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

Tapia Del Fierro, A; den Hamer, B; Benetti, N; Jansz, N; Chen, K; Beck, T; Vanyai, H; Gurzau, AD; Daxinger, L; Xue, S; Ly, TTN; Wanigasuriya, I; Iminitoff, M; Breslin, K; Oey, H; Krom, YD; van der Hoorn, D; Bouwman, LF; Johanson, TM; Ritchie, ME; Gouil, QA; Reversade, B; Prin, F; Mohun, T; van der Maarel, SM; McGlinn, E; Murphy, JM; Keniry, A; de Greef, JC; Blewitt, ME

Author(s): Tapia Del Fierro, A; den Hamer, B; Benetti, N; Jansz, N; Chen, K; Beck, T; Vanyai, H; Gurzau, AD; Daxinger, L; Xue, S; Ly, TTN; Wanigasuriya, I; Iminitoff, M; Breslin, K; Oey, H; Krom, YD; van der Hoorn, D; Bouwman, LF; Johanson, TM; Ritchie, ME; Gouil, QA; Reversade, B; Prin, F; Mohun, T; van der Maarel, SM; McGlinn, E; Murphy, JM; Keniry, A; de Greef, JC; Blewitt, ME;
Details: Publication Year 2023-09-25,Volume 14,Issue #1,Page 5466
Journal Title: Nature Communications
Publication Type: epub ahead of print
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.
Publisher: NPG
Research Division(s): Immunology; Inflammation; Epigenetics And Development
PubMed ID: 37749075
Publisher's Version: https://doi.org/10.1038/s41467-023-40992-6
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-023-40992-6
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: s41467-023-40992-6.pdf - (49.23MB, application/pdf)

Creation Date: 2023-09-27 08:47:36

Last Modified: 2023-09-27 08:50:14