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SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease

Author

Listed:
  • Andres Tapia del Fierro

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Bianca den Hamer

    (Leiden University Medical Center)

  • Natalia Benetti

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Natasha Jansz

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kelan Chen

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Tamara Beck

    (The Walter and Eliza Hall Institute of Medical Research)

  • Hannah Vanyai

    (The Francis Crick Institute)

  • Alexandra D. Gurzau

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Lucia Daxinger

    (Queensland Institute of Medical Research)

  • Shifeng Xue

    (National University of Singapore
    Institute of Molecular and Cell Biology, A*STAR)

  • Thanh Thao Nguyen Ly

    (National University of Singapore
    Institute of Molecular and Cell Biology, A*STAR)

  • Iromi Wanigasuriya

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Megan Iminitoff

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kelsey Breslin

    (The Walter and Eliza Hall Institute of Medical Research)

  • Harald Oey

    (Queensland Institute of Medical Research)

  • Yvonne D. Krom

    (Leiden University Medical Center)

  • Dinja van der Hoorn

    (Leiden University Medical Center)

  • Linde F. Bouwman

    (Leiden University Medical Center)

  • Timothy M. Johanson

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Matthew E. Ritchie

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Quentin A. Gouil

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Bruno Reversade

    (Institute of Molecular and Cell Biology, A*STAR
    Genome Institute of Singapore, A*STAR)

  • Fabrice Prin

    (The Francis Crick Institute)

  • Timothy Mohun

    (The Francis Crick Institute)

  • Silvère M. van der Maarel

    (Leiden University Medical Center)

  • Edwina McGlinn

    (Monash University
    Monash University)

  • James M. Murphy

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Monash University)

  • Andrew Keniry

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jessica C. de Greef

    (Leiden University Medical Center)

  • Marnie E. Blewitt

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

Abstract

The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at the facioscapulohumeral muscular dystrophy associated macrosatellite-array, D4Z4, resulting in enhanced repression of DUX4 encoded by this repeat. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against other epigenetic regulators, including PRC2 and CTCF, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1’s role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease.

Suggested Citation

  • Andres Tapia del Fierro & Bianca den Hamer & Natalia Benetti & Natasha Jansz & Kelan Chen & Tamara Beck & Hannah Vanyai & Alexandra D. Gurzau & Lucia Daxinger & Shifeng Xue & Thanh Thao Nguyen Ly & Ir, 2023. "SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40992-6
    DOI: 10.1038/s41467-023-40992-6
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    References listed on IDEAS

    as
    1. Smyth Gordon K, 2004. "Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 3(1), pages 1-28, February.
    2. Natalia Benetti & Quentin Gouil & Andres Tapia del Fierro & Tamara Beck & Kelsey Breslin & Andrew Keniry & Edwina McGlinn & Marnie E. Blewitt, 2022. "Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Michal R. Gdula & Tatyana B. Nesterova & Greta Pintacuda & Jonathan Godwin & Ye Zhan & Hakan Ozadam & Michael McClellan & Daniella Moralli & Felix Krueger & Catherine M. Green & Wolf Reik & Skirmantas, 2019. "The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    4. Chen-Yu Wang & David Colognori & Hongjae Sunwoo & Danni Wang & Jeannie T. Lee, 2019. "PRC1 collaborates with SMCHD1 to fold the X-chromosome and spread Xist RNA between chromosome compartments," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
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