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. RitchieQuentin A. Gouil, Bruno Reversade, Fabrice Prin, Timothy Mohun, Silvère M. van der Maarel, Edwina McGlinn, James M. Murphy, Andrew Keniry, Jessica C. de Greef, Marnie E. Blewitt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageEnglish (US)
Article number5466
JournalNature Communications
Issue number1
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, Springer Nature Limited.

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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