Nature Communications (Sep 2023)
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,
- Marnie E. Blewitt
Affiliations
- Andres Tapia del Fierro
- The Walter and Eliza Hall Institute of Medical Research
- Bianca den Hamer
- Department of Human Genetics, 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
- Crick Advanced Light Microscopy Facility, 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
- Department of Biological Sciences, National University of Singapore
- Thanh Thao Nguyen Ly
- Department of Biological Sciences, 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
- Department of Human Genetics, Leiden University Medical Center
- Dinja van der Hoorn
- Department of Human Genetics, Leiden University Medical Center
- Linde F. Bouwman
- Department of Human Genetics, 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
- Crick Advanced Light Microscopy Facility, The Francis Crick Institute
- Timothy Mohun
- Crick Advanced Light Microscopy Facility, The Francis Crick Institute
- Silvère M. van der Maarel
- Department of Human Genetics, Leiden University Medical Center
- Edwina McGlinn
- EMBL Australia, 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
- Department of Human Genetics, Leiden University Medical Center
- Marnie E. Blewitt
- The Walter and Eliza Hall Institute of Medical Research
- DOI
- https://doi.org/10.1038/s41467-023-40992-6
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
