, DNA sequence and histone modifications is less understood. A large region of fission yeast DNA inserted into a mouse chromosome was previously observed to adopt a mitotic organisation distinct from that of surrounding mouse DNA. Here we show that a similar distinct structure is common to a large subset of insertion events in both mouse and human cells and is coincident with the presence of high levels of heterochromatic H3 lysine 9 trimethylation (H3K9me3). Hi-C and microscopy indicate that the heterochromatinised fission yeast DNA is organised into smaller chromatin loops than flanking euchromatic mouse chromatin. We conclude that heterochromatin alters chromatin loop size, thus contributing to the distinct appearance of heterochromatin on mitotic chromosomes.

Data availability

DNA sequencing and nanopore data were uploaded to the Sequence Read Archive with project ID PRJNA629899. Hi-C data was uploaded to GEO with accession ID GSE149677.

The following data sets were generated

Article and author information

Author details

  1. Maximilian H. Fitz-James

    Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6084-5887
  2. Pin Tong

    Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  3. Alison L Pidoux

    Institute of Cell Biology, Wellcome Trust Centre for Cell Biology, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  4. Hakan Ozadam

    Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  5. Liyan Yang

    Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  6. Sharon A. White

    Wellcome Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  7. Job Dekker

    Program in Systems Biology, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    job.dekker@umassmed.edu
    Competing interests
    Job Dekker, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5631-0698
  8. Robin Allshire

    Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    robin.allshire@ed.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8005-3625

Funding

Wellcome Trust (Wellcome 4 year PhD studentship,102336/Z/13/Z)

  • Maximilian H. Fitz-James

Wellcome Trust (Principal Research Fellowship,095021)

  • Robin Allshire

Wellcome Trust (Principal Research Fellowship,200885)

  • Robin Allshire

Wellcome Trust (Wellcome Centre for Cell Biology Core grant,203149)

  • Maximilian H. Fitz-James
  • Pin Tong
  • Alison L Pidoux
  • Sharon A. White
  • Robin Allshire

National Human Genome Research Institute (HG003143)

  • Hakan Ozadam
  • Liyan Yang
  • Job Dekker

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

Reviewing Editor

  1. Gary H Karpen, University of California, Berkeley, United States

Publication history

  1. Received: March 24, 2020
  2. Accepted: September 10, 2020
  3. Accepted Manuscript published: September 11, 2020 (version 1)
  4. Accepted Manuscript updated: September 14, 2020 (version 2)
  5. Version of Record published: September 24, 2020 (version 3)

Copyright

© 2020, Fitz-James 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

  • 2,481
    Page views
  • 349
    Downloads
  • 7
    Citations

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

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. Maximilian H. Fitz-James
  2. Pin Tong
  3. Alison L Pidoux
  4. Hakan Ozadam
  5. Liyan Yang
  6. Sharon A. White
  7. Job Dekker
  8. Robin Allshire
(2020)
Large domains of heterochromatin direct the formation of short mitotic chromosome loops
eLife 9:e57212.
https://doi.org/10.7554/eLife.57212
  1. Further reading

Further reading

    1. Cell Biology
    Joris P Nassal, Fiona H Murphy ... Matthijs Verhage
    Research Article

    Different organelles traveling through neurons exhibit distinct properties in vitro, but this has not been investigated in the intact mammalian brain. We established simultaneous dual color two-photon microscopy to visualize the trafficking of Neuropeptide Y (NPY)-, LAMP1-, and RAB7-tagged organelles in thalamocortical axons imaged in mouse cortex in vivo. This revealed that LAMP1- and RAB7-tagged organelles move significantly faster than NPY-tagged organelles in both anterograde and retrograde direction. NPY traveled more selectively in anterograde direction than LAMP1 and RAB7. By using a synapse marker and a calcium sensor, we further investigated the transport dynamics of NPY-tagged organelles. We found that these organelles slow down and pause at synapses. In contrast to previous in vitro studies, a significant increase of transport speed was observed after spontaneous activity and elevated calcium levels in vivo as well as electrically stimulated activity in acute brain slices. Together, we show a remarkable diversity in speeds and properties of three axonal organelle marker in vivo that differ from properties previously observed in vitro.

    1. Cell Biology
    2. Neuroscience
    Ge Gao, Shuyu Guo ... Gang Peng
    Research Article Updated

    Unbiased genetic screens implicated a number of uncharacterized genes in hearing loss, suggesting some biological processes required for auditory function remain unexplored. Loss of Kiaa1024L/Minar2, a previously understudied gene, caused deafness in mice, but how it functioned in the hearing was unclear. Here, we show that disruption of kiaa1024L/minar2 causes hearing loss in the zebrafish. Defects in mechanotransduction, longer and thinner hair bundles, and enlarged apical lysosomes in hair cells are observed in the kiaa1024L/minar2 mutant. In cultured cells, Kiaa1024L/Minar2 is mainly localized to lysosomes, and its overexpression recruits cholesterol and increases cholesterol labeling. Strikingly, cholesterol is highly enriched in the hair bundle membrane, and loss of kiaa1024L/minar2 reduces cholesterol localization to the hair bundles. Lowering cholesterol levels aggravates, while increasing cholesterol levels rescues the hair cell defects in the kiaa1024L/minar2 mutant. Therefore, cholesterol plays an essential role in hair bundles, and Kiaa1024L/Minar2 regulates cholesterol distribution and homeostasis to ensure normal hearing.