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Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy

View ORCID ProfileAlessandro Bertero, View ORCID ProfilePaul A. Fields, View ORCID ProfileAlec S. T. Smith, Andrea Leonard, View ORCID ProfileKevin Beussman, View ORCID ProfileNathan J. Sniadecki, View ORCID ProfileDeok-Ho Kim, View ORCID ProfileHung-Fat Tse, View ORCID ProfileLil Pabon, View ORCID ProfileJay Shendure, View ORCID ProfileWilliam S. Noble, View ORCID ProfileCharles E. Murry
doi: https://doi.org/10.1101/555250
Alessandro Bertero
1Department of Pathology, University of Washington, Seattle, WA, USA
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
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  • ORCID record for Alessandro Bertero
Paul A. Fields
1Department of Pathology, University of Washington, Seattle, WA, USA
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
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Alec S. T. Smith
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
4Department of Bioengineering, University of Washington, Seattle, WA, USA
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Andrea Leonard
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
5Department of Mechanical Engineering, University of Washington, Seattle, WA, USA
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Kevin Beussman
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
5Department of Mechanical Engineering, University of Washington, Seattle, WA, USA
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Nathan J. Sniadecki
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
4Department of Bioengineering, University of Washington, Seattle, WA, USA
5Department of Mechanical Engineering, University of Washington, Seattle, WA, USA
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Deok-Ho Kim
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
4Department of Bioengineering, University of Washington, Seattle, WA, USA
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Hung-Fat Tse
6Cardiology Division, Department of Medicine, The University of Hong Kong, Hong Kong, China
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Lil Pabon
1Department of Pathology, University of Washington, Seattle, WA, USA
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
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Jay Shendure
7Department of Genome Sciences, University of Washington, Seattle, Washington, USA
8Howard Hughes Medical Institute, Seattle, Washington, USA
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William S. Noble
7Department of Genome Sciences, University of Washington, Seattle, Washington, USA
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Charles E. Murry
1Department of Pathology, University of Washington, Seattle, WA, USA
2Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA
3Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
4Department of Bioengineering, University of Washington, Seattle, WA, USA
9Department of Medicine/Cardiology, University of Washington, Seattle, WA, USA
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Abstract

Pathogenic mutations in A-type nuclear lamins cause dilated cardiomyopathy, which is postulated to result from dysregulated gene expression due to changes in chromatin organization into active and inactive compartments. To test this, we performed genome-wide chromosome conformation analyses (Hi-C) in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with a haploinsufficient mutation for lamin A/C. Compared to gene-corrected cells, mutant hiPSC-CMs have marked electrophysiological and contractile alterations, with modest gene expression changes. While large-scale changes in chromosomal topology are evident, differences in chromatin compartmentalization are limited to a few hotspots that escape inactivation during cardiogenesis. These regions exhibit upregulation of multiple non-cardiac genes including CACNA1A, encoding for neuronal P/Q-type calcium channels. Pharmacological inhibition of the resulting current partially mitigates the electrical alterations. On the other hand, A/B compartment changes do not explain most gene expression alterations in mutant hiPSC-CMs. We conclude that global errors in chromosomal compartmentation are not the primary pathogenic mechanism in heart failure due to lamin A/C haploinsufficiency.

Summary Bertero et al. observe that lamin A/C haploinsufficiency in human cardiomyocytes markedly alters electrophysiology, contractility, gene expression, and chromosomal topology. Contrary to expectations, however, changes in chromatin compartments involve just few regions, and most dysregulated genes lie outside these hotspots.

Condensed title Genomic effects of lamin A/C haploinsufficiency

  • Abbreviations

    3D-EHT(s)
    three-dimensional engineered heart tissue(s)
    A/B
    active/inactive (chromatin compartment)
    CCQ
    contraction correlation quantification
    FPD
    field potential duration
    DCM
    dilated cardiomyopathy
    Hi-C
    genome-wide chromosome conformation capture
    hESC(s)
    human embryonic stem cell(s)
    hESC-CM(s)
    human embryonic stem cell-derived cardiomyocyte(s)
    hiPSC(s)
    human induced pluripotent stem cell(s)
    hiPSC-CM(s)
    human induced pluripotent stem cell-derived cardiomyocyte(s)
    LAD(s)
    lamin-associated domains
    MEA(s)
    multi-electrode array(s)
    PC
    principal component
    RNA-seq
    ribonucleic acid sequencing
    RT-qPCR
    quantitative reverse transcription polymerase chain reaction
    TAD(s)
    topologically associating domain(s)
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted February 19, 2019.
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    Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy
    Alessandro Bertero, Paul A. Fields, Alec S. T. Smith, Andrea Leonard, Kevin Beussman, Nathan J. Sniadecki, Deok-Ho Kim, Hung-Fat Tse, Lil Pabon, Jay Shendure, William S. Noble, Charles E. Murry
    bioRxiv 555250; doi: https://doi.org/10.1101/555250
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    Chromatin compartment dynamics in a haploinsufficient model of cardiac laminopathy
    Alessandro Bertero, Paul A. Fields, Alec S. T. Smith, Andrea Leonard, Kevin Beussman, Nathan J. Sniadecki, Deok-Ho Kim, Hung-Fat Tse, Lil Pabon, Jay Shendure, William S. Noble, Charles E. Murry
    bioRxiv 555250; doi: https://doi.org/10.1101/555250

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