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Chromatin arranges in chains of mesoscale domains with nanoscale functional topography independent of cohesin

View ORCID ProfileEzequiel Miron, Roel Oldenkamp, Jill M. Brown, David M. S. Pinto, View ORCID ProfileC. Shan Xu, Ana R. Faria, Haitham A. Shaban, James D. P. Rhodes, Cassandravictoria Innocent, Sara de Ornellas, View ORCID ProfileHarald F. Hess, Veronica Buckle, View ORCID ProfileLothar Schermelleh
doi: https://doi.org/10.1101/566638
Ezequiel Miron
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
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  • ORCID record for Ezequiel Miron
Roel Oldenkamp
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
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Jill M. Brown
MRC Weatherall Institute of Molecular Medicine, Haematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
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David M. S. Pinto
Micron Oxford Advanced Bioimaging Unit, University of Oxford, Oxford OX1 3QU, United Kingdom
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C. Shan Xu
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Ana R. Faria
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
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Haitham A. Shaban
Spectroscopy Department, Physics Division, National Research Centre, 12622 Dokki, Cairo, Egypt
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James D. P. Rhodes
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
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Cassandravictoria Innocent
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
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Sara de Ornellas
Micron Oxford Advanced Bioimaging Unit, University of Oxford, Oxford OX1 3QU, United Kingdom
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Harald F. Hess
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA
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Veronica Buckle
Micron Oxford Advanced Bioimaging Unit, University of Oxford, Oxford OX1 3QU, United Kingdom
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Lothar Schermelleh
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United KingdomMRC Weatherall Institute of Molecular Medicine, Haematology Unit, University of Oxford, Oxford OX3 9DS, United Kingdom
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  • For correspondence: lothar.schermelleh@bioch.ox.ac.uk
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ABSTRACT

Three-dimensional (3D) chromatin organization plays a key role in regulating mammalian genome function, however many of its physical features at the single-cell level remain underexplored. Here we use 3D super-resolution and scanning electron microscopy to analyze structural and functional nuclear organization in somatic cells. We identify linked chromatin domains (CDs) composed of irregular ∼200-300-nm-wide aggregates of nucleosomes that can overlap with individual topologically associating domains and are distinct from a surrounding RNA-populated interchromatin region. High-content mapping uncovers confinement of cohesin and active histone modifications to surfaces and enrichment of repressive modifications towards the core of CDs in both hetero- and euchromatic regions. This nanoscale functional topography is temporarily relaxed in post-replicative chromatin, but remarkably persists after ablation of cohesin. Our findings establish CDs as physical and functional modules of mesoscale genome organization.

Footnotes

  • Revised version now includes FIB-SEM data provided by Harald F. Hess and C. Shan Xu (HHMI Janelia; added as coauthors). FIB-SEM of cryo-fixed HeLa cells followed by machine-learning segmentation with Ilastik confirms mesoscale 200-300 nm wide chromatin domains ('blobs') and separation by interchromatin space at 4 nm isotropic resolution. All figures were improved for clarity. The text was revised to introduce new data, improve structure and better highlight the novelty of findings.

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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-ND 4.0 International license.
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Posted January 13, 2020.
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Chromatin arranges in chains of mesoscale domains with nanoscale functional topography independent of cohesin
Ezequiel Miron, Roel Oldenkamp, Jill M. Brown, David M. S. Pinto, C. Shan Xu, Ana R. Faria, Haitham A. Shaban, James D. P. Rhodes, Cassandravictoria Innocent, Sara de Ornellas, Harald F. Hess, Veronica Buckle, Lothar Schermelleh
bioRxiv 566638; doi: https://doi.org/10.1101/566638
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Chromatin arranges in chains of mesoscale domains with nanoscale functional topography independent of cohesin
Ezequiel Miron, Roel Oldenkamp, Jill M. Brown, David M. S. Pinto, C. Shan Xu, Ana R. Faria, Haitham A. Shaban, James D. P. Rhodes, Cassandravictoria Innocent, Sara de Ornellas, Harald F. Hess, Veronica Buckle, Lothar Schermelleh
bioRxiv 566638; doi: https://doi.org/10.1101/566638

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