Nature communications · 2023
SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Tapia Del Fierro Andres, den Hamer Bianca, Benetti Natalia, Jansz Natasha, Chen Kelan, Beck Tamara, Vanyai Hannah, Gurzau Alexandra D, Daxinger Lucia, Xue Shifeng, Ly Thanh Thao Nguyen, Wanigasuriya Iromi, Iminitoff Megan, Breslin Kelsey, Oey Harald, Krom Yvonne D, van der Hoorn Dinja, Bouwman Linde F, Johanson Timothy M, Ritchie Matthew E, Gouil Quentin A, Reversade Bruno, Prin Fabrice, Mohun Timothy, van der Maarel Silvère M, McGlinn Edwina, Murphy James M, Keniry Andrew, de Greef Jessica C, Blewitt Marnie E
Аннотация
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.