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Strong interactions between highly-dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin

Igor S Tolokh, Nicholas Allen Kinney, View ORCID ProfileIgor V Sharakhov, View ORCID ProfileAlexey V Onufriev
doi: https://doi.org/10.1101/2022.01.28.478236
Igor S Tolokh
1Department of Computer Science, Virginia Tech, 24061, Blacksburg, VA, USA
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Nicholas Allen Kinney
1Department of Computer Science, Virginia Tech, 24061, Blacksburg, VA, USA
2Department of Entomology, Virginia Tech, 24061, Blacksburg, VA, USA
3Edward Via College of Osteopathic Medicine, 2265 Kraft Drive, 24060, Blacksburg, VA, USA
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Igor V Sharakhov
2Department of Entomology, Virginia Tech, 24061, Blacksburg, VA, USA
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  • For correspondence: igor@vt.edu alexey@cs.vt.edu
Alexey V Onufriev
1Department of Computer Science, Virginia Tech, 24061, Blacksburg, VA, USA
4Department of Physics, Virginia Tech, 24061, Blacksburg, VA, USA
5Center for Soft Matter and Biological Physics, Virginia Tech, 24061, Blacksburg, VA, USA
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  • ORCID record for Alexey V Onufriev
  • For correspondence: igor@vt.edu alexey@cs.vt.edu
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Abstract

Background Interactions between topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of 3D chromatin structure and dynamics at the level of the entire nucleus; however, a full quantitative picture is still lacking. Relevant genome-wide experiments that may provide statistically significant conclusions remain difficult.

Results We have developed a coarse-grained dynamic model of the Drosophila melanogaster nucleus at TAD (∼100 kb) resolution that explicitly accounts for four distinct epigenetic classes of TADs and describes time evolution of the chromatin over the entire interphase. Best agreement with experiment is achieved when the simulation includes an entire biological system – an ensemble of complete nuclei, corresponding to the experimentally observed set of mutual arrangements of chromosomes, properly weighted according to experiment. The model is validated against multiple experiments, including those that describe changes in chromatin induced by lamin depletion.

Predicted positioning of LADs at the NE is highly dynamic (mobile) – the same LAD can attach, detach, and re-attach itself to the NE multiple times during interphase. The average probability of a LAD to be found at the NE varies by an order of magnitude, determined by the highly variable local density of nearby LADs along the genome. The distribution of LADs along the genome has a strong effect on the average radial positioning of individual TADs, playing a notable role in maintaining a non-random average global structure of chromatin.

Predicted sensitivity of fruit fly chromatin structure to the balance between TAD-TAD and LAD-NE interactions, also observed previously in models of mammalian chromosomes, suggests conservation of this principle of chromatin organisation across species of higher eukaryotes. Reduction of LAD-NE affinity weakly affects local chromatin structure, as seen in the model-derived Hi-C maps, however, its wild-type strength substantially reduces sensitivity of the chromatin density distribution to variations in the strength of TAD-TAD interactions.

Conclusions A dynamical model of the entire 3D fruit fly genome makes multiple genome-wide predictions of biological interest. We conjecture that one important role of LADs and their attractive interactions with the NE is to create the average global chromatin structure and stabilize it against inevitable cell-to-cell variations of TAD-TAD interactions.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    3D
    three-dimensional
    CEN
    centromeric
    Chr
    chromosome
    HET
    pericentromeric constitutive heterochromatin
    LAD
    lamina-associated domain
    L-TAD
    TAD that contains LADs
    LJ
    Lennard-Jones
    MSD
    mean squared displacement
    NE
    nuclear envelope
    TAD
    topologically associating domain
    WT
    wild-type.
  • Copyright 
    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 4.0 International license.
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    Posted January 28, 2022.
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    Strong interactions between highly-dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin
    Igor S Tolokh, Nicholas Allen Kinney, Igor V Sharakhov, Alexey V Onufriev
    bioRxiv 2022.01.28.478236; doi: https://doi.org/10.1101/2022.01.28.478236
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    Strong interactions between highly-dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin
    Igor S Tolokh, Nicholas Allen Kinney, Igor V Sharakhov, Alexey V Onufriev
    bioRxiv 2022.01.28.478236; doi: https://doi.org/10.1101/2022.01.28.478236

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