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

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, Iromi Wanigasuriya, Megan Iminitoff, Kelsey Breslin, Harald Oey, Yvonne D. Krom, Dinja van der Hoorn, Linde F. Bouwman, Timothy M. Johanson, Matthew E. Ritchie, Quentin A. Gouil, Bruno Reversade, Fabrice Prin, Timothy Mohun, Silvère M. van der Maarel, Edwina McGlinn, James M. Murphy, Andrew Keniry, Jessica C. de Greef and Marnie E. Blewitt ()
Additional contact information
Andres Tapia del Fierro: The Walter and Eliza Hall Institute of Medical Research
Bianca den Hamer: Leiden University Medical Center
Natalia Benetti: The Walter and Eliza Hall Institute of Medical Research
Natasha Jansz: The Walter and Eliza Hall Institute of Medical Research
Kelan Chen: The Walter and Eliza Hall Institute of Medical Research
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
Lucia Daxinger: Queensland Institute of Medical Research
Shifeng Xue: National University of Singapore
Thanh Thao Nguyen Ly: National University of Singapore
Iromi Wanigasuriya: The Walter and Eliza Hall Institute of Medical Research
Megan Iminitoff: The Walter and Eliza Hall Institute of Medical Research
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
Matthew E. Ritchie: The Walter and Eliza Hall Institute of Medical Research
Quentin A. Gouil: The Walter and Eliza Hall Institute of Medical Research
Bruno Reversade: Institute of Molecular and Cell Biology, 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
James M. Murphy: The Walter and Eliza Hall Institute of Medical Research
Andrew Keniry: The Walter and Eliza Hall Institute of Medical Research
Jessica C. de Greef: Leiden University Medical Center
Marnie E. Blewitt: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40992-6

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